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1. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TV, Nielsen, FC, Ejlertsen, B, Osorio, A, Muñoz-Repeto, I, Durán, M, Godino, J, Pertesi, M, Benítez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Gómez García, EB, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, Os, TV, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schäfer, D, Gevensleben, H, and Caux-Moncoutier, V
Abstract: Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers. © 2011 Mulligan et al.; licensee BioMed Central Ltd.
Published: 2011

2. Multiplex PCR/liquid chromatography assay for detection of gene rearrangements: application to RB1 gene

Author: Dehainault, C., Laugé, A., Caux-Moncoutier, V., Pagès-Berhouet, S., Doz, F., Desjardins, L., Couturier, J., Gauthier-Villars, M., Stoppa-Lyonnet, D., and Houdayer, C.
Published: 2004

3. Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families

Author: Gad, S, Klinger, M, Caux-Moncoutier, V, Pages-Berhouet, S, Gauthier-Villars, M, Coupier, I, Bensimon, A, Aurias, A, and Stoppa-Lyonnet, D
Published: 2002

4. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Author: Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., Schmidt G., Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., and Schmidt G.
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.Copyright © 2019 Wiley Periodicals, Inc.
Published: 2019

5. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author: Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Published: 2019

6. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author: Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Published: 2019

7. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

Author: Ding, Y.C., McGuffog, L., Healey, S., Friedman, E., Laitman, Y., Shani-Paluch-Shimon, Kaufman, B., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Gronwald, J., Huzarski, T., Cybulski, C., Byrski, T., Osorio, A., Cajal, T.R., Stavropoulou, A.V., Benitez, J., Hamann, U., Rookus, M., Aalfs, C.M., Lange, J.L. de, Meijers-Heijboer, H.E.J., Oosterwijk, J.C., Asperen, C.J. van, Garcia, E.B.G., Hoogerbrugge, N., Jager, A., Luijt, R.B. van der, Easton, D.F., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Tischkowitz, M., Godwin, A.K., Pathak, H., Stoppa-Lyonnet, D., Sinilnikova, O.M., Mazoyer, S., Barjhoux, L., Leone, M., Gauthier-Villars, M., Caux-Moncoutier, V., Pauw, A. de, Hardouin, A., Berthet, P., Dreyfus, H., Ferrer, S.F., Collonge-Rame, M.A., Sokolowska, J., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W., John, E.M., Southey, M., Goldgar, D., Singer, C.F., Tea, M.K.M., Gschwantler-Kaulich, D., Fink-Retter, A., Hansen, T.V.O., Ejlertsen, B., Johannsson, O.T., Offit, K., Sarrel, K., Gaudet, M.M., Vijai, J., Robson, M., Piedmonte, M.R., Andrews, L., Cohn, D., DeMars, L.R., DiSilvestro, P., Rodriguez, G., Toland, A.E., Montagna, M., Agata, S., Imyanitov, E., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Ramus, S.J., Sucheston, L., Karlan, B.Y., Gross, J., Ganz, P.A., Beattie, M.S., Schmutzler, R.K., Wappenschmidt, B., Meindl, A., Arnold, N., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Nevanlinna, H., Aittomaki, K., Simard, J., Spurdle, A.B., Beesley, J., Chen, X.Q., Tomlinson, G.E., Weitzel, J., Garber, J.E., Olopade, O.I., Rubinstein, W.S., Tung, N., Blum, J.L., Narod, S.A., Brummel, S., Gillen, D.L., Lindor, N., Fredericksen, Z., Pankratz, V.S., Couch, F.J., Radice, P., Peterlongo, P., Greene, M.H., Loud, J.T., Mai, P.L., Andrulis, I.L., Glendon, G., Ozcelik, H., Gerdes, A.M., Thomassen, M., Jensen, U.B., Skytte, A.B., Caligo, M.A., Lee, A., Chenevix-Trench, G., Antoniou, A.C., Neuhausen, S.L., SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators, KConFab Investigators, OCGN, Consortium Investigators Modifiers, Human genetics, CCA - Oncogenesis, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human Genetics, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Medical Oncology, Clinical Genetics, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: Nonsynonymous substitution, endocrine system diseases, Epidemiology, Genes, BRCA2, Genes, BRCA1, Cohort Studies, 0302 clinical medicine, Genotype, skin and connective tissue diseases, Ovarian Neoplasms, 0303 health sciences, GENETIC-VARIATION, INSULIN, 3. Good health, FAMILY, Oncology, 030220 oncology & carcinogenesis, Cohort, Female, Cohort study, EXPRESSION, AMINO-ACID POLYMORPHISM, endocrine system, PROTEINS, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], NEOPLASIA, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], GROWTH-FACTOR-I, medicine, Humans, Genetic Predisposition to Disease, IGF, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], RECEPTOR, Retrospective cohort study, medicine.disease, IRS1, Mutation, Cancer research, Insulin Receptor Substrate Proteins, Ovarian cancer
Abstract: Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods:IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06–1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39–3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28–2.70; class I HR, 0.86; 95%CI, 0.69–1.09; Pdifference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362–70. ©2012 AACR.
Published: 2012
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8. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author: Milne, R.L., Kuchenbaecker, K.B., Michailidou, K., Beesley, J., Kar, S., Lindstrom, S., Hui, S., Lemacon, A., Soucy, P., Dennis, J., Jiang, X, Rostamianfar, A., Finucane, H., Bolla, M.K., McGuffog, L., Wang, Q., Aalfs, C.M., Adams, M., Adlard, J., Agata, S., Ahmed, S., Ahsan, H., Aittomaki, K., Al-Ejeh, F., Allen, J., Ambrosone, C.B., Amos, C.I., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arndt, V., Arnold, N., Aronson, K.J., Auber, B., Auer, P.L., Ausems, M., Azzollini, J., Bacot, F., Balmana, J., Barile, M., Barjhoux, L., Barkardottir, R.B., Barrdahl, M., Barnes, D., Barrowdale, D., Baynes, C., Beckmann, M.W., Benitez, J., Bermisheva, M., Bernstein, L., Bignon, Y.J., Blazer, K.R., Blok, M.J., Blomqvist, C., Blot, W., Bobolis, K., Boeckx, B., Bogdanova, N.V., Bojesen, A., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Bozsik, A., Bradbury, A.R., Brand, J.S., Brauch, H., Brenner, H., Bressac-de Paillerets, B., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Brunet, J., Bruning, T., Burwinkel, B., Buys, S.S., Byun, J., Cai, Q., Caldes, T., Caligo, M.A., Campbell, I., Canzian, F., Caron, O., Carracedo, A., Carter, B.D., Castelao, J.E., Castera, L., Caux-Moncoutier, V., Chan, S.B., Chang-Claude, J., Chanock, S.J., Chen, X, Cheng, T.D., Chiquette, J., Christiansen, H., Claes, K.B.M., Clarke, C.L., Conner, T., Conroy, D.M., Cook, J., Kets, C.M., Simard, J., Milne, R.L., Kuchenbaecker, K.B., Michailidou, K., Beesley, J., Kar, S., Lindstrom, S., Hui, S., Lemacon, A., Soucy, P., Dennis, J., Jiang, X, Rostamianfar, A., Finucane, H., Bolla, M.K., McGuffog, L., Wang, Q., Aalfs, C.M., Adams, M., Adlard, J., Agata, S., Ahmed, S., Ahsan, H., Aittomaki, K., Al-Ejeh, F., Allen, J., Ambrosone, C.B., Amos, C.I., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arndt, V., Arnold, N., Aronson, K.J., Auber, B., Auer, P.L., Ausems, M., Azzollini, J., Bacot, F., Balmana, J., Barile, M., Barjhoux, L., Barkardottir, R.B., Barrdahl, M., Barnes, D., Barrowdale, D., Baynes, C., Beckmann, M.W., Benitez, J., Bermisheva, M., Bernstein, L., Bignon, Y.J., Blazer, K.R., Blok, M.J., Blomqvist, C., Blot, W., Bobolis, K., Boeckx, B., Bogdanova, N.V., Bojesen, A., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Bozsik, A., Bradbury, A.R., Brand, J.S., Brauch, H., Brenner, H., Bressac-de Paillerets, B., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Brunet, J., Bruning, T., Burwinkel, B., Buys, S.S., Byun, J., Cai, Q., Caldes, T., Caligo, M.A., Campbell, I., Canzian, F., Caron, O., Carracedo, A., Carter, B.D., Castelao, J.E., Castera, L., Caux-Moncoutier, V., Chan, S.B., Chang-Claude, J., Chanock, S.J., Chen, X, Cheng, T.D., Chiquette, J., Christiansen, H., Claes, K.B.M., Clarke, C.L., Conner, T., Conroy, D.M., Cook, J., Kets, C.M., and Simard, J.
Abstract: Item does not contain fulltext, Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 x 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017

9. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author: Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R.J., McGuffog, L., Healy, S., Sinilnikova, O.M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Wachenfeldt, A. von, Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, R., Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K.L., Domchek, S.M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T.R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C.M., Kluijt, I., Boessenkool-Pape, J.L., Meijers-Heijboer, H.E.J., Oosterwijk, J.C., Asperen, C.J. van, Blok, M.J., Nelen, M.R., Ouweland, A.M.W. van den, Seynaeve, C., Luijt, R.B. van der, Devilee, P., Easton, D.F., Peock, S., Frost, D., Platte, R., Ellis, S.D., Fineberg, E., Evans, D.G., Lalloo, F., Eeles, R., Jacobs, C., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J.P., Vennin, P., Muller, D., Fricker, J.P., Venat-Bouvet, L., Johannsson, O., Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P.L., Loud, J.T., Lubinski, J., OCGN, SWE BRCA, HEBON, EMBRACE, GEMO Study Collaborators, KConFab, CIMBA, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Medical Oncology, IHS, Human genetics, and CCA - Oncogenesis
Subjects: Oncology, Cancer Research, endocrine system diseases, BRCA1/2 mutation carriers, METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR, Genes, BRCA2, Genes, BRCA1, DCN PAC - Perception action and control, SUSCEPTIBILITY, medicine.disease_cause, Bioinformatics, T+polymorphism%22">PHB 1630 C>T polymorphism, 0302 clinical medicine, PROHIBITIN 3'-UNTRANSLATED REGION, Genotype, Prohibitin, skin and connective tissue diseases, breast/ovarian cancer risk, Ovarian Neoplasms, 0303 health sciences, FOLATE STATUS, CARCINOGENESIS, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Female, +T+polymorphism%22">PHB 1630 C > T polymorphism, CHROMOSOME-17, Risk, EXPRESSION, medicine.medical_specialty, Heterozygote, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, +T+polymorphism%22">MTHFR 677 C > T polymorphism, Biology, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Internal medicine, Prohibitins, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, Polymorphism, Genetic, Hereditary cancer and cancer-related syndromes [ONCOL 1], Biology and Life Sciences, Genetics and Genomics, medicine.disease, GENE, Minor allele frequency, Repressor Proteins, COMMON MUTATION, T+polymorphism%22">MTHFR 677 C>T polymorphism, Methylenetetrahydrofolate reductase, Mutation, biology.protein, RNA, Carcinogenesis, Ovarian cancer
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
Published: 2012
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10. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, K.B. (Karoline), Neuhausen, S.L. (Susan), Robson, M. (Mark), Barrowdale, D. (Daniel), McGuffog, L. (Lesley), Mulligan, A.M. (Anna Marie), Andrulis, I.L. (Irene), Spurdle, A.B. (Amanda), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Engel, C. (Christoph), Wapenschmidt, B. (Barbara), Nevanlinna, H. (Heli), Thomassen, M. (Mads), Southey, M.C. (Melissa), Radice, P. (Paolo), Ramus, S.J. (Susan), Domchek, S.M. (Susan), Nathanson, K.L. (Katherine), Lee, A. (Andrew), Healey, S. (Sue), Nussbaum, R. (Robert), Rebbeck, R. (Timothy), Arun, B.K. (Banu), James, M. (Margaret), Karlan, B.Y. (Beth), Lester, K.J. (Kathryn), Cass, I. (Ilana), Terry, M.B. (Mary Beth), Daly, M.J. (Mark), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Steele, L. (Linda), Overeem Hansen, T. (Thomas) van, Ejlertsen, B. (Bent), Gerdes, A-M. (Anne-Marie), Nielsen, F. (Finn), Dennis, J. (Joe), Cunningham, J.M. (Julie), Hart, S. (Stewart), Slager, S. (Susan), Osorio, A. (Ana), Benítez, J. (Javier), Duran, M. (Mercedes), Weitzel, J.N. (Jeffrey), Tafur, I. (Isaac), Hander, M. (Mary), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Roversi, G. (Gaia), Scuvera, G. (Giulietta), Bonnani, B. (Bernardo), Mariani, P. (Paolo), Volorio, S. (Sara), Dolcetti, R. (Riccardo), Varesco, L. (Liliana), Papi, L. (Laura), Tibiletti, M.G. (Maria Grazia), Giannini, G. (Giuseppe), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Garber, J. (Judy), Hamann, U. (Ute), Donaldson, A. (Alan), Brewer, C. (Carole), Foo, C. (Claire), Evans, D.G. (Gareth), Frost, D. (Debra), Eccles, D. (Diana), Douglas, F. (Fiona), Brady, A. (A.), Cook, J. (Jackie), Tischkowitz, M. (Marc), Adlard, L., Barwell, J. (Julian), Ong, K., Walker, L.J. (Lisa), Izatt, L. (Louise), Side, L. (Lucy), Kennedy, M.J. (John), Rogers, M.T. (Mark), Porteous, M.E. (Mary), Morrison, P.J. (Patrick), Platte, R. (Radka), Eeles, R. (Ros), Davidson, R. (Rosemarie), Hodgson, S. (Shirley), Ellis, S.D. (Steve), Godwin, A.K. (Andrew), Rhiem, K. (Kerstin), Meindl, A. (Alfons), Ditsch, N. (Nina), Arnold, N. (Norbert), Plendl, H. (Hansjoerg), Niederacher, D. (Dieter), Sutter, C. (Christian), Steinemann, D. (Doris), Bogdanova-Markov, N. (Nadja), Kast, K. (Karin), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Gehrig, P.A. (Paola A.), Markiefka, B. (Birgid), Buecher, B. (Bruno), Lefol, C. (Cédrick), Stoppa-Lyonnet, D. (Dominique), Rouleau, E. (Etienne), Prieur, F. (Fabienne), Damiola, F. (Francesca), Barjhoux, L. (Laure), Faivre, L. (Laurence), Longy, M. (Michel), Sevenet, N. (Nicolas), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Bonadona, V. (Valérie), Caux-Moncoutier, V. (Virginie), Isaacs, C. (Claudine), Van Maerken, T. (Tom), Claes, K.B.M. (Kathleen B.M.), Piedmonte, M. (Marion), Andrews, L. (Lesley), Hays, J. (John), Rodriguez, G.C. (Gustavo), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Khan, S. (Sofia), Hogervorst, F.B.L. (Frans), Aalfs, C.M. (Cora), Lange, J.L. (J.) de, Meijers-Heijboer, E.J. (Hanne), Hout, A.H. (Annemarie) van der, Wijnen, J.T. (Juul), Roozendaal, K.E. (Kees) van, Mensenkamp, A.R. (Arjen), Ouweland, A.M.W. (Ans) van den, Deurzen, C.H.M. (Carolien) van, Luijt, R.B. (Rob) van der, Olah, E., Díez, O. (Orland), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Teulé, A. (A.), Menéndez, M. (Mireia), Jakubowska, A. (Anna), Lubinski, J. (Jan), Cybulski, C. (Cezary), Gronwald, J. (Jacek), Jaworska-Bieniek, K. (Katarzyna), Durda, K. (Katarzyna), Arason, A. (Adalgeir), Maugard, C., Soucy, P. (Penny), Montagna, M. (Marco), Agata, S. (Simona), Teixeira, P.J., Olswold, C. (Curtis), Lindor, N.M. (Noralane), Pankratz, V.S. (Shane), Hallberg, B. (Boubou), Wang, X. (Xianshu), Szabo, C. (Csilla), Vijai, J. (Joseph), Jacobs, L. (Lauren), Corines, M. (Marina), Lincoln, A. (Anne), Berger, A. (Andreas), Fink-Retter, A. (Anneliese), Singer, C.F. (Christian), Rappaport, C. (Christine), Kaulich, D.G. (Daphne Gschwantler), Pfeiler, G. (Georg), Tea, M.-K., Phelan, C. (Catherine), Mai, P.L. (Phuong), Greene, M.H. (Mark), Rennert, G. (Gad), Imyanitov, E.N. (Evgeny), Glendon, G. (Gord), Toland, A.E. (Amanda), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Jensen, U.B., Caligo, M.A. (Maria), Friedman, E. (Eitan), Berger, R. (Raanan), Laitman, Y. (Yael), Rantala, J. (Johanna), Arver, B. (Brita Wasteson), Loman, N. (Niklas), Borg, Å. (Åke), Ehrencrona, H. (Hans), Olopade, O.I. (Olofunmilayo), Simard, J. (Jacques), Easton, D.F. (Douglas), Chenevix-Trench, G. (Georgia), Offit, K. (Kenneth), Couch, F.J. (Fergus), Antoniou, A.C. (Antonis), Kuchenbaecker, K.B. (Karoline), Neuhausen, S.L. (Susan), Robson, M. (Mark), Barrowdale, D. (Daniel), McGuffog, L. (Lesley), Mulligan, A.M. (Anna Marie), Andrulis, I.L. (Irene), Spurdle, A.B. (Amanda), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Engel, C. (Christoph), Wapenschmidt, B. (Barbara), Nevanlinna, H. (Heli), Thomassen, M. (Mads), Southey, M.C. (Melissa), Radice, P. (Paolo), Ramus, S.J. (Susan), Domchek, S.M. (Susan), Nathanson, K.L. (Katherine), Lee, A. (Andrew), Healey, S. (Sue), Nussbaum, R. (Robert), Rebbeck, R. (Timothy), Arun, B.K. (Banu), James, M. (Margaret), Karlan, B.Y. (Beth), Lester, K.J. (Kathryn), Cass, I. (Ilana), Terry, M.B. (Mary Beth), Daly, M.J. (Mark), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Steele, L. (Linda), Overeem Hansen, T. (Thomas) van, Ejlertsen, B. (Bent), Gerdes, A-M. (Anne-Marie), Nielsen, F. (Finn), Dennis, J. (Joe), Cunningham, J.M. (Julie), Hart, S. (Stewart), Slager, S. (Susan), Osorio, A. (Ana), Benítez, J. (Javier), Duran, M. (Mercedes), Weitzel, J.N. (Jeffrey), Tafur, I. (Isaac), Hander, M. (Mary), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Roversi, G. (Gaia), Scuvera, G. (Giulietta), Bonnani, B. (Bernardo), Mariani, P. (Paolo), Volorio, S. (Sara), Dolcetti, R. (Riccardo), Varesco, L. (Liliana), Papi, L. (Laura), Tibiletti, M.G. (Maria Grazia), Giannini, G. (Giuseppe), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Garber, J. (Judy), Hamann, U. (Ute), Donaldson, A. (Alan), Brewer, C. (Carole), Foo, C. (Claire), Evans, D.G. (Gareth), Frost, D. (Debra), Eccles, D. (Diana), Douglas, F. (Fiona), Brady, A. (A.), Cook, J. (Jackie), Tischkowitz, M. (Marc), Adlard, L., Barwell, J. (Julian), Ong, K., Walker, L.J. (Lisa), Izatt, L. (Louise), Side, L. (Lucy), Kennedy, M.J. (John), Rogers, M.T. (Mark), Porteous, M.E. (Mary), Morrison, P.J. (Patrick), Platte, R. (Radka), Eeles, R. (Ros), Davidson, R. (Rosemarie), Hodgson, S. (Shirley), Ellis, S.D. (Steve), Godwin, A.K. (Andrew), Rhiem, K. (Kerstin), Meindl, A. (Alfons), Ditsch, N. (Nina), Arnold, N. (Norbert), Plendl, H. (Hansjoerg), Niederacher, D. (Dieter), Sutter, C. (Christian), Steinemann, D. (Doris), Bogdanova-Markov, N. (Nadja), Kast, K. (Karin), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Gehrig, P.A. (Paola A.), Markiefka, B. (Birgid), Buecher, B. (Bruno), Lefol, C. (Cédrick), Stoppa-Lyonnet, D. (Dominique), Rouleau, E. (Etienne), Prieur, F. (Fabienne), Damiola, F. (Francesca), Barjhoux, L. (Laure), Faivre, L. (Laurence), Longy, M. (Michel), Sevenet, N. (Nicolas), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Bonadona, V. (Valérie), Caux-Moncoutier, V. (Virginie), Isaacs, C. (Claudine), Van Maerken, T. (Tom), Claes, K.B.M. (Kathleen B.M.), Piedmonte, M. (Marion), Andrews, L. (Lesley), Hays, J. (John), Rodriguez, G.C. (Gustavo), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Khan, S. (Sofia), Hogervorst, F.B.L. (Frans), Aalfs, C.M. (Cora), Lange, J.L. (J.) de, Meijers-Heijboer, E.J. (Hanne), Hout, A.H. (Annemarie) van der, Wijnen, J.T. (Juul), Roozendaal, K.E. (Kees) van, Mensenkamp, A.R. (Arjen), Ouweland, A.M.W. (Ans) van den, Deurzen, C.H.M. (Carolien) van, Luijt, R.B. (Rob) van der, Olah, E., Díez, O. (Orland), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Teulé, A. (A.), Menéndez, M. (Mireia), Jakubowska, A. (Anna), Lubinski, J. (Jan), Cybulski, C. (Cezary), Gronwald, J. (Jacek), Jaworska-Bieniek, K. (Katarzyna), Durda, K. (Katarzyna), Arason, A. (Adalgeir), Maugard, C., Soucy, P. (Penny), Montagna, M. (Marco), Agata, S. (Simona), Teixeira, P.J., Olswold, C. (Curtis), Lindor, N.M. (Noralane), Pankratz, V.S. (Shane), Hallberg, B. (Boubou), Wang, X. (Xianshu), Szabo, C. (Csilla), Vijai, J. (Joseph), Jacobs, L. (Lauren), Corines, M. (Marina), Lincoln, A. (Anne), Berger, A. (Andreas), Fink-Retter, A. (Anneliese), Singer, C.F. (Christian), Rappaport, C. (Christine), Kaulich, D.G. (Daphne Gschwantler), Pfeiler, G. (Georg), Tea, M.-K., Phelan, C. (Catherine), Mai, P.L. (Phuong), Greene, M.H. (Mark), Rennert, G. (Gad), Imyanitov, E.N. (Evgeny), Glendon, G. (Gord), Toland, A.E. (Amanda), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Jensen, U.B., Caligo, M.A. (Maria), Friedman, E. (Eitan), Berger, R. (Raanan), Laitman, Y. (Yael), Rantala, J. (Johanna), Arver, B. (Brita Wasteson), Loman, N. (Niklas), Borg, Å. (Åke), Ehrencrona, H. (Hans), Olopade, O.I. (Olofunmilayo), Simard, J. (Jacques), Easton, D.F. (Douglas), Chenevix-Trench, G. (Georgia), Offit, K. (Kenneth), Couch, F.J. (Fergus), and Antoniou, A.C. (Antonis)
Abstract: Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive ass
Published: 2014
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11. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, KB, Neuhausen, SL, Robson, M, Barrowdale, D, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, SJ, Domchek, SM, Nathanson, KL, Lee, A, Healey, S, Nussbaum, RL, Rebbeck, TR, Arun, BK, James, P, Karlan, BY, Lester, J, Cass, I, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, Hansen, TVO, Ejlertsen, B, Gerdes, A-M, Nielsen, FC, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, JN, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, MG, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K-R, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, AK, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova-Markov, N, Kast, K, Varon-Mateeva, R, Wang-Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa-Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, OM, Mazoyer, S, Bonadona, V, Caux-Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, GC, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, FBL, Aalfs, CM, de lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, Wijnen, JT, van Roozendaal, KEP, Mensenkamp, AR, van den Ouweland, AMW, van Deurzen, CHM, van der Luijt, RB, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teule, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, MR, Olswold, C, Lindor, N, Pankratz, VS, Hallberg, E, Wang, X, Szabo, CI, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Phelan, CM, Mai, PL, Greene, MH, Rennert, G, Imyanitov, EN, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Jensen, UB, Caligo, MA, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, OI, Simard, J, Easton, DF, Chenevix-Trench, G, Offit, K, Couch, FJ, Antoniou, AC, Kuchenbaecker, KB, Neuhausen, SL, Robson, M, Barrowdale, D, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, SJ, Domchek, SM, Nathanson, KL, Lee, A, Healey, S, Nussbaum, RL, Rebbeck, TR, Arun, BK, James, P, Karlan, BY, Lester, J, Cass, I, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, Hansen, TVO, Ejlertsen, B, Gerdes, A-M, Nielsen, FC, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, JN, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, MG, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K-R, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, AK, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova-Markov, N, Kast, K, Varon-Mateeva, R, Wang-Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa-Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, OM, Mazoyer, S, Bonadona, V, Caux-Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, GC, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, FBL, Aalfs, CM, de lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, Wijnen, JT, van Roozendaal, KEP, Mensenkamp, AR, van den Ouweland, AMW, van Deurzen, CHM, van der Luijt, RB, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teule, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, MR, Olswold, C, Lindor, N, Pankratz, VS, Hallberg, E, Wang, X, Szabo, CI, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Phelan, CM, Mai, PL, Greene, MH, Rennert, G, Imyanitov, EN, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Jensen, UB, Caligo, MA, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, OI, Simard, J, Easton, DF, Chenevix-Trench, G, Offit, K, Couch, FJ, and Antoniou, AC
Abstract: INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement
Published: 2014

12. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Kuchenbaecker, KB, Neuhausen, SL, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Ramus, SJ, Domchek, SM, Nathanson, KL, Nussbaum, RL, Rebbeck, TR, Arun, BK, Karlan, BY, Breast Cancer Family Registry, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Dorfling, CM, van Rensburg, EJ, Gerdes, AM, Nielsen, FC, Weitzel, JN, ROVERSI, GAIA, Tibiletti, MG, Evans, DG, EMBRACE Study, Ong, KR, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Godwin, AK, GEMO Study Collaborators, Sinilnikova, OM, Rodriguez, GC, Hogervorst, FB, Aalfs, CM, de Lange, JL, Meijers Heijboer, HE, van der Hout, AH, Wijnen, JT, van Roozendaal, KE, Mensenkamp, AR, van den Ouweland, AM, van Deurzen, CH, van der Luijt, RB, HEBON, Teixeira, MR, KConFab, Investigators, Pankratz, VS, Szabo, CI, Singer, CF, Kaulich, DG, Tea, MK, Phelan, CM, Mai, PL, Greene, MH, Imyanitov, EN, Toland, AE, Pedersen, IS, Jensen, UB, Caligo, MA, Olopade, OI, Easton, DF, Couch, FJ, Antoniou, AC, CIMBA, Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Kuchenbaecker, KB, Neuhausen, SL, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Ramus, SJ, Domchek, SM, Nathanson, KL, Nussbaum, RL, Rebbeck, TR, Arun, BK, Karlan, BY, Breast Cancer Family Registry, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Dorfling, CM, van Rensburg, EJ, Gerdes, AM, Nielsen, FC, Weitzel, JN, ROVERSI, GAIA, Tibiletti, MG, Evans, DG, EMBRACE Study, Ong, KR, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Godwin, AK, GEMO Study Collaborators, Sinilnikova, OM, Rodriguez, GC, Hogervorst, FB, Aalfs, CM, de Lange, JL, Meijers Heijboer, HE, van der Hout, AH, Wijnen, JT, van Roozendaal, KE, Mensenkamp, AR, van den Ouweland, AM, van Deurzen, CH, van der Luijt, RB, HEBON, Teixeira, MR, KConFab, Investigators, Pankratz, VS, Szabo, CI, Singer, CF, Kaulich, DG, Tea, MK, Phelan, CM, Mai, PL, Greene, MH, Imyanitov, EN, Toland, AE, Pedersen, IS, Jensen, UB, Caligo, MA, Olopade, OI, Easton, DF, Couch, FJ, Antoniou, AC, and CIMBA
Abstract: Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Con
Published: 2014

13. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

Author: Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R.J., McGuffog, L., Healy, S., Sinilnikova, O.M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Wachenfeldt, A. von, Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, R., Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K.L., Domchek, S.M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T.R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C.M., Kluijt, I., Boessenkool-Pape, J.L., Meijers-Heijboer, H.E., Oosterwijk, J.C., Asperen, C.J. van, Blok, M.J., Nelen, M.R., Ouweland, A.M. van den, Seynaeve, C., Luijt, R.B. van der, Devilee, P., Easton, D.F., Peock, S., Frost, D., Platte, R., Ellis, S.D., Fineberg, E., Evans, D.G., Lalloo, F., Eeles, R., Jacobs, C, Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J.P., Vennin, P., Muller, D., Fricker, J.P., Venat-Bouvet, L., Johannsson, O.T., Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P.L., Loud, J.T., Lubinski, J., Ligtenberg, M.J.L., Hoogerbrugge, N., et al., Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R.J., McGuffog, L., Healy, S., Sinilnikova, O.M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Wachenfeldt, A. von, Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, R., Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K.L., Domchek, S.M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T.R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C.M., Kluijt, I., Boessenkool-Pape, J.L., Meijers-Heijboer, H.E., Oosterwijk, J.C., Asperen, C.J. van, Blok, M.J., Nelen, M.R., Ouweland, A.M. van den, Seynaeve, C., Luijt, R.B. van der, Devilee, P., Easton, D.F., Peock, S., Frost, D., Platte, R., Ellis, S.D., Fineberg, E., Evans, D.G., Lalloo, F., Eeles, R., Jacobs, C, Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J.P., Vennin, P., Muller, D., Fricker, J.P., Venat-Bouvet, L., Johannsson, O.T., Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P.L., Loud, J.T., Lubinski, J., Ligtenberg, M.J.L., Hoogerbrugge, N., and et al.
Abstract: Item does not contain fulltext, BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
Published: 2012

14. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author: Ramus, S.J., Antoniou, A.C., Kuchenbaecker, K.B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O.M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M., Gerdes, A.M., Kruse, T.A., Jensen, U.B., Skytte, A.B., Caligo, M.A., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Swe, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Osorio, A., Benitez, J., Duran, M., Tejada, M.I., Hamann, U., Rookus, M., van Leeuwen, F.E., Aalfs, C.M., Meijers-Heijboer, H.E., Asperen, C.J. van, van Roozendaal, K.E., Hoogerbrugge-van der Linden, N., Collee, J.M., Kriege, M., van der Luijt, R.B., Hebon, ., Embrace, ., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Jacobs, C, Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P.J., Walker, L., Porteous, M.E., Kennedy, M.J., Pathak, H., Godwin, A.K., Stoppa-Lyonnet, D., Caux-Moncoutier, V., de Pauw, A., Gauthier-Villars, M., Mazoyer, S., Leone, M., Calender, A., Lasset, C., Bonadona, V., Hardouin, A., Berthet, P., Bignon, Y.J., Uhrhammer, N., Faivre, L., Loustalot, C., Gemo, ., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W.K., John, E.M., Ligtenberg, M.J., et al., Ramus, S.J., Antoniou, A.C., Kuchenbaecker, K.B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O.M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M., Gerdes, A.M., Kruse, T.A., Jensen, U.B., Skytte, A.B., Caligo, M.A., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Swe, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Osorio, A., Benitez, J., Duran, M., Tejada, M.I., Hamann, U., Rookus, M., van Leeuwen, F.E., Aalfs, C.M., Meijers-Heijboer, H.E., Asperen, C.J. van, van Roozendaal, K.E., Hoogerbrugge-van der Linden, N., Collee, J.M., Kriege, M., van der Luijt, R.B., Hebon, ., Embrace, ., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Jacobs, C, Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P.J., Walker, L., Porteous, M.E., Kennedy, M.J., Pathak, H., Godwin, A.K., Stoppa-Lyonnet, D., Caux-Moncoutier, V., de Pauw, A., Gauthier-Villars, M., Mazoyer, S., Leone, M., Calender, A., Lasset, C., Bonadona, V., Hardouin, A., Berthet, P., Bignon, Y.J., Uhrhammer, N., Faivre, L., Loustalot, C., Gemo, ., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W.K., John, E.M., Ligtenberg, M.J., and et al.
Abstract: Item does not contain fulltext, Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
Published: 2012

15. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

Author: Ding, Y.C. (Yuan), McGuffog, L. (Lesley), Healey, S. (Sue), Friedman, E. (Eitan), Laitman, Y. (Yael), Shimon, S.-P. (Shani-Paluch), Kaufman, B. (Bella), Liljegren, A. (Annelie), Lindblom, A. (Annika), Olsson, H., Kristoffersson, U. (Ulf), Stenmark-Askmalm, M. (M.), Melin, B. (Beatrice), Domchek, S.M. (Susan), Nathanson, K.L. (Katherine), Rebbeck, R. (Timothy), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Gronwald, J. (Jacek), Huzarski, T. (Tomasz), Cybulski, C. (Cezary), Byrski, T. (Tomasz), Osorio, A. (Ana), Cajal, T.R., Stavropoulou, A. (Alexandra), Benítez, J. (Javier), Hamann, U. (Ute), Rookus, M.A. (Matti), Aalfs, C.M. (Cora), Lange, J.L. (J.) de, Meijers-Heijboer, E.J. (Hanne), Oosterwijk, J.C. (Jan), Asperen, C.J. (Christi) van, Gómez García, E.B. (Encarna), Hoogerbrugge, N. (Nicoline), Jager, A. (Agnes), Luijt, R.B. (Rob) van der, Easton, D.F. (Douglas), Peock, S. (Susan), Frost, D. (Debra), Ellis, S.D. (Steve), Platte, R. (Radka), Fineberg, E. (Elena), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Izatt, L. (Louise), Eeles, R. (Rosalind), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T.J. (Trevor), Cook, J. (Jackie), Brewer, C. (Carole), Tischkowitz, M. (Marc), Godwin, A.K. (Andrew), Pathak, S.S., Stoppa-Lyonnet, D. (Dominique), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Léone, M. (Mélanie), Gauthier-Villars, M. (Marion), Caux-Moncoutier, V. (Virginie), Pauw, A. (Antoine) de, Hardouin, A. (Agnès), Berthet, P. (Pascaline), Dreyfus, H. (Hélène), Ferrer, S.F., Collonge-Rame, M.-A., Sokolowska, J. (Johanna), Buys, S.S. (Saundra), Daly, M.B. (Mary), Miron, A. (Alexander), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), John, E.M. (Esther), Southey, M.C. (Melissa), Goldgar, D. (David), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Hansen, T.V.O. (Thomas), Ejlertsen, B. (Bent), Johannson, O.T. (Oskar), Offit, K. (Kenneth), Sarrel, K. (Kara), Gaudet, M.M. (Mia), Vijai, J. (Joseph), Robson, M. (Mark), Piedmonte, M. (Marion), Andrews, L. (Lesley), Cohn, D.E. (David), DeMars, L.R. (Leslie), DiSilvestro, P. (Paul), Rodriguez, G.C. (Gustavo), Toland, A.E. (Amanda), Montagna, M. (Marco), Agata, S. (Simona), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Janavicius, R. (Ramunas), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Ramus, S.J. (Susan), Sucheston, L. (Lara), Karlan, B.Y. (Beth), Gross, J. (Jenny), Ganz, P.A. (Patricia), Beattie, M.S. (Mary), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Arnold, N. (Norbert), Niederacher, D. (Dieter), Preisler-Adams, S. (Sabine), Gadzicki, D. (Dorothea), Varon-Mateeva, R. (Raymonda), Deissler, H. (Helmut), Gehrig, P.A. (Paola A.), Sutter, C. (Christian), Kast, K. (Karin), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Simard, J. (Jacques), Spurdle, A.B. (Amanda), Beesley, J. (Jonathan), Chen, X. (Xiaoqing), Tomlinson, G. (Gail), Weitzel, J.N. (Jeffrey), Garber, J., Olopade, O.I. (Olofunmilayo), Rubinstein, W.S. (Wendy), Tung, N. (Nadine), Blum, J.L. (Joanne), Narod, S. (Steven), Brummel, S. (Sean), Gillen, D.L. (Daniel), Lindor, N.M. (Noralane), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Couch, F.J. (Fergus), Radice, P. (Paolo), Peterlongo, P. (Paolo), Greene, M.H. (Mark), Loud, J.T. (Jennifer), Mai, P.L. (Phuong), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Lee, A. (Andrew), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), McGuffog, L. (Lesley), Healey, S. (Sue), Friedman, E. (Eitan), Laitman, Y. (Yael), Shimon, S.-P. (Shani-Paluch), Kaufman, B. (Bella), Liljegren, A. (Annelie), Lindblom, A. (Annika), Olsson, H., Kristoffersson, U. (Ulf), Stenmark-Askmalm, M. (M.), Melin, B. (Beatrice), Domchek, S.M. (Susan), Nathanson, K.L. (Katherine), Rebbeck, R. (Timothy), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Gronwald, J. (Jacek), Huzarski, T. (Tomasz), Cybulski, C. (Cezary), Byrski, T. (Tomasz), Osorio, A. (Ana), Cajal, T.R., Stavropoulou, A. (Alexandra), Benítez, J. (Javier), Hamann, U. (Ute), Rookus, M.A. (Matti), Aalfs, C.M. (Cora), Lange, J.L. (J.) de, Meijers-Heijboer, E.J. (Hanne), Oosterwijk, J.C. (Jan), Asperen, C.J. (Christi) van, Gómez García, E.B. (Encarna), Hoogerbrugge, N. (Nicoline), Jager, A. (Agnes), Luijt, R.B. (Rob) van der, Easton, D.F. (Douglas), Peock, S. (Susan), Frost, D. (Debra), Ellis, S.D. (Steve), Platte, R. (Radka), Fineberg, E. (Elena), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Izatt, L. (Louise), Eeles, R. (Rosalind), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T.J. (Trevor), Cook, J. (Jackie), Brewer, C. (Carole), Tischkowitz, M. (Marc), Godwin, A.K. (Andrew), Pathak, S.S., Stoppa-Lyonnet, D. (Dominique), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Léone, M. (Mélanie), Gauthier-Villars, M. (Marion), Caux-Moncoutier, V. (Virginie), Pauw, A. (Antoine) de, Hardouin, A. (Agnès), Berthet, P. (Pascaline), Dreyfus, H. (Hélène), Ferrer, S.F., Collonge-Rame, M.-A., Sokolowska, J. (Johanna), Buys, S.S. (Saundra), Daly, M.B. (Mary), Miron, A. (Alexander), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), John, E.M. (Esther), Southey, M.C. (Melissa), Goldgar, D. (David), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Hansen, T.V.O. (Thomas), Ejlertsen, B. (Bent), Johannson, O.T. (Oskar), Offit, K. (Kenneth), Sarrel, K. (Kara), Gaudet, M.M. (Mia), Vijai, J. (Joseph), Robson, M. (Mark), Piedmonte, M. (Marion), Andrews, L. (Lesley), Cohn, D.E. (David), DeMars, L.R. (Leslie), DiSilvestro, P. (Paul), Rodriguez, G.C. (Gustavo), Toland, A.E. (Amanda), Montagna, M. (Marco), Agata, S. (Simona), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Janavicius, R. (Ramunas), Lázaro, C. (Conxi), Blanco, I. (Ignacio), Ramus, S.J. (Susan), Sucheston, L. (Lara), Karlan, B.Y. (Beth), Gross, J. (Jenny), Ganz, P.A. (Patricia), Beattie, M.S. (Mary), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Arnold, N. (Norbert), Niederacher, D. (Dieter), Preisler-Adams, S. (Sabine), Gadzicki, D. (Dorothea), Varon-Mateeva, R. (Raymonda), Deissler, H. (Helmut), Gehrig, P.A. (Paola A.), Sutter, C. (Christian), Kast, K. (Karin), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Simard, J. (Jacques), Spurdle, A.B. (Amanda), Beesley, J. (Jonathan), Chen, X. (Xiaoqing), Tomlinson, G. (Gail), Weitzel, J.N. (Jeffrey), Garber, J., Olopade, O.I. (Olofunmilayo), Rubinstein, W.S. (Wendy), Tung, N. (Nadine), Blum, J.L. (Joanne), Narod, S. (Steven), Brummel, S. (Sean), Gillen, D.L. (Daniel), Lindor, N.M. (Noralane), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Couch, F.J. (Fergus), Radice, P. (Paolo), Peterlongo, P. (Paolo), Greene, M.H. (Mark), Loud, J.T. (Jennifer), Mai, P.L. (Phuong), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Lee, A. (Andrew), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), and Neuhausen, S.L. (Susan)
Abstract: Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1
Published: 2012
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16. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

Author: Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Shani-Paluch-Shimon, Kaufman, B, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Gronwald, J, Huzarski, T, Cybulski, C, Byrski, T, Osorio, A, Ramony Cajal, T, Stavropoulou, AV, Benitez, J, Hamann, U, Rookus, M, Aalfs, CM, de Lange, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Garcia, EBG, Hoogerbrugge, N, Jager, A, van der Luijt, RB, Easton, DF, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Godwin, AK, Pathak, H, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Barjhoux, L, Leone, M, Gauthier-Villars, M, Caux-Moncoutier, V, de Pauw, A, Hardouin, A, Berthet, P, Dreyfus, H, Ferrer, SF, Collonge-Rame, M-A, Sokolowska, J, Buys, S, Daly, M, Miron, A, Terry, MB, Chung, W, John, EM, Southey, M, Goldgar, D, Singer, CF, Tea, M-KM, Gschwantler-Kaulich, D, Fink-Retter, A, Hansen, TVO, Ejlertsen, B, Johannsson, OT, Offit, K, Sarrel, K, Gaudet, MM, Vijai, J, Robson, M, Piedmonte, MR, Andrews, L, Cohn, D, DeMars, LR, DiSilvestro, P, Rodriguez, G, Toland, AE, Montagna, M, Agata, S, Imyanitov, E, Isaacs, C, Janavicius, R, Lazaro, C, Blanco, I, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Ganz, PA, Beattie, MS, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Nevanlinna, H, Aittomaki, K, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Tomlinson, GE, Weitzel, J, Garber, JE, Olopade, OI, Rubinstein, WS, Tung, N, Blum, JL, Narod, SA, Brummel, S, Gillen, DL, Lindor, N, Fredericksen, Z, Pankratz, VS, Couch, FJ, Radice, P, Peterlongo, P, Greene, MH, Loud, JT, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Gerdes, A-M, Thomassen, M, Jensen, UB, Skytte, A-B, Caligo, MA, Lee, A, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Shani-Paluch-Shimon, Kaufman, B, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Gronwald, J, Huzarski, T, Cybulski, C, Byrski, T, Osorio, A, Ramony Cajal, T, Stavropoulou, AV, Benitez, J, Hamann, U, Rookus, M, Aalfs, CM, de Lange, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Garcia, EBG, Hoogerbrugge, N, Jager, A, van der Luijt, RB, Easton, DF, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Godwin, AK, Pathak, H, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Barjhoux, L, Leone, M, Gauthier-Villars, M, Caux-Moncoutier, V, de Pauw, A, Hardouin, A, Berthet, P, Dreyfus, H, Ferrer, SF, Collonge-Rame, M-A, Sokolowska, J, Buys, S, Daly, M, Miron, A, Terry, MB, Chung, W, John, EM, Southey, M, Goldgar, D, Singer, CF, Tea, M-KM, Gschwantler-Kaulich, D, Fink-Retter, A, Hansen, TVO, Ejlertsen, B, Johannsson, OT, Offit, K, Sarrel, K, Gaudet, MM, Vijai, J, Robson, M, Piedmonte, MR, Andrews, L, Cohn, D, DeMars, LR, DiSilvestro, P, Rodriguez, G, Toland, AE, Montagna, M, Agata, S, Imyanitov, E, Isaacs, C, Janavicius, R, Lazaro, C, Blanco, I, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Ganz, PA, Beattie, MS, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Nevanlinna, H, Aittomaki, K, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Tomlinson, GE, Weitzel, J, Garber, JE, Olopade, OI, Rubinstein, WS, Tung, N, Blum, JL, Narod, SA, Brummel, S, Gillen, DL, Lindor, N, Fredericksen, Z, Pankratz, VS, Couch, FJ, Radice, P, Peterlongo, P, Greene, MH, Loud, JT, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Gerdes, A-M, Thomassen, M, Jensen, UB, Skytte, A-B, Caligo, MA, Lee, A, Chenevix-Trench, G, Antoniou, AC, and Neuhausen, SL
Abstract: BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
Published: 2012

17. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author: Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, Lubinski, J, Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, and Lubinski, J
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1 CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
Published: 2012

18. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, A.M., Couch, F.J., Barrowdale, D., Domchek, S.M., Eccles, D., Nevanlinna, H., Ramus, S.J., Robson, M., Sherman, M., Spurdle, A.B., Wappenschmidt, B., Lee, A., McGuffog, L., Healey, S., Sinilnikova, O.M., Janavicius, R., Hansen, T.V., Nielsen, F.C., Ejlertsen, B., Osorio, A., Munoz-Repeto, I., Duran, M., Godino, J., Pertesi, M., Benitez, J., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Bonanni, B., Viel, A., Pasini, B., Papi, L., Ottini, L., Savarese, A., Bernard, L., Radice, P., Hamann, U., Verheus, M., Meijers-Heijboer, H.E., Wijnen, J., Gomez Garcia, E.B., Nelen, M.R., Kets, C.M., Seynaeve, C., Tilanus-Linthorst, M.M., Luijt, R.B. van der, Os, T.V., Rookus, M., Frost, D., Jones, J.L., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Cook, J., Donaldson, A., Dorkins, H., Gregory, H., Eason, J., Houghton, C., Barwell, J., Side, L.E., McCann, E., Murray, A., Peock, S., Godwin, A.K., Schmutzler, R.K., Rhiem, K., Engel, C., Meindl, A., Ruehl, I., Arnold, N., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Kast, K., Preisler-Adams, S., Varon-Mateeva, R., Schoenbuchner, I., Fiebig, B., Heinritz, W., Schafer, D., Gevensleben, H., Caux-Moncoutier, V., Fassy-Colcombet, M., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Hardouin, A., Berthet, P., Muller, D., Fricker, J.P., Mortemousque, I., Pujol, P., et al., Mulligan, A.M., Couch, F.J., Barrowdale, D., Domchek, S.M., Eccles, D., Nevanlinna, H., Ramus, S.J., Robson, M., Sherman, M., Spurdle, A.B., Wappenschmidt, B., Lee, A., McGuffog, L., Healey, S., Sinilnikova, O.M., Janavicius, R., Hansen, T.V., Nielsen, F.C., Ejlertsen, B., Osorio, A., Munoz-Repeto, I., Duran, M., Godino, J., Pertesi, M., Benitez, J., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Bonanni, B., Viel, A., Pasini, B., Papi, L., Ottini, L., Savarese, A., Bernard, L., Radice, P., Hamann, U., Verheus, M., Meijers-Heijboer, H.E., Wijnen, J., Gomez Garcia, E.B., Nelen, M.R., Kets, C.M., Seynaeve, C., Tilanus-Linthorst, M.M., Luijt, R.B. van der, Os, T.V., Rookus, M., Frost, D., Jones, J.L., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Cook, J., Donaldson, A., Dorkins, H., Gregory, H., Eason, J., Houghton, C., Barwell, J., Side, L.E., McCann, E., Murray, A., Peock, S., Godwin, A.K., Schmutzler, R.K., Rhiem, K., Engel, C., Meindl, A., Ruehl, I., Arnold, N., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Kast, K., Preisler-Adams, S., Varon-Mateeva, R., Schoenbuchner, I., Fiebig, B., Heinritz, W., Schafer, D., Gevensleben, H., Caux-Moncoutier, V., Fassy-Colcombet, M., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Hardouin, A., Berthet, P., Muller, D., Fricker, J.P., Mortemousque, I., Pujol, P., and et al.
Abstract: Contains fulltext : 97737.pdf (publisher's version ) (Open Access), INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific
Published: 2011

19. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, A.M. (Anna Marie), Couch, F.J. (Fergus), Barrowdale, D. (Daniel), Domchek, S.M. (Susan), Eccles, D. (Diana), Nevanlinna, H. (Heli), Ramus, S.J. (Susan), Robson, M. (Mark), Sherman, M.E. (Mark), Spurdle, A.B. (Amanda), Wapenschmidt, B. (Barbara), Lee, A. (Andrew), McGuffog, L. (Lesley), Healey, S. (Sue), Sinilnikova, O. (Olga), Janavicius, R. (Ramunas), Hansen, T.V.O. (Thomas), Nielsen, F.C. (Finn), Ejlertsen, B. (Bent), Osorio, A. (Ana), Muñoz-Repeto, I. (Iván), Durán, M. (Mercedes), Godino, J. (Javier), Pertesi, M. (Maroulio), Benítez, J. (Javier), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Bonnani, B. (Bernardo), Viel, A. (Alessandra), Pasini, B. (Barbara), Papi, L. (Laura), Ottini, L. (Laura), Savarese, A. (Antonella), Bernard, L. (Loris), Radice, P. (Paolo), Hamann, U. (Ute), Verheus, M. (Martijn), Meijers-Heijboer, E.J. (Hanne), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Nelen, M.R. (Marcel), Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), Tilanus-Linthorst, M.M.A. (Madeleine), Luijt, R.B. (Rob) van der, Os, T.V. (Theo), Rookus, M.A. (Matti), Frost, D. (Debra), Jones, J.L. (J Louise), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Cook, J. (Jackie), Donaldson, A. (Alan), Dorkins, H. (Huw), Gregory, H. (Helen), Eason, J. (Jacqueline), Houghton, C. (Catherine), Barwell, J. (Julian), Side, L. (Lucy), McCann, E. (Emma), Murray, A. (Alexandra), Peock, S. (Susan), Godwin, A.K. (Andrew), Schmutzler, R.K. (Rita), Rhiem, K. (Kerstin), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Arnold, N. (Norbert), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Gadzicki, D. (Dorothea), Kast, K. (Karin), Preisler-Adams, S. (Sabine), Varon-Mateeva, R. (Raymonda), Schoenbuchner, I. (Ines), Fiebig, B. (Britta), Heinritz, W. (Wolfram), Schäfer, D. (Dieter), Gevensleben, H. (Heidrun), Caux-Moncoutier, V. (Virginie), Fassy-Colcombet, M. (Marion), Cornelis, F. (Franco̧is), Mazoyer, S. (Sylvie), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Hardouin, A. (Agnès), Berthet, P. (Pascaline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Mortemousque, I. (Isabelle), Pujol, P. (Pascal), Coupier, I. (Isabelle), Lebrun, M. (Marine), Kientz, C. (Caroline), Longy, M. (Michel), Sevenet, N. (Nicolas), Stoppa-Lyonnet, D. (Dominique), Isaacs, C. (Claudine), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Barkardottir, R.B. (Rosa), Soucy, P. (Penny), Dumont, M. (Martine), Simard, J. (Jacques), Montagna, M. (Marco), Tognazzo, S. (Silvia), D'Andrea, E. (Emma), Fox, S.B. (Stephen), Yan, M. (Max), Rebbeck, R. (Timothy), Olopade, O.I. (Olofunmilayo), Weitzel, J.N. (Jeffrey), Lynch, H. (Henry), Ganz, P.A. (Patricia), Tomlinson, G. (Gail), Wang, X. (Xing), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Lindor, N.M. (Noralane), Szabo, C. (Csilla), Offit, K. (Kenneth), Sakr, R. (Rita), Gaudet, M.M. (Mia), Bhatia, K.P. (Kailash), Kauff, N. (Noah), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Mai, P.L. (Phuong), Greene, M.H. (Mark), Imyanitov, E.N. (Evgeny), O'Malley, F.P. (Frances), Ozcelik, H. (Hilmi), Glendon, G. (Gord), Toland, A.E. (Amanda), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Kruse, T.A. (Torben), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Soller, M. (Maria), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Arver, B. (Brita Wasteson), Stenmark-Askmalm, M. (M.), Karlsson, P. (Per), Ding, Y.C. (Yuan), Neuhausen, S.L. (Susan), Beattie, M.S. (Mary), Pharoah, P.D.P. (Paul), Moysich, K.B. (Kirsten), Nathanson, K.L. (Katherine), Karlan, B.Y. (Beth), Gross, J. (Jenny), John, E.M. (Esther), Daly, M.B. (Mary), Buys, S.S. (Saundra), Southey, M.C. (Melissa), Hopper, J.L. (John), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), Miron, A. (Alexander), Goldgar, D. (David), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Andrulis, I.L. (Irene), Antoniou, A.C. (Antonis), Mulligan, A.M. (Anna Marie), Couch, F.J. (Fergus), Barrowdale, D. (Daniel), Domchek, S.M. (Susan), Eccles, D. (Diana), Nevanlinna, H. (Heli), Ramus, S.J. (Susan), Robson, M. (Mark), Sherman, M.E. (Mark), Spurdle, A.B. (Amanda), Wapenschmidt, B. (Barbara), Lee, A. (Andrew), McGuffog, L. (Lesley), Healey, S. (Sue), Sinilnikova, O. (Olga), Janavicius, R. (Ramunas), Hansen, T.V.O. (Thomas), Nielsen, F.C. (Finn), Ejlertsen, B. (Bent), Osorio, A. (Ana), Muñoz-Repeto, I. (Iván), Durán, M. (Mercedes), Godino, J. (Javier), Pertesi, M. (Maroulio), Benítez, J. (Javier), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Cattaneo, E. (Elisa), Bonnani, B. (Bernardo), Viel, A. (Alessandra), Pasini, B. (Barbara), Papi, L. (Laura), Ottini, L. (Laura), Savarese, A. (Antonella), Bernard, L. (Loris), Radice, P. (Paolo), Hamann, U. (Ute), Verheus, M. (Martijn), Meijers-Heijboer, E.J. (Hanne), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Nelen, M.R. (Marcel), Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), Tilanus-Linthorst, M.M.A. (Madeleine), Luijt, R.B. (Rob) van der, Os, T.V. (Theo), Rookus, M.A. (Matti), Frost, D. (Debra), Jones, J.L. (J Louise), Evans, D.G. (Gareth), Lalloo, F. (Fiona), Eeles, R. (Rosalind), Izatt, L. (Louise), Adlard, J.W. (Julian), Davidson, R. (Rosemarie), Cook, J. (Jackie), Donaldson, A. (Alan), Dorkins, H. (Huw), Gregory, H. (Helen), Eason, J. (Jacqueline), Houghton, C. (Catherine), Barwell, J. (Julian), Side, L. (Lucy), McCann, E. (Emma), Murray, A. (Alexandra), Peock, S. (Susan), Godwin, A.K. (Andrew), Schmutzler, R.K. (Rita), Rhiem, K. (Kerstin), Engel, C. (Christoph), Meindl, A. (Alfons), Ruehl, I. (Ina), Arnold, N. (Norbert), Niederacher, D. (Dieter), Sutter, C. (Christian), Deissler, H. (Helmut), Gadzicki, D. (Dorothea), Kast, K. (Karin), Preisler-Adams, S. (Sabine), Varon-Mateeva, R. (Raymonda), Schoenbuchner, I. (Ines), Fiebig, B. (Britta), Heinritz, W. (Wolfram), Schäfer, D. (Dieter), Gevensleben, H. (Heidrun), Caux-Moncoutier, V. (Virginie), Fassy-Colcombet, M. (Marion), Cornelis, F. (Franco̧is), Mazoyer, S. (Sylvie), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Hardouin, A. (Agnès), Berthet, P. (Pascaline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Mortemousque, I. (Isabelle), Pujol, P. (Pascal), Coupier, I. (Isabelle), Lebrun, M. (Marine), Kientz, C. (Caroline), Longy, M. (Michel), Sevenet, N. (Nicolas), Stoppa-Lyonnet, D. (Dominique), Isaacs, C. (Claudine), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Barkardottir, R.B. (Rosa), Soucy, P. (Penny), Dumont, M. (Martine), Simard, J. (Jacques), Montagna, M. (Marco), Tognazzo, S. (Silvia), D'Andrea, E. (Emma), Fox, S.B. (Stephen), Yan, M. (Max), Rebbeck, R. (Timothy), Olopade, O.I. (Olofunmilayo), Weitzel, J.N. (Jeffrey), Lynch, H. (Henry), Ganz, P.A. (Patricia), Tomlinson, G. (Gail), Wang, X. (Xing), Fredericksen, Z. (Zachary), Pankratz, V.S. (Shane), Lindor, N.M. (Noralane), Szabo, C. (Csilla), Offit, K. (Kenneth), Sakr, R. (Rita), Gaudet, M.M. (Mia), Bhatia, K.P. (Kailash), Kauff, N. (Noah), Singer, C.F. (Christian), Tea, M.-K., Gschwantler-Kaulich, D. (Daphne), Fink-Retter, A. (Anneliese), Mai, P.L. (Phuong), Greene, M.H. (Mark), Imyanitov, E.N. (Evgeny), O'Malley, F.P. (Frances), Ozcelik, H. (Hilmi), Glendon, G. (Gord), Toland, A.E. (Amanda), Gerdes, A-M. (Anne-Marie), Thomassen, M. (Mads), Kruse, T.A. (Torben), Jensen, U.B., Skytte, A.-B. (Anne-Bine), Caligo, M.A. (Maria), Soller, M. (Maria), Henriksson, K. (Karin), Wachenfeldt, A. (Anna) von, Arver, B. (Brita Wasteson), Stenmark-Askmalm, M. (M.), Karlsson, P. (Per), Ding, Y.C. (Yuan), Neuhausen, S.L. (Susan), Beattie, M.S. (Mary), Pharoah, P.D.P. (Paul), Moysich, K.B. (Kirsten), Nathanson, K.L. (Katherine), Karlan, B.Y. (Beth), Gross, J. (Jenny), John, E.M. (Esther), Daly, M.B. (Mary), Buys, S.S. (Saundra), Southey, M.C. (Melissa), Hopper, J.L. (John), Terry, M.-B. (Mary-Beth), Chung, W. (Wendy), Miron, A. (Alexander), Goldgar, D. (David), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Andrulis, I.L. (Irene), and Antoniou, A.C. (Antonis)
Abstract: Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models
Published: 2011
Full Text: View/download PDF

20. Diagnostic moléculaire du rétinoblastome dans une série de 192 patients

Author: Houdayer, C, primary, Gauthier-Villars, M, additional, Dehainault, C, additional, Pagès-Berhouet, S, additional, Laugé, A, additional, Caux-Moncoutier, V, additional, Karczynski, P, additional, Tosi, M, additional, Doz, F, additional, Desjardins, L, additional, Couturier, J, additional, and Stoppa-Lyonnet, D, additional
Published: 2004
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21. Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF

Author: Houdayer, C., primary, Gauthier‐Villars, M., additional, Laugé, A., additional, Pagès‐Berhouet, S., additional, Dehainault, C., additional, Caux‐Moncoutier, V., additional, Karczynski, P., additional, Tosi, M., additional, Doz, F., additional, Desjardins, L., additional, Couturier, J., additional, and Stoppa‐Lyonnet, D., additional
Published: 2004
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22. Mutation screening of the RB1 gene in 192 retinoblastoma patients.

Author: Houdayer, C., Gauthier-Villars, M., Dehainault, C., Pagès-Berhouet, S., Laugé, A., Caux-Moncoutier, V., Karczynski, P., Tosi, M., Doz, F., Desjardins, L., Couturier, J., and Stoppa-Lyonnet, D.
Abstract: Copyright of IBS, Immuno-analyse & Biologie Specialisee is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Published: 2004
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23. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Breast Cancer Family Registry, the, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE Study, the, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Steinemann, Doris, Bogdanova-Markov, Nadja, Kast, Karin, Varon-Mateeva, Raymonda, Wang-Gohrke, Shan, Gehrig, Andrea, Markiefka, Birgid, Buecher, Bruno, Lefol, Cédrick, Stoppa-Lyonnet, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, GEMO Study Collaborators, the, Barjhoux, Laure, Faivre, Laurence, Longy, Michel, Sevenet, Nicolas, Sinilnikova, Olga M, Mazoyer, Sylvie, Bonadona, Valérie, Caux-Moncoutier, Virginie, Isaacs, Claudine, Van Maerken, Tom, Claes, Kathleen, Piedmonte, Marion, Andrews, Lesley, Hays, John, Rodriguez, Gustavo C, Caldes, Trinidad, de la Hoya, Miguel, Khan, Sofia, Hogervorst, Frans BL, Aalfs, Cora M, de Lange, JL, Meijers-Heijboer, Hanne EJ, van der Hout, Annemarie H, Wijnen, Juul T, van Roozendaal, KEP, Mensenkamp, Arjen R, van den Ouweland, Ans MW, van Deurzen, Carolien HM, van der Luijt, Rob B, HEBON, ., Olah, Edith, Diez, Orland, Lazaro, Conxi, Blanco, Ignacio, Teulé, Alex, Menendez, Mireia, Jakubowska, Anna, Lubinski, Jan, Cybulski, Cezary, Gronwald, Jacek, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Arason, Adalgeir, Maugard, Christine, Soucy, Penny, Montagna, Marco, Agata, Simona, Teixeira, Manuel R, KConFab Investigators, the, Olswold, Curtis, Lindor, Noralane, Pankratz, Vernon S, Hallberg, Emily, Wang, Xianshu, Szabo, Csilla I, Vijai, Joseph, Jacobs, Lauren, Corines, Marina, Lincoln, Anne, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F, Rappaport, Christine, Gschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Phelan, Catherine M, Mai, Phuong L, Greene, Mark H, Rennert, Gad, Imyanitov, Evgeny N, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Jensen, Uffe Birk, Caligo, Maria A, Friedman, Eitan, Berger, Raanan, Laitman, Yael, Rantala, Johanna, Arver, Brita, Loman, Niklas, Borg, Ake, Ehrencrona, Hans, Olopade, Olufunmilayo I, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Offit, Kenneth, Couch, Fergus J, Antoniou, Antonis C, CIMBA, on behalf of, Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Cancer Research, Receptor, ErbB-2, Genes, BRCA2, BRCA, LOCI, Genes, BRCA1, MODIFIERS, VARIANTS, ErbB-2, 610 Medical sciences Medicine, Ductal, Receptors, Medicine and Health Sciences, INVESTIGATORS, Breast, skin and connective tissue diseases, Progesterone, Medicine(all), Carcinoma, Ductal, Breast, Middle Aged, Adult, Aged, Alleles, Breast Neoplasms, Carcinoma, Carcinoma, Lobular, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Neoplasm Grading, Neoplasm Staging, Receptors, Estrogen, Receptors, Progesterone, Oncology, TUMOR SUBTYPES, Receptor, Research Article, MEDULLARY CARCINOMA, OVARIAN-CANCER, Lobular, GENOME-WIDE ASSOCIATION, CONSORTIUM, BRCA1, Estrogen, BRCA2, ESTROGEN-RECEPTOR, Genes
Abstract: Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P
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24. SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing.

Author: Leman R, Parfait B, Vidaud D, Girodon E, Pacot L, Le Gac G, Ka C, Ferec C, Fichou Y, Quesnelle C, Aucouturier C, Muller E, Vaur D, Castera L, Boulouard F, Ricou A, Tubeuf H, Soukarieh O, Gaildrat P, Riant F, Guillaud-Bataille M, Caputo SM, Caux-Moncoutier V, Boutry-Kryza N, Bonnet-Dorion F, Schultz I, Rossing M, Quenez O, Goldenberg L, Harter V, Parsons MT, Spurdle AB, Frébourg T, Martins A, Houdayer C, and Krieger S
Subjects: Humans, Bayes Theorem, Exons genetics, Machine Learning, Introns genetics, RNA Splicing genetics, RNA Splice Sites genetics
Abstract: Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5'/3' splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs. We gathered a curated set of 4616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. The Bayesian analysis provided us with the number of control variants, that is, variants without impact on splicing, to mimic the deluge of variants from high-throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, better than SpliceAI and SQUIRLS (0.965 and 0.766) for the same data set. SPiP lends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: https://sourceforge.net/projects/splicing-prediction-pipeline/., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Published: 2022
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25. Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System.

Author: Tubeuf H, Caputo SM, Sullivan T, Rondeaux J, Krieger S, Caux-Moncoutier V, Hauchard J, Castelain G, Fiévet A, Meulemans L, Révillion F, Léoné M, Boutry-Kryza N, Delnatte C, Guillaud-Bataille M, Cleveland L, Reid S, Southon E, Soukarieh O, Drouet A, Di Giacomo D, Vezain M, Bonnet-Dorion F, Bourdon V, Larbre H, Muller D, Pujol P, Vaz F, Audebert-Bellanger S, Colas C, Venat-Bouvet L, Solano AR, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Gaildrat P, Sharan SK, and Martins A
Subjects: Alternative Splicing, Animals, Exons, Female, Humans, Mice, Protein Isoforms, Breast Neoplasms genetics, Genes, BRCA2, Genetic Predisposition to Disease genetics, Ovarian Neoplasms genetics
Abstract: BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored BRCA2 exon 3 ( BRCA2 e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency. In silico predictions, minigene splicing assays, patients' RNA analyses, a mouse embryonic stem cell (mESC) complementation assay and retrieval of patient-related information were combined to determine the minimal requirement of FL BRCA2 transcripts. Of 100 BRCA2 e3 variants tested in the minigene assay, 64 were found to be spliceogenic, causing mild to severe RNA defects. Splicing defects were also confirmed in patients' RNA when available. Analysis of a neutral leaky variant (c.231T>G) showed that a reduction of approximately 60% of FL BRCA2 transcripts from a mutant allele does not cause any increase in cancer risk. Moreover, data obtained from mESCs suggest that variants causing a decline in FL BRCA2 with approximately 30% of wild-type are not pathogenic, given that mESCs are fully viable and resistant to DNA-damaging agents in those conditions. In contrast, mESCs producing lower relative amounts of FL BRCA2 exhibited either null or hypomorphic phenotypes. Overall, our findings are likely to have broader implications on the interpretation of BRCA2 variants affecting the splicing pattern of other essential exons. SIGNIFICANCE: These findings demonstrate that BRCA2 tumor suppressor function tolerates substantial reduction in full-length transcripts, helping to determine the pathogenicity of BRCA2 leaky splicing variants, some of which may not increase cancer risk., (©2020 American Association for Cancer Research.)
Published: 2020
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26. Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12.

Author: Meulemans L, Mesman RLS, Caputo SM, Krieger S, Guillaud-Bataille M, Caux-Moncoutier V, Léone M, Boutry-Kryza N, Sokolowska J, Révillion F, Delnatte C, Tubeuf H, Soukarieh O, Bonnet-Dorion F, Guibert V, Bronner M, Bourdon V, Lizard S, Vilquin P, Privat M, Drouet A, Grout C, Calléja FMGR, Golmard L, Vrieling H, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Vreeswijk MPG, Martins A, and Gaildrat P
Subjects: Adult, Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Embryonic Stem Cells, Exons genetics, Female, Humans, Loss of Function Mutation, Male, Mice, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Recombinant Proteins genetics, Alternative Splicing, BRCA2 Protein genetics, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome genetics
Abstract: Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced BRCA2 exon 12 (E12) as a model system because its in-frame skipping leads to a potentially functional protein. All E12 variants corresponding to putative LoF variants or predicted to alter splicing ( n = 40) were selected from human variation databases and characterized for their impact on splicing in minigene assays and, when available, in patient lymphoblastoid cell lines. Moreover, a selection of variants was analyzed in a mouse embryonic stem cell-based functional assay. Using these complementary approaches, we demonstrate that a subset of variants, including nonsense variants, induced in-frame E12 skipping through the modification of splice sites or regulatory elements and, consequently, led to an internally deleted but partially functional protein. These data provide evidence, for the first time in a cancer-predisposition gene, that certain presumed null variants can retain function due to their impact on splicing. Further studies are required to estimate cancer risk associated with these hypomorphic variants. More generally, our findings highlight the need to exercise caution in the interpretation of putative LoF variants susceptible to induce in-frame splicing modifications. SIGNIFICANCE: This study presents evidence that certain presumed loss-of-function variants in a cancer predisposition gene can retain function due to their direct impact on RNA splicing., (©2020 American Association for Cancer Research.)
Published: 2020
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27. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.

Author: Leman R, Gaildrat P, Le Gac G, Ka C, Fichou Y, Audrezet MP, Caux-Moncoutier V, Caputo SM, Boutry-Kryza N, Léone M, Mazoyer S, Bonnet-Dorion F, Sevenet N, Guillaud-Bataille M, Rouleau E, Bressac-de Paillerets B, Wappenschmidt B, Rossing M, Muller D, Bourdon V, Revillon F, Parsons MT, Rousselin A, Davy G, Castelain G, Castéra L, Sokolowska J, Coulet F, Delnatte C, Férec C, Spurdle AB, Martins A, Krieger S, and Houdayer C
Published: 2020
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28. Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants.

Author: Leman R, Tubeuf H, Raad S, Tournier I, Derambure C, Lanos R, Gaildrat P, Castelain G, Hauchard J, Killian A, Baert-Desurmont S, Legros A, Goardon N, Quesnelle C, Ricou A, Castera L, Vaur D, Le Gac G, Ka C, Fichou Y, Bonnet-Dorion F, Sevenet N, Guillaud-Bataille M, Boutry-Kryza N, Schultz I, Caux-Moncoutier V, Rossing M, Walker LC, Spurdle AB, Houdayer C, Martins A, and Krieger S
Subjects: Alternative Splicing, Computational Biology methods, Humans, Nucleotide Motifs, Position-Specific Scoring Matrices, RNA Processing, Post-Transcriptional, ROC Curve, Reproducibility of Results, Introns, RNA Precursors, RNA Splice Sites, RNA Splicing
Abstract: Background: Branch points (BPs) map within short motifs upstream of acceptor splice sites (3'ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3'ss., Results: We used a large set of constitutive and alternative human 3'ss collected from Ensembl (n = 264,787 3'ss) and from in-house RNAseq experiments (n = 51,986 3'ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3'ss (99.48 and 65.84% accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17%., Conclusions: Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3'ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area.
Published: 2020
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29. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Author: Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, Borg Å, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldés T, Caliebe A, Caligo MA, Calvello M, Capone GL, Caputo SM, Carnevali I, Carrasco E, Caux-Moncoutier V, Cavalli P, Cini G, Clarke EM, Concolino P, Cops EJ, Cortesi L, Couch FJ, Darder E, de la Hoya M, Dean M, Debatin I, Del Valle J, Delnatte C, Derive N, Diez O, Ditsch N, Domchek SM, Dutrannoy V, Eccles DM, Ehrencrona H, Enders U, Evans DG, Farra C, Faust U, Felbor U, Feroce I, Fine M, Foulkes WD, Galvao HCR, Gambino G, Gehrig A, Gensini F, Gerdes AM, Germani A, Giesecke J, Gismondi V, Gómez C, Gómez Garcia EB, González S, Grau E, Grill S, Gross E, Guerrieri-Gonzaga A, Guillaud-Bataille M, Gutiérrez-Enríquez S, Haaf T, Hackmann K, Hansen TVO, Harris M, Hauke J, Heinrich T, Hellebrand H, Herold KN, Honisch E, Horvath J, Houdayer C, Hübbel V, Iglesias S, Izquierdo A, James PA, Janssen LAM, Jeschke U, Kaulfuß S, Keupp K, Kiechle M, Kölbl A, Krieger S, Kruse TA, Kvist A, Lalloo F, Larsen M, Lattimore VL, Lautrup C, Ledig S, Leinert E, Lewis AL, Lim J, Loeffler M, López-Fernández A, Lucci-Cordisco E, Maass N, Manoukian S, Marabelli M, Matricardi L, Meindl A, Michelli RD, Moghadasi S, Moles-Fernández A, Montagna M, Montalban G, Monteiro AN, Montes E, Mori L, Moserle L, Müller CR, Mundhenke C, Naldi N, Nathanson KL, Navarro M, Nevanlinna H, Nichols CB, Niederacher D, Nielsen HR, Ong KR, Pachter N, Palmero EI, Papi L, Pedersen IS, Peissel B, Perez-Segura P, Pfeifer K, Pineda M, Pohl-Rescigno E, Poplawski NK, Porfirio B, Quante AS, Ramser J, Reis RM, Revillion F, Rhiem K, Riboli B, Ritter J, Rivera D, Rofes P, Rump A, Salinas M, Sánchez de Abajo AM, Schmidt G, Schoenwiese U, Seggewiß J, Solanes A, Steinemann D, Stiller M, Stoppa-Lyonnet D, Sullivan KJ, Susman R, Sutter C, Tavtigian SV, Teo SH, Teulé A, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tornero E, Törngren T, Torres-Esquius S, Toss A, Trainer AH, Tucker KM, van Asperen CJ, van Mackelenbergh MT, Varesco L, Vargas-Parra G, Varon R, Vega A, Velasco Á, Vesper AS, Viel A, Vreeswijk MPG, Wagner SA, Waha A, Walker LC, Walters RJ, Wang-Gohrke S, Weber BHF, Weichert W, Wieland K, Wiesmüller L, Witzel I, Wöckel A, Woodward ER, Zachariae S, Zampiga V, Zeder-Göß C, Lázaro C, De Nicolo A, Radice P, Engel C, Schmutzler RK, Goldgar DE, and Spurdle AB
Subjects: Alternative Splicing, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Male, Multifactorial Inheritance, Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Computational Biology methods, Mutation, Missense, Neoplasms diagnosis
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., (© 2019 Wiley Periodicals, Inc.)
Published: 2019
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30. Corrigendum: Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.

Author: Leman R, Gaildrat P, Gac GL, Ka C, Fichou Y, Audrezet MP, Caux-Moncoutier V, Caputo SM, Boutry-Kryza N, Léone M, Mazoyer S, Bonnet-Dorion F, Sevenet N, Guillaud-Bataille M, Rouleau E, Paillerets BB, Wappenschmidt B, Rossing M, Muller D, Bourdon V, Revillon F, Parsons MT, Rousselin A, Davy G, Castelain G, Castéra L, Sokolowska J, Coulet F, Delnatte C, Férec C, Spurdle AB, Martins A, Krieger S, and Houdayer C
Published: 2018
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31. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.

Author: Leman R, Gaildrat P, Le Gac G, Ka C, Fichou Y, Audrezet MP, Caux-Moncoutier V, Caputo SM, Boutry-Kryza N, Léone M, Mazoyer S, Bonnet-Dorion F, Sevenet N, Guillaud-Bataille M, Rouleau E, Bressac-de Paillerets B, Wappenschmidt B, Rossing M, Muller D, Bourdon V, Revillon F, Parsons MT, Rousselin A, Davy G, Castelain G, Castéra L, Sokolowska J, Coulet F, Delnatte C, Férec C, Spurdle AB, Martins A, Krieger S, and Houdayer C
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Female, Humans, International Cooperation, Internet, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Reproducibility of Results, Sensitivity and Specificity, Computational Biology methods, Computer Simulation, Genetic Variation, RNA Splice Sites genetics, RNA Splicing
Abstract: Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5' and 3' consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).
Published: 2018
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32. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Author: Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, and Simard J
Subjects: Breast Neoplasms ethnology, Breast Neoplasms metabolism, Female, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study methods, Heterozygote, Humans, Receptors, Estrogen metabolism, Risk Factors, White People genetics, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mutation, Polymorphism, Single Nucleotide
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017
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33. Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer.

Author: Davy G, Rousselin A, Goardon N, Castéra L, Harter V, Legros A, Muller E, Fouillet R, Brault B, Smirnova AS, Lemoine F, de la Grange P, Guillaud-Bataille M, Caux-Moncoutier V, Houdayer C, Bonnet F, Blanc-Fournier C, Gaildrat P, Frebourg T, Martins A, Vaur D, and Krieger S
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms diagnosis, Female, Genome, Human, Humans, Ovarian Neoplasms diagnosis, Alternative Splicing, Breast Neoplasms genetics, Genetic Testing methods, Ovarian Neoplasms genetics, Sequence Analysis, RNA methods
Abstract: Interpretation of variants of unknown significance (VUS) is a major challenge for laboratories performing molecular diagnosis of hereditary breast and ovarian cancer (HBOC), especially considering that many genes are now known to be involved in this syndrome. One important way these VUS can have a functional impact is through their effects on RNA splicing. Here we present a custom RNA-Seq assay plus bioinformatics and biostatistics pipeline to analyse specifically alternative and abnormal splicing junctions in 11 targeted HBOC genes. Our pipeline identified 14 new alternative splices in BRCA1 and BRCA2 in addition to detecting the majority of known alternative spliced transcripts therein. We provide here the first global splicing pattern analysis for the other nine genes, which will enable a comprehensive interpretation of splicing defects caused by VUS in HBOC. Previously known splicing alterations were consistently detected, occasionally with a more complex splicing pattern than expected. We also found that splicing in the 11 genes is similar in blood and breast tissue, supporting the utility and simplicity of blood splicing assays. Our pipeline is ready to be integrated into standard molecular diagnosis for HBOC, but it could equally be adapted for an integrative analysis of any multigene disorder.
Published: 2017
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34. Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas.

Author: Manié E, Popova T, Battistella A, Tarabeux J, Caux-Moncoutier V, Golmard L, Smith NK, Mueller CR, Mariani O, Sigal-Zafrani B, Dubois T, Vincent-Salomon A, Houdayer C, Stoppa-Lyonnet D, and Stern MH
Subjects: Breast Neoplasms pathology, Carcinoma pathology, Chromosome Breakage, Female, Genes, BRCA2, Humans, Oligonucleotide Array Sequence Analysis, Receptor, ErbB-2 genetics, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Carcinoma genetics, Recombinational DNA Repair genetics, Transcriptome genetics
Abstract: Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors., (© 2015 UICC.)
Published: 2016
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35. Loss of heterozygosity at 13q13 and 14q32 predicts BRCA2 inactivation in luminal breast carcinomas.

Author: Pécuchet N, Popova T, Manié E, Lucchesi C, Battistella A, Vincent-Salomon A, Caux-Moncoutier V, Bollet M, Sigal-Zafrani B, Sastre-Garau X, Stoppa-Lyonnet D, and Stern MH
Subjects: Breast Neoplasms pathology, Chromosome Aberrations, Female, Humans, Middle Aged, Mutation, Ploidies, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 14, Genes, BRCA2, Loss of Heterozygosity
Abstract: BRCA2 is the major high-penetrance predisposition gene for luminal (estrogen receptor [ER] positive) breast cancers. However, many BRCA2 mutant carriers lack family history of breast/ovarian cancers and do not benefit from genetic testing. Specific genomic features associated with BRCA2 inactivation in tumors could help identify patients for whom a genetic test for BRCA2 may be proposed. A series of ER-positive invasive ductal carcinomas (IDCs) including 30 carriers of BRCA2 mutations and 215 control cases was studied by single-nucleotide polymorphism (SNP) arrays. Cases and controls were stratified by grade and HER2 status. Independently, 7 BRCA2 and 51 control cases were used for validation. Absolute copy number and Loss of heterozygosity (LOH) profiles were obtained from SNP arrays by the genome alteration print (GAP) method. BRCA2 tumors were observed to display a discriminatively greater number of chromosomal breaks calculated after filtering out and smoothing <3 Mb variations. This argues for a BRCA2-associated genomic instability responsible for long-segment aberrations. Co-occurrence of two genomic features-LOH of 13q13 and 14q32-was found to predict BRCA2 status with 90% of sensitivity and 87% of specificity in discovery series of high-grade HER2-negative IDCs and 100% of sensitivity and 88% of specificity in an independent series of 58 IDCs. Estimated positive predictive value was 17.2% (confidence interval: 6.7-33.5) in the whole series. In conclusion, the simplified BRCA2 classifier based on the co-occurrence of LOH at 13q13 and 14q32 could provide an indication to test for BRCA2 mutation in patients with ER-positive IDC., (Copyright © 2013 UICC.)
Published: 2013
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36. Germline mutation in the RAD51B gene confers predisposition to breast cancer.

Author: Golmard L, Caux-Moncoutier V, Davy G, Al Ageeli E, Poirot B, Tirapo C, Michaux D, Barbaroux C, d'Enghien CD, Nicolas A, Castéra L, Sastre-Garau X, Stern MH, Houdayer C, and Stoppa-Lyonnet D
Subjects: Breast Neoplasms metabolism, DNA Mutational Analysis, DNA-Binding Proteins metabolism, Exons, Female, Hereditary Breast and Ovarian Cancer Syndrome genetics, Hereditary Breast and Ovarian Cancer Syndrome metabolism, Humans, Immunohistochemistry, Pedigree, RNA Splicing, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Germ-Line Mutation
Abstract: Background: Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition., Methods: The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis., Results: Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases., Conclusions: This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.
Published: 2013
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37. Germline BAP1 mutations predispose to renal cell carcinomas.

Author: Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manié E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, and Stern MH
Subjects: Adult, Base Sequence, Carcinoma, Renal Cell enzymology, Carcinoma, Renal Cell pathology, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Kidney Neoplasms enzymology, Kidney Neoplasms pathology, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Carcinoma, Renal Cell genetics, Germ-Line Mutation, Kidney Neoplasms genetics, Mutation, Missense, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics
Abstract: The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2013
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38. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author: Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, and Dunning AM
Subjects: Alternative Splicing, Breast Neoplasms pathology, Case-Control Studies, Chromatin genetics, DNA Methylation, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases metabolism, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms etiology, Genetic Loci genetics, Ovarian Neoplasms etiology, Polymorphism, Single Nucleotide genetics, Telomerase genetics, Telomere genetics
Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Published: 2013
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39. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.

Author: Popova T, Manié E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, Delattre O, Sigal-Zafrani B, Bollet M, Longy M, Houdayer C, Sastre-Garau X, Vincent-Salomon A, Stoppa-Lyonnet D, and Stern MH
Subjects: Adenocarcinoma genetics, Adenocarcinoma pathology, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Female, Fluorescent Antibody Technique, Humans, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Genes, BRCA1, Genes, BRCA2, Genetic Testing methods, Genomic Instability, Ploidies
Abstract: BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer., (©2012 AACR.)
Published: 2012
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40. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.

Author: Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Léone M, Mazoyer S, Muller D, Remenieras A, Révillion F, Rouleau E, Sokolowska J, Vert JP, Lidereau R, Soubrier F, Sobol H, Sevenet N, Bressac-de Paillerets B, Hardouin A, Tosi M, Sinilnikova OM, and Stoppa-Lyonnet D
Subjects: Exons genetics, Female, Humans, BRCA1 Protein genetics, BRCA2 Protein genetics, Pathology, Molecular methods, Pathology, Molecular standards, RNA Splicing genetics
Abstract: Assessing the impact of variants of unknown significance (VUS) on splicing is a key issue in molecular diagnosis. This impact can be predicted by in silico tools, but proper evaluation and user guidelines are lacking. To fill this gap, we embarked upon the largest BRCA1 and BRCA2 splice study to date by testing 272 VUSs (327 analyses) within the BRCA splice network of Unicancer. All these VUSs were analyzed by using six tools (splice site prediction by neural network, splice site finder (SSF), MaxEntScan (MES), ESE finder, relative enhancer and silencer classification by unanimous enrichment, and human splicing finder) and the predictions obtained were compared with transcript analysis results. Combining MES and SSF gave 96% sensitivity and 83% specificity for VUSs occurring in the vicinity of consensus splice sites, that is, the surrounding 11 and 14 bases for the 5' and 3' sites, respectively. This study was also an opportunity to define guidelines for transcript analysis along with a tentative classification of splice variants. The guidelines drawn from this large series should be useful for the whole community, particularly in the context of growing sequencing capacities that require robust pipelines for variant interpretation., (© 2012 Wiley Periodicals, Inc.)
Published: 2012
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41. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Author: Ramus SJ, Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, McGuffog L, Sinilnikova OM, Healey S, Barrowdale D, Lee A, Thomassen M, Gerdes AM, Kruse TA, Jensen UB, Skytte AB, Caligo MA, Liljegren A, Lindblom A, Olsson H, Kristoffersson U, Stenmark-Askmalm M, Melin B, Domchek SM, Nathanson KL, Rebbeck TR, Jakubowska A, Lubinski J, Jaworska K, Durda K, Złowocka E, Gronwald J, Huzarski T, Byrski T, Cybulski C, Toloczko-Grabarek A, Osorio A, Benitez J, Duran M, Tejada MI, Hamann U, Rookus M, van Leeuwen FE, Aalfs CM, Meijers-Heijboer HE, van Asperen CJ, van Roozendaal KE, Hoogerbrugge N, Collée JM, Kriege M, van der Luijt RB, Peock S, Frost D, Ellis SD, Platte R, Fineberg E, Evans DG, Lalloo F, Jacobs C, Eeles R, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Paterson J, Douglas F, Brewer C, Hodgson S, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Pathak H, Godwin AK, Stoppa-Lyonnet D, Caux-Moncoutier V, de Pauw A, Gauthier-Villars M, Mazoyer S, Léoné M, Calender A, Lasset C, Bonadona V, Hardouin A, Berthet P, Bignon YJ, Uhrhammer N, Faivre L, Loustalot C, Buys S, Daly M, Miron A, Terry MB, Chung WK, John EM, Southey M, Goldgar D, Singer CF, Tea MK, Pfeiler G, Fink-Retter A, Hansen Tv, Ejlertsen B, Johannsson OT, Offit K, Kirchhoff T, Gaudet MM, Vijai J, Robson M, Piedmonte M, Phillips KA, Van Le L, Hoffman JS, Ewart Toland A, Montagna M, Tognazzo S, Imyanitov E, Issacs C, Janavicius R, Lazaro C, Blanco I, Tornero E, Navarro M, Moysich KB, Karlan BY, Gross J, Olah E, Vaszko T, Teo SH, Ganz PA, Beattie MS, Dorfling CM, van Rensburg EJ, Diez O, Kwong A, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Ditsch N, Arnold N, Heidemann S, Niederacher D, Preisler-Adams S, Gadzicki D, Varon-Mateeva R, Deissler H, Gehrig A, Sutter C, Kast K, Fiebig B, Schäfer D, Caldes T, de la Hoya M, Nevanlinna H, Aittomäki K, Plante M, Spurdle AB, Neuhausen SL, Ding YC, Wang X, Lindor N, Fredericksen Z, Pankratz VS, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Bonanni B, Bernard L, Dolcetti R, Papi L, Ottini L, Radice P, Greene MH, Mai PL, Andrulis IL, Glendon G, Ozcelik H, Pharoah PD, Gayther SA, Simard J, Easton DF, Couch FJ, and Chenevix-Trench G
Subjects: Adult, Cohort Studies, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Odds Ratio, Retrospective Studies, BRCA1 Protein genetics, BRCA2 Protein genetics, Mutation, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., (© 2012 Wiley Periodicals, Inc.)
Published: 2012
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42. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients.

Author: Caux-Moncoutier V, Castéra L, Tirapo C, Michaux D, Rémon MA, Laugé A, Rouleau E, De Pauw A, Buecher B, Gauthier-Villars M, Viovy JL, Stoppa-Lyonnet D, and Houdayer C
Subjects: BRCA1 Protein analysis, BRCA2 Protein analysis, Breast Neoplasms genetics, Chromosome Aberrations, Cost-Benefit Analysis, DNA Mutational Analysis economics, DNA, Recombinant, Electrophoresis, Capillary, Female, Frameshift Mutation, High-Throughput Screening Assays methods, Humans, Mutation, Missense, Ovarian Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, DNA Mutational Analysis methods, Genes, BRCA1, Genes, BRCA2, Genetic Testing methods, Point Mutation
Abstract: The detection of unknown mutations remains a serious challenge and, despite the expected benefits for the patient's health, a large number of genes are not screened on a routine basis. We present the diagnostic application of EMMA (Enhanced Mismatch Mutation Analysis(®) , Fluigent, Paris, France), a novel method based on heteroduplex analysis by capillary electrophoresis using innovative matrices. BRCA1 and BRCA2 were screened for point mutations and large rearrangements in 1,525 unrelated patients (372 for the validation step and 1,153 in routine diagnosis) using a single analytical condition. Seven working days were needed for complete BRCA1/2 screening in 30 patients by one technician (excluding DNA extraction and sequencing). A total of 137 mutations were found, including a BRCA2 duplication of exons 19 and 20, previously missed by Comprehensive BRACAnalysis(®) . The mutation detection rate was 11.9%, which is consistent with patient inclusions. This study therefore suggests that EMMA represents a valuable short-term and midterm option for many diagnostic laboratories looking for an easy, reliable, and affordable strategy, enabling fast and sensitive analysis for a large number of genes., (© 2011 Wiley-Liss, Inc.)
Published: 2011
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43. Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study.

Author: Caux-Moncoutier V, Pagès-Berhouet S, Michaux D, Asselain B, Castéra L, De Pauw A, Buecher B, Gauthier-Villars M, Stoppa-Lyonnet D, and Houdayer C
Subjects: Female, Humans, Mutation, Regulatory Elements, Transcriptional, Allelic Imbalance, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Ovarian Neoplasms genetics, RNA Splicing
Abstract: Nearly one-half of BRCA1 and BRCA2 sequence variations are variants of uncertain significance (VUSs) and are candidates for splice alterations for example, by disrupting/creating splice sites. As out-of-frame splicing defects lead to a marked reduction of the level of the mutant mRNA cleared through nonsense-mediated mRNA decay, a cDNA-based test was developed to show the resulting allelic imbalance (AI). Fifty-four VUSs identified in 53 hereditary breast/ovarian cancer (HBOC) patients without BRCA1/2 mutation were included in the study. Two frequent exonic single-nucleotide polymorphisms on both BRCA1 and BRCA2 were investigated by using a semiquantitative single-nucleotide primer extension approach and the cDNA allelic ratios obtained were corrected using genomic DNA ratios from the same sample. A total of five samples showed AI. Subsequent transcript analyses ruled out the implication of VUS on AI and identified a deletion encompassing BRCA2 exons 12 and 13 in one sample. No sequence abnormality was found in the remaining four samples, suggesting implication of cis- or trans-acting factors in allelic expression regulation that might be disease causative in these HBOC patients. Overall, this study showed that AI screening is a simple way to detect deleterious splicing defects and that a major role for VUSs and deep intronic mutations in splicing anomalies is unlikely in BRCA1/2 genes. Methods to analyze gene expression and identify regulatory elements in BRCA1/2 are now needed to complement standard approaches to mutational analysis.
Published: 2009
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44. Evaluation of in silico splice tools for decision-making in molecular diagnosis.

Author: Houdayer C, Dehainault C, Mattler C, Michaux D, Caux-Moncoutier V, Pagès-Berhouet S, d'Enghien CD, Laugé A, Castera L, Gauthier-Villars M, and Stoppa-Lyonnet D
Subjects: Decision Making, Humans, Retinoblastoma Protein genetics, Algorithms, Diagnosis, Computer-Assisted, Molecular Diagnostic Techniques, RNA Splice Sites
Abstract: It appears that all types of genomic nucleotide variations can be deleterious by affecting normal pre-mRNA splicing via disruption/creation of splice site consensus sequences. As it is neither pertinent nor realistic to perform functional testing for all of these variants, it is important to identify those that could lead to a splice defect in order to restrict transcript analyses to the most appropriate cases. Web-based tools designed to provide such predictions are available. We evaluated the performance of six of these tools (Splice Site Prediction by Neural Network [NNSplice], Splice-Site Finder [SSF], MaxEntScan [MES], Automated Splice-Site Analyses [ASSA], Exonic Splicing Enhancer [ESE] Finder, and Relative Enhancer and Silencer Classification by Unanimous Enrichment [RESCUE]-ESE) using 39 unrelated retinoblastoma patients carrying different RB1 variants (31 intronic and eight exonic). These 39 patients were screened for abnormal splicing using puromycin-treated cell lines and the results were compared to the predictions. As expected, 17 variants impacting canonical AG/GT splice sites were correctly predicted as deleterious. A total of 22 variations occurring at loosely defined positions (+/-60 nucleotides from an AG/GT site) led to a splice defect in 19 cases and 16 of them were classified as deleterious by at least one tool (84% sensitivity). In other words, three variants escaped in silico detection and the remaining three were correctly predicted as neutral. Overall our results suggest that a combination of complementary in silico tools is necessary to guide molecular geneticists (balance between the time and cost required by RNA analysis and the risk of missing a deleterious mutation) because the weaknesses of one in silico tool may be overcome by the results of another tool.
Published: 2008
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45. A deep intronic mutation in the RB1 gene leads to intronic sequence exonisation.

Author: Dehainault C, Michaux D, Pagès-Berhouet S, Caux-Moncoutier V, Doz F, Desjardins L, Couturier J, Parent P, Stoppa-Lyonnet D, Gauthier-Villars M, and Houdayer C
Subjects: Amino Acid Sequence, Child, Preschool, DNA Mutational Analysis, DNA, Complementary genetics, Humans, Male, Molecular Sequence Data, Polymorphism, Genetic, RNA Splice Sites genetics, RNA Splicing, Retinal Neoplasms genetics, Exons, Genes, Retinoblastoma, Introns genetics, Mutagenesis, Insertional, Mutation genetics, Retinoblastoma genetics, Retinoblastoma Protein genetics
Abstract: Familial forms of retinoblastoma, an embryonic neoplasm of retinal origin, are caused by constitutional mutations of the RB1 gene. In this paper, we describe a family with retinoblastoma affecting two brothers with no previous family history of cancer. Complete RB1 mutational screening including point mutation and large rearrangement screening failed to demonstrate any mutation. The whole coding sequence was therefore investigated at the cDNA level, demonstrating a 103 bp intronic insertion between exons 23 and 24, leading to subsequent frameshift and premature termination of translation. This intronic exonisation was caused by a deep intronic mutation in intron 23 generating a cryptic 3' splice site. This is the first report of a deep intronic mutation in RB1 and is a proof of concept that some undetected RB1 mutations should be investigated at the cDNA level, particularly in hereditary forms of retinoblastoma.
Published: 2007
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46. A high-throughput mutation detection method based on heteroduplex analysis using graft copolymer matrixes: application to Brca1 and Brca2 analysis.

Author: Weber J, Barbier V, Pages-Berhouet S, Caux-Moncoutier V, Stoppa-Lyonnet D, and Viovy JL
Subjects: Base Sequence, DNA blood, DNA genetics, DNA Primers, Electrophoresis, Capillary, Humans, Polymorphism, Single-Stranded Conformational, Sequence Deletion, Genes, BRCA1, Genes, BRCA2, Nucleic Acid Heteroduplexes analysis, Point Mutation
Abstract: We present here a new approach to electrophoretic heteroduplex analysis (EHDA) based on improved matrixes. EHDA is an appealing technique for the detection of unknown point mutations because of its simplicity and high throughput. We present here a new matrix for electrophoretic heteroduplex analysis much more sensitive for insertions, deletions, and substitutions than reported for previous EHDA separations and also superior to DHPLC. This separation matrix is based on a copolymer with a comb architecture, poly(acrylamide-g-polydimethylacrylamide), made of a high molecular weight polyacrylamide backbone grafted with poly(dimethylacrylamide) side chains. The effect of operational parameters on electrophoretic resolution and sensitivity to single-nucleotide mismatches was studied using a collection of samples from patients bearing mutations in the breast cancer predisposition genes BRCA1 and BRCA2. Seventeen fragments (10 mutations), implying mostly substitutions on fragments with sizes ranging from 200 to 600 bp, were analyzed using a single set of separation conditions. A success rate of 94% was achieved with a qualitative analysis in terms of number of peaks, and 100% identification of mutations was obtained with a more quantitative test using peak width analysis. This strong improvement of performance with regard to previous HDA methods is attributed to a composite mechanism of separation, combining steric and chromatographic effects. It opens the route to a significant reduction of development time and operation cost for diagnostic and genomic applications.
Published: 2004
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47. Fidelity of DNA double-strand break repair in heterozygous cell lines harbouring BRCA1 missense mutations.

Author: Coupier I, Baldeyron C, Rousseau A, Mosseri V, Pages-Berhouet S, Caux-Moncoutier V, Papadopoulo D, and Stoppa-Lyonnet D
Subjects: Cell Line, Humans, DNA Damage, DNA Repair, Genes, BRCA1, Heterozygote, Mutation, Missense
Abstract: Germ-line mutations of the BRCA1 and BRCA2 genes, when they lead to a truncated protein, confer a high risk of breast and ovarian cancer. However, the role of BRCA1 missense mutations in cancer predisposition is unclear. Functional assays may be very helpful to more clearly define the biological effect of these mutations, and could therefore be useful in clinical practice. A recent study using a Host Cell End-Joining assay showed that a truncating mutation results in impaired fidelity of DSB repair by DNA end-joining. In the present study, we examined the fidelity of DSB repair in four lymphoblastoid cell lines with BRCA1 missense mutations. The fidelity of DNA end-joining was impaired in the four cell lines studied compared to the normal control cell line. The fidelity of end-joining was similar to that of a truncated mutation control cell line for one cell line and slightly higher for the other cell lines.
Published: 2004
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48. Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families.

Author: Gad S, Caux-Moncoutier V, Pagès-Berhouet S, Gauthier-Villars M, Coupier I, Pujol P, Frénay M, Gilbert B, Maugard C, Bignon YJ, Chevrier A, Rossi A, Fricker JP, Nguyen TD, Demange L, Aurias A, Bensimon A, and Stoppa-Lyonnet D
Subjects: Adult, Female, Genes, BRCA2, Humans, Middle Aged, Point Mutation, Polymerase Chain Reaction, Breast Neoplasms genetics, Gene Rearrangement, Genes, BRCA1, Ovarian Neoplasms genetics
Abstract: Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8-13, a 17.2 kb duplication of exons 3-8 and a 8.6 kb duplication of exons 18-20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.
Published: 2002
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49. Identification of a large rearrangement of the BRCA1 gene using colour bar code on combed DNA in an American breast/ovarian cancer family previously studied by direct sequencing.

Author: Gad S, Scheuner MT, Pages-Berhouet S, Caux-Moncoutier V, Bensimon A, Aurias A, Pinto M, and Stoppa-Lyonnet D
Subjects: Adult, Color, DNA, Neoplasm analysis, Family Health, Female, Humans, Middle Aged, Pedigree, RNA, Neoplasm analysis, Sequence Deletion, United States, Breast Neoplasms genetics, DNA Mutational Analysis methods, Gene Rearrangement, Genes, BRCA1, Ovarian Neoplasms genetics
Published: 2001
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