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1. Genetic analysis of subsequent second primary malignant neoplasms in long-term pancreatic cancer survivors suggests new potential hereditary genetic alterations

Author

Lovecek M, Janatova M, Skalicky P, Zemanek T, Havlik R, Ehrmann J, Strouhal O, Zemankova P, Lhotova K, Borecka M, Soukupova J, Svebisova H, Soucek P, Hlavac V, Kleibl Z, Neoral C, Melichar B, and Mohelnikova-Duchonova B

Subjects
pancreatic ductal adenocarcinoma, second primary neoplasms, subsequent malignant neoplasm, hereditary cancer genes, long-term survivors, surgical treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Martin Lovecek,1,* Marketa Janatova,2,* Pavel Skalicky,1 Tomas Zemanek,3 Roman Havlik,1 Jiri Ehrmann,4 Ondrej Strouhal,3 Petra Zemankova,2 Klara Lhotova,2 Marianna Borecka,2 Jana Soukupova,2 Hana Svebisova,3 Pavel Soucek,5 Viktor Hlavac,5 Zdenek Kleibl,2 Cestmir Neoral,1 Bohuslav Melichar,3 Beatrice Mohelnikova-Duchonova3 1Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic; 2Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic; 3Department of Oncology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; 4Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic; 5Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen Czech Republic *These authors contributed equally to this work Background: The principal aim of this report was to study second primary malignant neoplasms (SMNs) in long-term survivors of pancreatic ductal adenocarcinoma (PDAC) with regard to the germline genetic background.Patients and methods: A total of 118 PDAC patients after a curative-intent surgery who were treated between 2006 and 2011 were analyzed. Of the 22 patients surviving for >5 years, six went on to develop SMNs. A genetic analysis of 219 hereditary cancer-predisposition and candidate genes was performed by targeted next-generation sequencing in germline DNA from 20 of these patients.Results: Of all the radically resected PDAC patients, six patients went on to subsequently develop SMNs, which accounted for 27% of the long-term survivors. The median time to diagnosis of SMNs, which included two cases of rectal cancer, and one case each of prostate cancer, malignant melanoma, breast cancer, and urinary bladder cancer, was 52.5 months. At the time of analysis, none of these patients had died as a result of PDAC progression. We identified four carriers of germline pathogenic mutations in 20 analyzed long-term survivors. One carrier of the CHEK2 mutation was found among four analyzed patients who developed SMNs. Of the remaining 16 long-term PDAC survivors, 3 patients (19%) carried germline mutation(s) in the MLH1+ ATM, CHEK2, and RAD51D gene, respectively.Conclusion: This retrospective analysis indicates that SMNs in PDAC survivors are an important clinical problem and may be more common than has been acknowledged to be the case. In patients with good performance status, surgical therapy should be considered, as the SMNs often have a favorable prognosis. Keywords: pancreatic ductal adenocarcinoma, second primary neoplasms, subsequent malignant neoplasm, hereditary cancer genes, long-term survivors, surgical treatment

Published
2019

5. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author

O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, Lesueur, F, O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, and Lesueur, F

Abstract

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Published
2023

8. The spectrum of fancm protein truncating variants in European breast cancer cases.

Author

Torngren T., Teixeira M., Toss A., Urioste M., Vega A., Vlckova Z., Yannoukakos D., Zampiga V., Kleibl Z., Radice P., Nevanlinna H., Ehrencrona H., Janavicius R., Peterlongo P., Figlioli G., Kvist A., Tham E., Soukupova J., Kleiblova P., Muranen T.A., Andrieu N., Azzollini J., Balmana J., Barroso A., Benitez J., Bertelsen B., Blanco A., Bonanni B., Borg A., Brunet J., Calistri D., Calvello M., Chvojka S., Cortesi L., Darder E., Del Valle J., Diez O., Eon-Marchais S., Fostira F., Gensini F., Houdayer C., Janatova M., Kiiski J.I., Konstantopoulou I., Kubelka-Sabit K., Lazaro C., Lesueur F., Manoukian S., Marcinkute R., Mickys U., Moncoutier V., Myszka A., Nguyen-Dumont T., Nielsen F.C., Norvilas R., Olah E., Osorio A., Papi L., Peissel B., Peixoto A., Plaseska-Karanfilska D., Pocza T., Rossing M., Rudaitis V., Santamarina M., Santos C., Smichkoska S., Southey M.C., Stoppa-Lyonnet D., Torngren T., Teixeira M., Toss A., Urioste M., Vega A., Vlckova Z., Yannoukakos D., Zampiga V., Kleibl Z., Radice P., Nevanlinna H., Ehrencrona H., Janavicius R., Peterlongo P., Figlioli G., Kvist A., Tham E., Soukupova J., Kleiblova P., Muranen T.A., Andrieu N., Azzollini J., Balmana J., Barroso A., Benitez J., Bertelsen B., Blanco A., Bonanni B., Borg A., Brunet J., Calistri D., Calvello M., Chvojka S., Cortesi L., Darder E., Del Valle J., Diez O., Eon-Marchais S., Fostira F., Gensini F., Houdayer C., Janatova M., Kiiski J.I., Konstantopoulou I., Kubelka-Sabit K., Lazaro C., Lesueur F., Manoukian S., Marcinkute R., Mickys U., Moncoutier V., Myszka A., Nguyen-Dumont T., Nielsen F.C., Norvilas R., Olah E., Osorio A., Papi L., Peissel B., Peixoto A., Plaseska-Karanfilska D., Pocza T., Rossing M., Rudaitis V., Santamarina M., Santos C., Smichkoska S., Southey M.C., and Stoppa-Lyonnet D.

Abstract

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.Copyright © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2020

9. Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families.

Author

Hake C., Redman J., Kleibl Z., Kleiblova P., Konstantopoulou I., Kvist A., Laduca H., Lee A.S.G., Lesueur F., Maher E.R., Mannermaa A., Manoukian S., McFarland R., McKinnon W., Meindl A., Metcalfe K., Taib N.A.M., Moilanen J., Nathanson K.L., Neuhausen S., Ng P.S., Nguyen-Dumont T., Nielsen S.M., Obermair F., Offit K., Olopade O.I., Ottini L., Penkert J., Pylkas K., Radice P., Ramus S.J., Rudaitis V., Side L., Silva-Smith R., Silvestri V., Skytte A.-B., Slavin T., Soukupova J., Tondini C., Trainer A.H., Unzeitig G., Usha L., Van Overeem Hansen T., Whitworth J., Wood M., Yip C.H., Yoon S.-Y., Yussuf A., Zogopoulos G., Goldgar D., Hopper J.L., Chenevix-Trench G., Pharoah P., George S.H.L., Balmana J., Houdayer C., James P., El-Haffaf Z., Ehrencrona H., Janatova M., Peterlongo P., Nevanlinna H., Schmutzler R., Teo S.-H., Robson M., Pal T., Couch F., Weitzel J.N., Elliott A., Southey M., Winqvist R., Easton D.F., Foulkes W.D., Antoniou A.C., Tischkowitz M., Yang X., Leslie G., Doroszuk A., Schneider S., Allen J., Decker B., Dunning A.M., Scarth J., Plaskocinska I., Luccarini C., Shah M., Pooley K., Dorling L., Leei A., Adank M.A., Adlard J., Aittomaki K., Andrulis I.L., Ang P., Barwell J., Bernstein J.L., Bobolis K., Borg A., Blomqvist C., Claes K.B.M., Concannon P., Cuggia A., Culver J.O., Damiola F., De Pauw A., Diez O., Dolinsky J.S., Domchek S.M., Engel C., Evans D.G., Fostira F., Garber J., Golmard L., Goode E.L., Gruber S.B., Hahnen E., Heikkinen T., Hurley J.E., Janavicius R., Hake C., Redman J., Kleibl Z., Kleiblova P., Konstantopoulou I., Kvist A., Laduca H., Lee A.S.G., Lesueur F., Maher E.R., Mannermaa A., Manoukian S., McFarland R., McKinnon W., Meindl A., Metcalfe K., Taib N.A.M., Moilanen J., Nathanson K.L., Neuhausen S., Ng P.S., Nguyen-Dumont T., Nielsen S.M., Obermair F., Offit K., Olopade O.I., Ottini L., Penkert J., Pylkas K., Radice P., Ramus S.J., Rudaitis V., Side L., Silva-Smith R., Silvestri V., Skytte A.-B., Slavin T., Soukupova J., Tondini C., Trainer A.H., Unzeitig G., Usha L., Van Overeem Hansen T., Whitworth J., Wood M., Yip C.H., Yoon S.-Y., Yussuf A., Zogopoulos G., Goldgar D., Hopper J.L., Chenevix-Trench G., Pharoah P., George S.H.L., Balmana J., Houdayer C., James P., El-Haffaf Z., Ehrencrona H., Janatova M., Peterlongo P., Nevanlinna H., Schmutzler R., Teo S.-H., Robson M., Pal T., Couch F., Weitzel J.N., Elliott A., Southey M., Winqvist R., Easton D.F., Foulkes W.D., Antoniou A.C., Tischkowitz M., Yang X., Leslie G., Doroszuk A., Schneider S., Allen J., Decker B., Dunning A.M., Scarth J., Plaskocinska I., Luccarini C., Shah M., Pooley K., Dorling L., Leei A., Adank M.A., Adlard J., Aittomaki K., Andrulis I.L., Ang P., Barwell J., Bernstein J.L., Bobolis K., Borg A., Blomqvist C., Claes K.B.M., Concannon P., Cuggia A., Culver J.O., Damiola F., De Pauw A., Diez O., Dolinsky J.S., Domchek S.M., Engel C., Evans D.G., Fostira F., Garber J., Golmard L., Goode E.L., Gruber S.B., Hahnen E., Heikkinen T., Hurley J.E., and Janavicius R.

Abstract

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 x 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 x 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 x 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 x 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer ri

Published
2020

10. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Author

Yang, X, Leslie, G, Doroszuk, A, Schneider, S, Allen, J, Decker, B, Dunning, AM, Redman, J, Scarth, J, Plaskocinska, I, Luccarini, C, Shah, M, Pooley, K, Dorling, L, Lee, A, Adank, MA, Adlard, J, Aittomaki, K, Andrulis, IL, Ang, P, Barwell, J, Bernstein, JL, Bobolis, K, Borg, A, Blomqvist, C, Claes, KBM, Concannon, P, Cuggia, A, Culver, JO, Damiola, F, de Pauw, A, Diez, O, Dolinsky, JS, Domchek, SM, Engel, C, Evans, DG, Fostira, F, Garber, J, Golmard, L, Goode, EL, Gruber, SB, Hahnen, E, Hake, C, Heikkinen, T, Hurley, JE, Janavicius, R, Kleibl, Z, Kleiblova, P, Konstantopoulou, I, Kvist, A, Laduca, H, Lee, ASG, Lesueur, F, Maher, ER, Mannermaa, A, Manoukian, S, McFarland, R, McKinnon, W, Meindl, A, Metcalfe, K, Taib, NAM, Moilanen, J, Nathanson, KL, Neuhausen, S, Ng, PS, Nguyen-Dumont, T, Nielsen, SM, Obermair, F, Offit, K, Olopade, O, Ottini, L, Penkert, J, Pylkas, K, Radice, P, Ramus, SJ, Rudaitis, V, Side, L, Silva-Smith, R, Silvestri, V, Skytte, A-B, Slavin, T, Soukupova, J, Tondini, C, Trainer, AH, Unzeitig, G, Usha, L, Hansen, TVO, Whitworth, J, Wood, M, Yip, CH, Yoon, S-Y, Yussuf, A, Zogopoulos, G, Goldgar, D, Hopper, JL, Chenevix-Trench, G, Pharoah, P, George, SHL, Balmana, J, Houdayer, C, James, P, El-Haffaf, Z, Ehrencrona, H, Janatova, M, Peterlongo, P, Nevanlinna, H, Schmutzler, R, Teo, S-H, Robson, M, Pal, T, Couch, F, Weitzel, JN, Elliott, A, Southey, M, Winqvist, R, Easton, DF, Foulkes, WD, Antoniou, AC, Tischkowitz, M, Yang, X, Leslie, G, Doroszuk, A, Schneider, S, Allen, J, Decker, B, Dunning, AM, Redman, J, Scarth, J, Plaskocinska, I, Luccarini, C, Shah, M, Pooley, K, Dorling, L, Lee, A, Adank, MA, Adlard, J, Aittomaki, K, Andrulis, IL, Ang, P, Barwell, J, Bernstein, JL, Bobolis, K, Borg, A, Blomqvist, C, Claes, KBM, Concannon, P, Cuggia, A, Culver, JO, Damiola, F, de Pauw, A, Diez, O, Dolinsky, JS, Domchek, SM, Engel, C, Evans, DG, Fostira, F, Garber, J, Golmard, L, Goode, EL, Gruber, SB, Hahnen, E, Hake, C, Heikkinen, T, Hurley, JE, Janavicius, R, Kleibl, Z, Kleiblova, P, Konstantopoulou, I, Kvist, A, Laduca, H, Lee, ASG, Lesueur, F, Maher, ER, Mannermaa, A, Manoukian, S, McFarland, R, McKinnon, W, Meindl, A, Metcalfe, K, Taib, NAM, Moilanen, J, Nathanson, KL, Neuhausen, S, Ng, PS, Nguyen-Dumont, T, Nielsen, SM, Obermair, F, Offit, K, Olopade, O, Ottini, L, Penkert, J, Pylkas, K, Radice, P, Ramus, SJ, Rudaitis, V, Side, L, Silva-Smith, R, Silvestri, V, Skytte, A-B, Slavin, T, Soukupova, J, Tondini, C, Trainer, AH, Unzeitig, G, Usha, L, Hansen, TVO, Whitworth, J, Wood, M, Yip, CH, Yoon, S-Y, Yussuf, A, Zogopoulos, G, Goldgar, D, Hopper, JL, Chenevix-Trench, G, Pharoah, P, George, SHL, Balmana, J, Houdayer, C, James, P, El-Haffaf, Z, Ehrencrona, H, Janatova, M, Peterlongo, P, Nevanlinna, H, Schmutzler, R, Teo, S-H, Robson, M, Pal, T, Couch, F, Weitzel, JN, Elliott, A, Southey, M, Winqvist, R, Easton, DF, Foulkes, WD, Antoniou, AC, and Tischkowitz, M

Abstract

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cance

Published
2020

11. The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Author

Figlioli, G, Kvist, A, Tham, E, Soukupova, J, Kleiblova, P, Muranen, TA, Andrieu, N, Azzollini, J, Balmana, J, Barroso, A, Benitez, J, Bertelsen, B, Blanco, A, Bonanni, B, Borg, A, Brunet, J, Calistri, D, Calvello, M, Chvojka, S, Cortesi, L, Darder, E, Del Valle, J, Diez, O, Eon-Marchais, S, Fostira, F, Gensini, F, Houdayer, C, Janatova, M, Kiiski, J, Konstantopoulou, I, Kubelka-Sabit, K, Lazaro, C, Lesueur, F, Manoukian, S, Marcinkute, R, Mickys, U, Moncoutier, V, Myszka, A, Tu, N-D, Nielsen, FC, Norvilas, R, Olah, E, Osorio, A, Papi, L, Peissel, B, Peixoto, A, Plaseska-Karanfilska, D, Pocza, T, Rossing, M, Rudaitis, V, Santamarina, M, Santos, C, Smichkoska, S, Southey, MC, Stoppa-Lyonnet, D, Teixeira, M, Torngren, T, Toss, A, Urioste, M, Vega, A, Vlckova, Z, Yannoukakos, D, Zampiga, V, Kleibl, Z, Radice, P, Nevanlinna, H, Ehrencrona, H, Janavicius, R, Peterlongo, P, Figlioli, G, Kvist, A, Tham, E, Soukupova, J, Kleiblova, P, Muranen, TA, Andrieu, N, Azzollini, J, Balmana, J, Barroso, A, Benitez, J, Bertelsen, B, Blanco, A, Bonanni, B, Borg, A, Brunet, J, Calistri, D, Calvello, M, Chvojka, S, Cortesi, L, Darder, E, Del Valle, J, Diez, O, Eon-Marchais, S, Fostira, F, Gensini, F, Houdayer, C, Janatova, M, Kiiski, J, Konstantopoulou, I, Kubelka-Sabit, K, Lazaro, C, Lesueur, F, Manoukian, S, Marcinkute, R, Mickys, U, Moncoutier, V, Myszka, A, Tu, N-D, Nielsen, FC, Norvilas, R, Olah, E, Osorio, A, Papi, L, Peissel, B, Peixoto, A, Plaseska-Karanfilska, D, Pocza, T, Rossing, M, Rudaitis, V, Santamarina, M, Santos, C, Smichkoska, S, Southey, MC, Stoppa-Lyonnet, D, Teixeira, M, Torngren, T, Toss, A, Urioste, M, Vega, A, Vlckova, Z, Yannoukakos, D, Zampiga, V, Kleibl, Z, Radice, P, Nevanlinna, H, Ehrencrona, H, Janavicius, R, and Peterlongo, P

Abstract

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

Published
2020

14. BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

Author

Burke, LJ, Sevcik, J, Gambino, G, Tudini, E, Mucaki, EJ, Shirley, BC, Whiley, P, Parsons, MT, De Leeneer, K, Gutierrez-Enriquez, S, Santamarina, M, Caputo, SM, dos Santos, ES, Soukupova, J, Janatova, M, Zemankova, P, Lhotova, K, Stolarova, L, Borecka, M, Moles-Fernandez, A, Manoukian, S, Bonanni, B, Edwards, SL, Blok, MJ, Hansen, TVO, Rossing, M, Diez, O, Vega, A, Claes, KBM, Goldgar, DE, Rouleau, E, Radice, P, Peterlongo, P, Rogan, PK, Caligo, M, Spurdle, AB, Brown, MA, Burke, LJ, Sevcik, J, Gambino, G, Tudini, E, Mucaki, EJ, Shirley, BC, Whiley, P, Parsons, MT, De Leeneer, K, Gutierrez-Enriquez, S, Santamarina, M, Caputo, SM, dos Santos, ES, Soukupova, J, Janatova, M, Zemankova, P, Lhotova, K, Stolarova, L, Borecka, M, Moles-Fernandez, A, Manoukian, S, Bonanni, B, Edwards, SL, Blok, MJ, Hansen, TVO, Rossing, M, Diez, O, Vega, A, Claes, KBM, Goldgar, DE, Rouleau, E, Radice, P, Peterlongo, P, Rogan, PK, Caligo, M, Spurdle, AB, and Brown, MA

Abstract

The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.

Published
2018

25. 42 THE EFFICACY OF LENALIDOMIDE IN LOWER RISK MYELODYSPLASTIC SYNDROME WITH ISOLATED 5Q DELETION IS DEPENDENT ON HIGH LEVEL OF FULL-LENGTH CEREBLON MESSENGER RNA

Author

Fuchs, O., primary, Polak, J., additional, Bokorova, R., additional, Vostry, M., additional, Kostecka, A., additional, Hajkova, H., additional, Neuwirtova, R., additional, Siskova, M., additional, Cermak, J., additional, Sponerova, D., additional, Lauermannova, M., additional, Soukupova, J., additional, Cervinek, L., additional, Brezinova, J., additional, Michalova, K., additional, and Jonasova, A., additional

Published
2015
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37. Hereditary truncating mutations of DNA repair and other genes in BRCA1/ BRCA2/ PALB2-negatively tested breast cancer patients.

Author

Lhota, F., Zemankova, P., Kleiblova, P., Soukupova, J., Vocka, M., Stranecky, V., Janatova, M., Hartmannova, H., Hodanova, K., Kmoch, S., and Kleibl, Z.

Subjects
DNA repair, BRCA genes, BREAST cancer patients, GENETIC testing, NUCLEOTIDE sequencing, FANCONI'S anemia, GENETICS
Abstract

Hereditary breast cancer comprises a minor but clinically meaningful breast cancer ( BC) subgroup. Mutations in the major BC-susceptibility genes are important prognostic and predictive markers; however, their carriers represent only 25% of high-risk BC patients. To further characterize variants influencing BC risk, we performed SOLiD sequencing of 581 genes in 325 BC patients (negatively tested in previous BRCA1/ BRCA2/ PALB2 analyses). In 105 (32%) patients, we identified and confirmed 127 truncating variants (89 unique; nonsense, frameshift indels, and splice site), 19 patients harbored more than one truncation. Forty-six (36 unique) truncating variants in 25 DNA repair genes were found in 41 (12%) patients, including 16 variants in the Fanconi anemia ( FA) genes. The most frequent variant in FA genes was c.1096_1099dupATTA in FANCL that also show a borderline association with increased BC risk in subsequent analysis of enlarged groups of BC patients and controls. Another 81 (53 unique) truncating variants were identified in 48 non- DNA repair genes in 74 patients (23%) including 16 patients carrying variants in genes coding proteins of estrogen metabolism/signaling. Our results highlight the importance of mutations in the FA genes' family, and indicate that estrogen metabolism genes may reveal a novel candidate genetic component for BC susceptibility. [ABSTRACT FROM AUTHOR]

Published
2016
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47. Glycoxidation and inflammation in chronic haemodialysis patients

Author

Kalousova, M., primary, Sulkova, S., additional, Fialova, L., additional, Soukupova, J., additional, Malbohan, I. M., additional, Spacek, P., additional, Braun, M., additional, Mikulikova, L., additional, Fortova, M., additional, Horejsi, M., additional, Tesar, V., additional, and Zima, T., additional

Published
2003
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49. Dementia and alzheimer's disease in the czech republic - what can be expected in the coming years?

Author

Benešová, K., Jarkovsky, J., Pokorná, A., and Soukupova, J.

Subjects
ALZHEIMER'S disease, HEALTH insurance companies, INPATIENT care, POISSON regression, CZECHS
Abstract

Introduction: Ageing of the population in the Czech Republic contributes to an increase of AD. Since the 2019, the data of national healthcare registries are combined with data of health insurance companies (NRRZS) and allows a comprehensive analysis of the AD and unconfirmed dementia from the period 2010-2018. Objectives: This study aims to describe the type, amount, and patterns of healthcare used by patients with AD and to make a prediction of prevalence that will help stakeholders to prepare effectivemeasures. Methods: Health characteristics of the population with AD were compared with a control population with comparable age and sex structure. The predictions were made using the Poisson regression; comorbidities were evaluated using the DCCI index. Results: Based on our data, 0.6% of the Czech population suffered from AD in 2018. Based on a prediction model, there will be 174,000 patients in 2030. Because the reported prevalence of AD in the Czech Republic is lower than in other Central European countries (see Fig. 1), AD is probably underdiagnosed. An average AD patient needs 1.3 times more outpatient and 2.1 times more inpatient care than non-AD patients. The geographical variance of healthcare demands is quite pronounced (see Fig. 2) and patients with AD suffer from more comorbidities (see Fig 3). Conclusions: The Alzheimer's disease presents a large burden for the healthcare system. The prevalence of AD grows significantly every year, and demographic trends will even enhance this phenomenon. Detailed data on AD patients are necessary for authorities to make efficient measures towards planning of healthcare. [ABSTRACT FROM AUTHOR]

Published
2020

50. National health information system as an efficient tool for mapping of the mental health care reform in the czech republic.

Author

Soukupova, J., Melicharová, H., Šanca, O., and Jarkovsky, J.

Subjects
*MENTAL health services, *HEALTH information systems, *GEOGRAPHICAL perception, *HEALTH insurance companies, *HEALTH care reform
Abstract

Introduction: The initial steps of the reform of mental health care in the Czech Republic have been done. Precise mapping of the process reorganisation of mental health care is essential for evaluation of its efficiency, definition of gaps and redistribution of the budget. Objectives: Assessment of changes of mental health care system over the past ten years using the data of National Health Information System (NZIS). Methods: NZIS has interconnected information on all Czech health service providers and professionalswith data reported by providers to health insurance companies (National Registry of Reimbursed Health Services - NRRHS). A combination of epidemiological and servicerelated information were grouped together with sociodemographic data, and mapping of geographical trends was used to track changes. Results: The analysis revealed that 650,000 patients was in contact with the healthcare system in 2018 due to psychiatric diagnoses and that this number increases mainly inr dementia (7-8% per year) and anxiety disorders (4-5%, Table 1). The number of outpatient consulting rooms has slightly increased over time: from 1,711 in 2010 to 1,843 in 2018 (Figure 1). However, a considerable inequality in the availability of consulting rooms was revealed with a significantly better situation in Prague (2,998 inhabitants per room) when compared to other regions (ranging from 5,453 to 8,401) in 2018 (Figure 2). Conclusions: Although the availability of mental health care has increased, there arelarge differences in availability among regions. Data from NHIS are the key tool for the mapping of mental health care and planning of the reform of mental health care. [ABSTRACT FROM AUTHOR]

Published
2020

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