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1. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Author

Burn, J., Gerdes, A.M., Macrae, F., Mecklin, J.P., Moeslein, G., Olschwang, S., Eccles, D., Evans, D.G., Maher, E.R., Bertario, L., Bisgaard, M.L., Dunlop, M.G., Ho, J.W.C., Hodgson, S.V., Lindblom, A., Lubinski, J., Morrison, P.J., Murday, V., Ramesar, R., Side, L., Scott, R.J., Thomas, H.J.W., Vasen, H.F., Barker, G., Crawford, G., Elliott, F., Movahedi, M., Pylvanainen, K., Wijnen, J.T., Fodde, R., Lynch, H.T., Mathers, J.C., Bishop, D.T., CAPP2 Investigators, and Pathology

Subjects
Adenoma, Heterozygote, medicine.medical_specialty, Colorectal cancer, Placebo, Chemoprevention, law.invention, Double-Blind Method, Randomized controlled trial, SDG 3 - Good Health and Well-being, law, Internal medicine, Adenoma - prevention and control, Dietary Carbohydrates, medicine, Humans, media_common.cataloged_instance, European union, media_common, Aspirin, Intention-to-treat analysis, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Cancer, Starch, General Medicine, Anti-Inflammatory Agents, Non-Steroidal - therapeutic use, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Surgery, Colorectal Neoplasms, Hereditary Nonpolyposis - genetics - prevention and control, Aspirin - therapeutic use, business, medicine.drug
Abstract

BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55.7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0.63 (95% CI 0.35-1.13, p=0.12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32-0.99, p=0.05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0.41 (0.19-0.86, p=0.02) and an IRR of 0.37 (0.18-0.78, p=0.008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma., link_to_OA_fulltext

Published
2011

2. Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Couch, F.J., Gaudet, M.M., Antoniou, A.C., Ramus, S.J., Kuchenbaecker, K.B., Soucy, P., Beesley, J., Chen, X.Q., Wang, X.S., Kirchhoff, T., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Sinilnikova, O.M., Andrulis, I.L., Ozcelik, H., Mulligan, A.M., Thomassen, M., Gerdes, A.M., Jensen, U.B., Skytte, A.B., Kruse, T.A., Caligo, M.A., Wachenfeldt, A. von, Barbany-Bustinza, G., Loman, N., Soller, M., Ehrencrona, H., Karlsson, P., Nathanson, K.L., Rebbeck, T.R., Domchek, S.M., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Huzarski, T., Byrski, T., Gronwald, J., Cybulski, C., Gorski, B., Osorio, A., Duran, M., Tejada, M.I., Benitez, J., Hamann, U., Hogervorst, F.B.L., Os, T.A. van, Leeuwen, F.E. van, Meijers-Heijboer, H.E.J., Wijnen, J., Blok, M.J., Kets, M., Hooning, M.J., Oldenburg, R.A., Ausems, M.G.E.M., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Jacobs, C., Eeles, R.A., Adlard, J., Davidson, R., Eccles, D.M., Cole, T., Cook, J., Paterson, J., Brewer, C., Douglas, F., Hodgson, S.V., Morrison, P.J., Walker, L., Porteous, M.E., Kennedy, M.J., Side, L.E., Bove, B., Godwin, A.K., Stoppa-Lyonnet, D., Fassy-Colcombet, M., Castera, L., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Bressac-de Paillerets, B., Caron, O., Pujol, P., Coupier, I., Delnatte, C., Akloul, L., Lynch, H.T., Snyder, C.L., Buys, S.S., Daly, M.B., Terry, M., Chung, W.K., John, E.M., Miron, A., Southey, M.C., Hopper, J.L., Goldgar, D.E., Singer, C.F., Rappaport, C., Tea, M.K.M., Fink-Retter, A., Hansen, T.V.O., Nielsen, F.C., Arason, A., Vijai, J., Shah, S., Sarrel, K., Robson, M.E., Piedmonte, M., Phillips, K., Basil, J., Rubinstein, W.S., Boggess, J., Wakeley, K., Ewart-Toland, A., Montagna, M., Agata, S., Imyanitov, E.N., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Feliubadalo, L., Brunet, J., Gayther, S.A., Pharoah, P.P.D., Odunsi, K.O., Karlan, B.Y., Walsh, C.S., Olah, E., Teo, S.H., Ganz, P.A., Beattie, M.S., Rensburg, E.J. van, Dorfling, C.M., Diez, O., Kwong, A., Schmutzler, R.K., 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., Heinritz, W., Caldes, T., Hoya, M. de la, Muranen, T.A., Nevanlinna, H., Tischkowitz, M., Spurdle, A.B., Neuhausen, S.L., Ding, Y.C., Lindor, N.M., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Bernard, L., Viel, A., Giannini, G., Varesco, L., Radice, P., Greene, M.H., Mai, P.L., Easton, D.F., Chenevix-Trench, G., Offit, K., Simard, J., OCGN, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators, kConFab Investigators, Consortium Investigators Modifiers, European Commission, National Institutes of Health (US), Breast Cancer Research Foundation, Cancer Research UK, Columbia University, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Ministerio de Ciencia e Innovación (España), National Institute for Health Research (UK), University of Helsinki, Generalitat de Catalunya, Instituto de Salud Carlos III, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministero della Salute, National Health and Medical Research Council (Australia), Instituto Nacional del Cáncer (España), National Cancer Institute (US), Avon Foundation for Women, VU University medical center, Human genetics, CCA - Oncogenesis, Clinical Genetics, Pediatric Surgery, Neurology, Medical Oncology, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human Genetics, CCA -Cancer Center Amsterdam, and ARD - Amsterdam Reproduction and Development

Subjects
Oncology, endocrine system diseases, Epidemiology, Estrogen receptor, Breast Neoplasms - epidemiology - genetics - metabolism, DCN PAC - Perception action and control, Immunoenzyme Techniques, 0302 clinical medicine, Risk Factors, Genotype, skin and connective tissue diseases, Ovarian Neoplasms, 0303 health sciences, Ovarian Neoplasms - epidemiology - genetics - metabolism, BRCA1 Protein, Middle Aged, BRCA2 Protein, Prognosis, 3. Good health, DNA-Binding Proteins, Receptors, Estrogen, Risk factors for breast cancer, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Adult, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], 030304 developmental biology, Aged, Chromosomes, Human, Pair 19 - genetics, Hereditary cancer and cancer-related syndromes [ONCOL 1], business.industry, Cancer, BRCA1 Protein - genetics, medicine.disease, United States, BRCA2 Protein - genetics, Immunology, Mutation, Ovarian cancer, business, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Transcription Factors
Abstract

PMCID: PMC3319317.-- et al., [Background]: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). [Methods]: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. [Results]: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). [Conclusions]: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. [Impact]: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers., This research was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. This work was also supported by Cancer Research UK (CR-UK) grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). Support was also provided by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and by the Canadian Breast Cancer Research Alliance-grant #019511., A.C. Antoniou is a CR-UK Senior Cancer Research Fellow. D.F. Easton is CR-UK Principal Research Fellow. G. Chenevix-Trench6 is a NHMRC Senior Principal Research Fellow. BFBOCC was supported by the Research Council of Lithuania grant LIG-19/2010 to R. Janavicius. BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to E.J. van Rensburg. BCFR was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (formerly the Northern California Cancer Center; U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). CBCS was supported by The Neye Foundation. CNIO was partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, the Spanish Ministry of Science and Innovation (FIS PI08 1120), and the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006. CONSIT TEAM was supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro” to L. Varesco and P. Radice, and “Progetto Tumori Femminili” to P. Radice), Ministero dell'Universita' e Ricerca (RBLAO3-BETH to P. Radice), Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors” to P. Radice), Associazione Italiana per la Ricerca sul Cancro (4017 to P. Pujol), and by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”)., The DKFZ study was supported by funds from the DKFZ. EMBRACE was supported by CR-UK Grants C1287/A10118 and C1287/A11990. D.G. Evans and Fiona Lalloo were supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.A. Eeles, Elizabeth Bancroft, and Lucia D'Mello were supported by CR-UK Grant C5047/A8385. GC-HBOC was supported by a grant of the German Cancer Aid (grant 109076) and by the Centre of Molecular Medicine Cologne (CMMC). The GEMO study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association “Le cancer du sein, parlons-en!” Award. The Georgetown study was supported by the Familial Cancer Registry at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. GOG was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program—COPTRG) NCI programs. K. Phillips is the Cancer Council Victoria, Colebatch Clinical Research Fellow. HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HEBON study was supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, and the ZonMW grant 91109024. HUNBOCS was supported by the Hungarian Research Grant KTIA-OTKA CK-80745. ICO was supported by Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; contract grant numbers ISCIIIRETIC RD06/0020/1051, PI10/01422, PI10/31488, and 2009SGR290. IHCC was supported by a Polish Foundation of Science award to K. Jaworska, a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. ILUH was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund., INHERIT was supported with J. Simard, Chairholder of the Canada Research Chair in Oncogenetics. IOVHBOCS was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), and “Ministero della Salute” (“Progetto Tumori Femminili and grant numbers RFPS 2006-5-341353, ACC2/R6.9”). kConFab was supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow-Up Study was funded by the NHMRC [145684, 288704, 454508]. A.-B. Skytte is supported by a NHMRC Senior Research Fellowship. A.K. Godwin was funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund while at FCCC. The author acknowledges support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor. The McGill study was supported by the Jewish General Hospital Weekend to End Breast Cancer. M. Thomassen holds a Fonds de la Recherche en Santé du Québec clinician-scientist award. The MSKCC study was supported by the Starr Cancer Consortium, the Breast Cancer Research Foundation, the Norman and Carol Stone Cancer Research Initiative, the Kate and Robert Niehaus Clinical Cancer Research Initiative, the Lymphoma Foundation, and the Sabin Family Research Initiative. The NCI study was supported by the Intramural Research Program of the U.S. National Cancer Institute and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc. NNPIO was supported by the Russian Federation for Basic Research (grants 10-04-92601, 10-04-92110, 11-04-00227) and the Federal Agency for Science and Innovations (contract 16.512.11.2237)., OCGN was supported by Cancer Care Ontario and the U.S. National Cancer Institute, NIH under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators. OSU-CCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS was supported by an Instituto Toscano Tumori grant to M.A. Caligo. SEABASS was supported by CARIF and University Malaya. The UCSF study was supported by the Helen Diller Family Comprehensive Cancer Center at UCSF, the Avon Foundation, and the Center for Translational and Policy Research in Personalized Medicine (TRANSPERS), NIH/NCI P01 CA130818-02A1. UKFOCR was supported by a project grant from CRUK to P.P.D. Pharoah. The UPENN study was supported Komen Foundation for the Cure to S.M. Domchek, the Breast Cancer Research Foundation to K.L. Nathanson, and NIH grants R01-CA083855 and R01-CA102776 to T.R. Rebbeck. WCRI was supported by the American Cancer Society Clinical Research Professorship #SIOP-06-258-06-COUN.

Published
2012

3. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Author

Antoniou, A.C., Beesley, J., McGuffog, L., Sinilnikova, O.M., Healey, S., Neuhausen, S.L., Ding, Y.C., Rebbeck, T.R., Weitzel, J.N., Lynch, H.T., Isaacs, C., Ganz, P.A., Tomlinson, G., Olopade, O.I., Couch, F.J., Wang, X.S., Lindor, N.M., Pankratz, V.S., Radice, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Viel, A., Allavena, A., Dall'Olio, V., Peterlongo, P., Szabo, C.I., Zikan, M., Claes, K., Poppe, B., Foretova, L., Mai, P.L., Greene, M.H., Rennert, G., Lejbkowicz, F., Glendon, G., Ozcelik, H., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Sunde, L., Cruger, D., Jensen, U.B., Caligo, M., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Dubrovsky, M., Cohen, S., Borg, A., Jernstrom, H., Lindblom, A., Rantala, J., Stenmark-Askmalm, M., Melin, B., Nathanson, K., Domchek, S., Jakubowska, A., Lubinski, J., Huzarski, T., Osorio, A., Lasa, A., Duran, M., Tejada, M.I., Godino, J., Benitez, J., Hamann, U., Kriege, M., Hoogerbrugge, N., Luijt, R.B. van der, Asperen, C.J. van, Devilee, P., Meijers-Heijboer, E.J., Blok, M.J., Aalfs, C.M., Hogervorst, F., Rookus, M., Cook, M., Oliver, C., Frost, D., Conroy, D., Evans, D.G., Lalloo, F., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Hodgson, S., Morrison, P.J., Porteous, M.E., Walker, L., Kennedy, M.J., Dorkins, H., Peock, S., Godwin, A.K., Stoppa-Lyonnet, D., Pauw, A. de, Mazoyer, S., Bonadona, V., Lasset, C., Dreyfus, H., Leroux, D., Hardouin, A., Berthet, P., Faivre, L., Loustalot, C., Noguchi, T., Sobol, H., Rouleau, E., Nogues, C., Frenay, M., Venat-Bouvet, L., Hopper, J.L., Daly, M.B., Terry, M.B., John, E.M., Buys, S.S., Yassin, Y., Miron, A., Goldgar, D., Singer, C.F., Dressler, A.C., Gschwantler-Kaulich, D., Pfeiler, G., Hansen, T.V.O., Jnson, L., Agnarsson, B.A., Kirchhoff, T., Offit, K., Devlin, V., Dutra-Clarke, A., Piedmonte, M., Rodriguez, G.C., Wakeley, K., Boggess, J.F., Basil, J., Schwartz, P.E., Blank, S.V., Toland, A.E., Montagna, M., Casella, C., Imyanitov, E., Tihomirova, L., Blanco, I., Lazaro, C., Ramus, S.J., Sucheston, L., Karlan, B.Y., Gross, J., Schmutzler, R., Wappenschmidt, B., Engel, C., Meindl, A., Lochmann, M., Arnold, N., Heidemann, S., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Kast, K., Schonbuchner, I., Caldes, T., Hoya, M. de la, Aittomaki, K., Nevanlinna, H., Simard, J., Spurdle, A.B., Holland, H., Chen, X.Q., Platte, R., Chenevix-Trench, G., Easton, D.F., Ontario Canc Genetics Network, SWE-BRCA, HEBON, EMBRACE, GEMO, Breast Canc Family Registry, kConFab, CIMBA, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Human Genetics, Pathology, Clinical Genetics, Pediatric Surgery, Medical Oncology, and Internal Medicine

Subjects
Oncology, Cancer Research, endocrine system diseases, Vesicular Transport Proteins, Gene mutation, 0302 clinical medicine, Risk Factors, Genotype, skin and connective tissue diseases, Aged, 80 and over, 0303 health sciences, BRCA1 Protein, High Mobility Group Proteins, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Adult, Heterozygote, medicine.medical_specialty, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Alleles, Aged, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], Sodium-Bicarbonate Symporters, Haplotype, Cancer, genome-wide association estrogen-receptor loci variants, medicine.disease, Survival Analysis, TOX3, Mutation, Trans-Activators, Cancer research, Apoptosis Regulatory Proteins
Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

Published
2010

4. Dawning of the epigenetic era in hereditary cancer.

Author

Hitchins, M.P. and Lynch, H.T.

Subjects
*LYNCH syndrome II, *EPIGENETICS, *PROGNOSIS, *DIAGNOSIS, *CANCER
Abstract

The article comments on research studies on Lynch syndrome. It specifically discusses the molecular basis for the syndrome and the role of epigenetic mechanisms in the pathogenesis of this high-risk hereditary cancer syndrome. It also discusses a study devised clinical criteria for the original clinic-based diagnosis of Lynch syndrome.

Published
2014
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5. Epidemiology of pancreatic cancer: an overview

Author

Ghadirian, P., Lynch, H.T., and Krewski, D.

Subjects
*PANCREATIC cancer, *CANCER risk factors, *EPIDEMIOLOGY, *PANCREATITIS
Abstract

Introduction: The incidence of pancreatic cancer worldwide appears to correlate with increasing age, and it is slightly more common among men and Jewish people. There is evidence that the incidence rate is higher among blacks than among whites. Methods: The published literature was reviewed for preparation of an overview on epidemiology of pancreatic cancer. Results: A possible role of diabetes in the etiology of pancreatic cancer has been suggested by different epidemiological studies. Several investigations indicate that a history of pancreatitis may increase the risk of pancreas cancer, and it appears that people with a history of pernicious anemia or partial gastrectomy for ulcer as well as cholecystectomy may be at higher risk. Individuals with familial adenomatous polyposis (FAP) also have a high risk of developing this cancer. Pancreatic cancer is seen in some breast cancer families with BRCA1 and BRCA2 mutations. Epidemiological studies have confirmed that relatives of individuals with pancreatic cancer have an increased risk of this malignancy. Affected family members of the familial atypical multiple-mole melanoma (FAMMM) as well as those with a positive family history of ataxia-telangiectasia (AT) have much higher risk of developing pancreatic cancer, compared with the general population. A positive association has been reported between pancreatic cancer risk and dietary intake such as fat and oil, meat, and dairy products, as well as with high intake of energy, fried foods, carbohydrates, cholesterol, and salt. The risk is found to decrease with increased consumption of fresh fruits and vegetables, fiber, natural foods, and Vitamin C. Cigarette smoking has shown the strongest positive association with risk of pancreatic cancer. Conclusion: Some diseases and medical conditions such as diabetes, chronic pancreatitis, AP, family aggregation of pancreatic cancer, FAMMM, AT, as well as nutrition and lifestyle factors, like smoking may play important role in the etiology of pancreatic cancer. [Copyright &y& Elsevier]

Published
2003
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6. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2.

Author

Jernstrom, H., Lerman, C., Ghadirian, P., Lynch, H.T., Weber, B., Garber, J., Daly, M., Olopade, O.I., Foulkes, W.D., Warner, E., Brunet, J.-S., and Narod, S.A.

Subjects
*BREAST cancer risk factors, *HEREDITARY cancer syndromes, *GENETIC disorders, *PREGNANCY, *CANCER
Abstract

SummaryBackground Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, whether pregnancy decreases the risk of early-onset hereditary breast cancer is unknown. There is concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk factor for hereditary breast cancer.Methods We did a matched case-control study of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases were carriers who developed breast cancer by age 40 years, and controls were carriers of the same age without breast cancer, or who were diagnosed with breast cancer after age 40 years. Women who had undergone preventive mastectomy, hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before the age at which breast cancer was diagnosed in the matched case were excluded. Information about pregnancies and pregnancy outcome was derived from a questionnaire completed by women in the course of genetic counselling.Findings A higher proportion of cases than controls had had a full term pregnancy (173/236 vs 146/236; odds ratio 1.71 [95% CI 1.13-2.62], p=0.01). The mean number of births was also greater for cases than for controls (1.62 vs 1.38, p=0.04). The risk increased with the number of births and did not diminish with time since last pregnancy. There were no significant differences in age at first birth or age at last birth between cases and controls. [ABSTRACT FROM AUTHOR]

Published
1999

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