Hereditäre Tumordiagnostik – Mammakarzinom: BRCA1, BRCA2 und derzeitiger Stand der Multigenanalysen

Fazit

Obwohl für einige der neuen Risikogene erste belastbare Daten erhoben wurden ([Tab. 2]), ist die Datenlage für viele Gene z. B. zu den altersabhängigen Erkrankungsrisiken oder Genotyp-Phänotyp-Korrelationen noch unzureichend. Die Erkrankungsrisiken sind genspezifisch und häufig niedriger als für BRCA1/2-Mutationsträgerinnen ([Tab. 2]). Für die übrigen Gene müssen die altersabhängigen Erkrankungsrisiken in prospektiven Kohortenstudien ermittelt werden, die eine wesentliche Aufgabe des DKFBE gemeinsam mit internationalen Kooperationspartnern darstellen. Kritisch ist insbesondere der Umgang mit VUS. Wird kein Recall-System angeboten, dann sollten Ratsuchende darauf bestehen, über die bei ihnen gefundenen VUS umfassend informiert zu werden. Eine Multigenanalyse erfordert begleitende wissenschaftliche Untersuchungen zur Etablierung und Evaluation effektiver Präventions- und Therapiemaßnahmen.

• Literatur

• 1 Zentrum für Krebsregisterdaten. Prognose. Online: http://www.rki.de/DE/Content/Gesundheitsmonitoring/Krebsregisterdaten/krebs_node.html Stand: 14.10.2016
• 2 Leitlinienprogramm Onkologie der AWMF; Deutsche Krebsgesellschaft e.V., Deutsche Krebshilfe e.V., Hrsg. Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms, 2012. Online: http://www.awmf.org/uploads/tx_szleitlinien/032-045OL_l_S3__Brustkrebs_Mammakarzinom_Diagnostik_Therapie_Nachsorge_2012-07.pdf Stand: 14.10.2016
• 3 Ärztekammer Westfalen-Lippe; Deutsche Krebsgesellschaft; Deutsche Gesellschaft für Senologie, Deutsches Konsortium für Erblichen Brust- und Eierstockkrebs. Checkliste zur Erfassung einer möglichen erblichen Belastung für Brust- und/oder Eierstockkrebs. Online: http://www.konsortium-familiaerer-brustkrebs.de/informationen-fuer-aerzte/checkliste-zur-risikoerfassung Stand: 14.10.2016
• 4 Kast K, Rhiem K, Wappenschmidt B. et al. German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J Med Genet 2016; 53: 465-471
• 5 King MC, Marks JH, Mandell JB. New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302: 643-646
• 6 Antoniou AC, Cunningham AP, Peto J. et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer 2008; 98: 1457-1466
• 7 Mavaddat N, Peock S, Frost D. et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013; 105: 812-822
• 8 Rebbeck TR, Mitra N, Wan F. et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 2015; 313: 1347-1361
• 9 Rhiem K, Engel C, Graeser M. et al. The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Breast Cancer Res 2012; 14: R156
• 10 Graeser MK, Engel C, Rhiem K. et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009; 27: 5887-5892
• 11 Fischer C, Kuchenbacker K, Engel C. et al. Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium. J Med Genet 2013; 50: 360-367
• 12 Loveday C, Turnbull C, Ramsay E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011; 43: 879-882
• 13 Wickramanyake A, Bernier G, Pennil C. et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol 2012; 127: 552-555
• 14 Meindl A, Hellebrand H, Wiek C. et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010; 42: 410-414
• 15 Osorio A, Endt D, Fernandez F. et al. Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 2012; 21: 2889-2898
• 16 Loveday C, Turnbull C, Ruark E. et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 2012; 44: 475-476 author reply 476
• 17 Coulet F, Fajac A, Colas C. et al. Germline RAD51C mutations in ovarian cancer susceptibility. Clin Genet 2013; 83: 332-336
• 18 Walsh T, Casadei S, Lee MK. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011; 108: 18032-18037
• 19 Schnurbein G, Hauke J, Wappenschmidt B. et al. RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast Cancer Res 2013; 15: R120
• 20 Goldgar DE, Healey S, Dowty JG. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 2011; 13: R73
• 21 Gao P, Ma N, Li M. et al. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis 2013; 28: 683-697
• 22 Antoniou AC, Foulkes WD, Tischkowitz M. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 1651-1652
• 23 Engel C, Loeffler M, Steinke V. et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol 2012; 30: 4409-4415
• 24 Easton DF, Pharoah PD, Antoniou AC. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015; 372: 2243-2257
• 25 Walsh CS. Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol 2015; 137: 343-350
• 26 Park DJ, Lesueur F, Nguyen-Dumont T. et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Med Genet 2012; 90: 734-739
• 27 Ruark E, Snape K, Humburg P. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 2013; 493: 406-410
• 28 Thompson ER, Doyle MA, Ryland GL. et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Gen 2012; 8: e1002894
• 29 Cybulski C, Carrot-Zhang F, Kluzniak W. et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet 2015; 47: 643-646
• 30 Sun J, Wang YX, Xia YS. et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Gen 2015; 11: e1005228
• 31 Lakhani SR, Reis-Filho JS, Fulford L. et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 2005; 11: 5175-5180
• 32 Stevens KN, Vachon CM, Couch FJ. Genetic susceptibility to triple-negative breast cancer. Cancer Res 2013; 73: 2025-2030
• 33 Cybulski C, Kluzniak W, Huzarski T. et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 2015; 16: 638-644
• 34 Antoniou AC, Casadei S, Heikkinen T. et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 497-506
• 35 Rhiem K, Wappenschmidt B, Bosse K. et al. Platinum sensitivity in a BRCA1 mutation carrier with advanced breast cancer. Clin Oncol 2009; 21: 448-450
• 36 Byrski T, Huzarski T, Dent R. et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2014; 147: 401-405
• 37 Pennington KP, Walsh T, Harrell MI. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014; 20: 764-775
• 38 Easton DF, Pharoah PD, Antoniou AC. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015; 372: 2243-2257
• 39 Ramus SJ, Song H, Dicks E. et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst 2015;
• 40 Schmidt MK, Hogervorst F, van Hien R. et al. Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol 2016; 34: 2750-2760