Sindrome Mama- Ovario
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Genetica Cancer de Mama, Consejeria Genetica Cancer de Mama, Mastologia. BRCA.Mutaciones
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Sindrome Mama- Ovario
- 1. SINDROME MAMA-OVARIO CARLOS ANDRES OSSA GOMEZ CIRUGIA ONCOLOGICA DE MAMA/MASTOLOGIA INSTITUTO NACIONAL DE CANCEROLOGIA
- 2. Poblacion total con riesgo de cáncer Familiar y Hereditario
- 3. ©2011, Myriad Genetic Laboratories, Inc. Teoría del Cáncer Hereditario
- 4. GENERALIDADES • Hasta el 22 % de las Ptes CA de Mama riesgo de Sindrome mama-Ovario. • 9% de las pacientes en la practica clinica tienen una historia familiar considerable de cáncer de mama-Ovario. • 63% de estos pacientes ( 6% de todos los pacientes) cumplen criterios de alto riesgo. • 6.2% de la población que se realiza tamizaje mamográfico anual se consideran de alto riesgo de portadoras de mutación Genética BRCA
- 5. Historia Familiar No es Suficiente
- 6. Consideraciones Historia Familiar • La Mitad de la herencia para Brca proviene de la línea paterna. • El cáncer de ovario es un factor muy importante. • El cáncer de mama de aparición temprana es mas importante que el numero de familiares afectados en la familia. • Un tamaño de familia pequeño o aquellos que contengan poco familares de sexo femenino pueden enmascarar Una mutacion del BRCA. Science 2003;302(5645):643-6 JAMA 2007;297(23):2587-95
- 7. LIKELIHOOD OF HAVING A BRCA1 OR BRCA2 MUTATION BASED ON AGE OF CÁNCER DIAGNOSIS Kayon Williams,Jeniffer Saam,Rajesh Kaldate American Society Breast Surgeons Chicago 2013
- 8. LIKELIHOOD OF HAVING A BRCA1 OR BRCA2 MUTATION BASED ON AGE OF CÁNCER DIAGNOSIS Kayon Williams,Jeniffer Saam,Rajesh Kaldate American Society Breast Surgeons Chicago 2013
- 9. ©2011, Myriad Genetic Laboratories, Inc. Mutacion Brca y Cáncer de Mama Heredado y Cáncer de Ovario
- 10. ©2011, Myriad Genetic Laboratories, Inc.
- 11. ©2011, Myriad Genetic Laboratories, Inc.
- 12. ©2011, Myriad Genetic Laboratories, Inc. Mutación BRCA y Riesgo de Cáncer de Mama y Cáncer de Ovario
- 13. ©2011, Myriad Genetic Laboratories, Inc. Mutacion Brca y riesgo de un segundo Primario
- 14. ©2011, Myriad Genetic Laboratories, Inc. Mutacion Brca en un Hombre y Riesgo de Ca
- 15. ©2011, Myriad Genetic Laboratories, Inc. Mutaciones en el Brca y Otros Tumores
- 16. ©2011, Myriad Genetic Laboratories, Inc. ESTRATEGIAS PARA EL MANEJO DE ESTAS PACIENTES • Vigilancia Estrecha • Cirugia Profiláctica • Quimio prevención
- 17. ©2011, Myriad Genetic Laboratories, Inc. VIGILANCIA EN LAS PACIENTES POSITIVAS PARA BRCA
- 18. ©2011, Myriad Genetic Laboratories, Inc. BRCA POSITIVOS Y MANEJO QUIRÚRGICO
- 19. ©2011, Myriad Genetic Laboratories, Inc. CIRUGIA PROFILACTICA SALPINGO-OOFORECTOMIA BILATERAL • Recomendada luego de paridad satisfecha, preferiblemente a la edad de 40 años. • Consideraciones quirurgicas : remover ambos ovarios,y ambas trompas uterinas a nivel de los cuernos. • Ligadura de los vasos Ovaricos a nivel del anillo pelvico. • Inspeccion de la cavidad peritoneal y y lavado pelvico. • Enviar tejido resecado a anatomia patologica. • Prevalencia de tumores ocultos 2%-26%
- 20. ©2011, Myriad Genetic Laboratories, Inc. QUIMIOPREVENCION. • Anticonceptivos Orales. • reducen el riesgo de ca de ovario hasta en un 60 % • Evidencia contradictoria acerca del reisgo de cáncer de mama. • Uso de Anticonceptivos es aceptable para anticoncepción. • Tamoxifeno : reduce el riesgo de cáncer contralateral en 53% • Datos reducción del riesgo en paciente de alto riesgo Brca + sin cáncer de mama del 45%
- 21. ©2011, Myriad Genetic Laboratories, Inc. HOMBRES PORTADORES DE LA MUTACION Y MANEJO
- 22. ©2011, Myriad Genetic Laboratories, Inc. PACIENTE NO AFECTADOS (MAMA)
- 23. ©2011, Myriad Genetic Laboratories, Inc. PACIENTES NO AFECTADOS (OVARIO)
- 24. ©2011, Myriad Genetic Laboratories, Inc. BENEFICIOS DE SOLICITAR LA PRUEBA. • Permite manejo medico individualizado de la paciente. • Permite estratificación del riesgo mas adecuada. • Alivia la incertidumbre y la ansiedad de la paciente por conocer sus características genéticas. • Estudio De La Familia. • Las pruebas BRCA1-BRCA2 no identifican todas las causas de cancer de mama y ovario hereditarias.
- 25. ©2011, Myriad Genetic Laboratories, Inc. HISTOLOGÍA TUMORAL Y PRONOSTICO • Cáncer de Mama • Brca 1 • Mayoria son triple Negativos ( Er-,Pr- ,Her2-) • Mayoria son de fenotipo Basal-like • Brca 2 No basal Like Receptor Hormonal Positivo.
- 26. ©2011, Myriad Genetic Laboratories, Inc. EXPERIENCIA PERSONAL • 1 Año y Medio • 26 pruebas Brca Solicitadas. • 14 Perfil Colombia • 3 Pruebas Secuenciación Completa MLPA Valencia España. • 9 Pruebas secuenciación Completa Perfil Myriad. • 2 Pruebas Positivas Para Mutación Deletérea. • 2 Misense Mutation
- 27. ©2011, Myriad Genetic Laboratories, Inc. EL FUTURO
- 28. ©2011, Myriad Genetic Laboratories, Inc. CONCLUSIONES • No Diagnosticamos Lo que No Conocemos • Debemos desarrollar en el Pais Centros de Alto Riesgo que permita ientificar estas pacientes. • Desarrollar estrategias de manejo basadas en guias de este grupo de manejo. • Desarrollar estudio para caracterizar nuestra población.
Notas del editor
- The Development of Hereditary Cancer A normal cell has two functional copies of each gene. Some genes (including BRCA1 and BRCA2) function as tumor suppressors, helping repair DNA damage and keeping the damaged cells from becoming cancerous. In a cell with two functional copies of a specific tumor suppressor gene, if only one copy of the gene is damaged, the cell will still function properly as the second “back up” copy of the gene is still functional. If the other copy of the gene is damaged within the same cell, the tumor suppressor function of the gene is taken away and the cell can become cancerous. This damage can occur through lifestyle, environmental exposures (carcinogens), and most commonly the normal aging process of cells. The chances of both copies of an important tumor suppressor gene being independently knocked out in the same cell are extremely small. Individuals with hereditary cancer have inherited one nonfunctional copy of a specific tumor suppressor gene in every cell of their body. Therefore these individuals require only one additional mutation to knock out the functional copy of the gene, making cancer development much more likely.References:Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971 Apr;68(4):820-3.
- Prevalence of BRCA Mutations in HBOC Families All cancer results from an accumulation of mutations in genes that normally control cell division. Most of these mutations are acquired during a person's lifetime, but in some individuals, an initial mutation in a critical gene is inherited. Approximately 7%1 of breast cancer and approximately 14% 2,3,10 of invasive ovarian cancer results from such genetic mutations passed down from either the father or mother. The majority (approximately 84%) of hereditary breast and ovarian cancer results from inherited mutations in two genes called BRCA1 (52%) and BRCA2 (32%).4,5 Although sometimes referred to as the “breast cancer genes,”BRCA1 and BRCA2 are also associated with the majority of hereditary cancers of the ovary. Although the risk of breast or ovarian cancer may sometimes be increased in other hereditary cancer syndromes, there do not appear to be other genes (such as a so-called "BRCA3") that are responsible for a significant proportion of hereditary breast and ovarian cancer. Studies have in fact indicated that “if there are additional genes, they are of minor importance, compared with BRCA1 and BRCA2, in families with breast and ovarian cancer.”5-7 Other genes that have been associated with an increased lifetime risk of breast cancer include p53, PTEN, CDH1, CHEK2, ATM, STK11.8 It is important to note that syndromes associated with these other gene mutations often include additional types of cancers and/or associated physical characteristics of the particular syndrome. In general, these “other” gene mutations carry an overall lower lifetime risk of breast cancer when compared to BRCA gene mutations and occur less frequently in the general population.8 In addition to BRCA gene mutations, mismatch repair gene mutations are associated with hereditary ovarian cancer. South et al. found that approximately 2% of 77 ovarian cancer patients who had negative BRCA gene sequencing and did not meet Amsterdam II criteria, had a deleterious mismatch repair gene mutation identified.9References:Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77:2318-24.Risch HA, McLaughlin JR, Cole DEC, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. American Journal of Human Genetics. 2001;68:700-710. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816.Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. American Journal of Human Genetcs. 1998;62:676-89.Frank TS, Deffenbaugh AM, Reid JE et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: Analysis of 10,000 individuals. Journal of Clinical Oncology. 2002 20:1480-1490.Gayther SA, Russell P, Harrington P et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: No evidence for other ovarian cancer- susceptibility genes. American Journal of Human Genetics. 1999;65:1021-9.Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nature Reviews: Cancer. 2004;4(9):665-76. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer Syndrome. Gene Reviews. http://www.ncbi.nlm.nih.gov/sites/GeneTests/South et al. Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers. Cancer. 2009 Jan 15;115(2):324-33. Zhang S. et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):352-7.
- A BRCA Mutation Increases Breast and Ovarian Cancer Risks Without intervention, the majority of women with inherited mutations in BRCA1 and BRCA2 will develop breast and/or ovarian cancer. The range of risks of breast and ovarian cancer associated with mutations in these genes has been characterized through numerous studies. The lower estimates of risk are derived from analysis of mutations in an unselected general population of individuals, whereas higher estimates of mutation-associated cancer risk are derived from families with a strong history of cancer. Generally, mutations in BRCA1 and BRCA2 are associated with a 45% to 87% risk of breast cancer by age 701-8; however, variability of this risk has been demonstrated among families, most likely due to other modifying factors.1-3,11,12 Most importantly, hereditary breast cancer occurs, on average, at an earlier age than the nonhereditary (sporadic) form. Women in the general population have only a 2% chance of developing breast cancer before age 50.9 However, a woman with a mutation in BRCA1 or BRCA2 has a 33% to 50% likelihood of developing breast cancer before reaching 50 years of age.2,4,10 The risk of ovarian cancer due to inherited BRCA1 mutations is 28%7 to 44%1 by age 70, compared to the general population risk of <1%. Mutations in BRCA2 confer a risk of ovarian cancer of 11%3 to 27%8 by age 70, which represents up to a 15-fold increase compared to the general population. References:Ford D, et al. Breast Cancer Linkage Consortium: Risks of cancer in BRCA1-mutation carriers. Lancet. 1994;343:692-695. Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. NEJM. 1997;336:1401-1408.Antoniou A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. AJHG. 2003;72:1117-1130.Easton DF, et al. Breast and ovarian cancer incidence in BRCA1-mutation carriers. AJHG. 1995;56:265-271.King MC, et al. Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2. Science. Oct 24 2003:643-646.Narod SA, Offit K. Prevention and Management of Hereditary Breast Cancer. J Clin Oncol. 2005 Mar10;23(8):1656-63.Whittemore AS, Gong G, Itnyre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer. Am J Hum Genet. 1997;60:496-504.Ford D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62:676-689.DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0. Statistical Research and Applications Branch, National Cancer Institute, 2005. http://srab.cancer.gov/devcan. Accessed May 2011.The Breast Cancer Linkage Consortium: Cancer Risks in BRCA2 Mutation Carriers. JNCI. 1999;15:1310 1316.Begg CB, et al. Variation of Breast Cancer Risk Among BRCA1/2 Carriers. JAMA. 2008 Jan 9;299(2):194-201.Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007 Apr 10;25(11):1329-33.
- A BRCA Mutation Increases the Risk of a Second Cancer Women who have developed breast cancer are at greatly increased risk of a second cancer if they carry a mutation in BRCA1 or BRCA2.1-5 The risk of a contralateral breast cancer is increased up to 64% by age 70,2 compared to the general population risk of 2 to 11%.6 Additionally, the risk for a second breast cancer within five years of the initial diagnosis in women with BRCA1 mutations is 27.1%.5 Mutations in BRCA2 increase these risks to about 50% by age 70,3 or 23.5% within five years of the first breast cancer.5One recent study7 suggested that the age of onset of the first breast cancer may play a role in the level of risk for a woman who carries a BRCA mutation to develop a second breast cancer; with a younger age of onset (under 40 years of age) correlating to a higher risk of a second breast cancer occurrence. Women diagnosed with initial breast cancer younger than age 40 had a significantly higher risk of contralateral breast cancer in BRCA1 families (and a similar trend was seen in BRCA2 families but not statistically significant). 62.9% of women from BRCA1 mutation families with first breast cancer under 40 developed contralateral breast cancer within 25 years compared to 19.6% of women whose first breast cancer was over age 40. Another recent study by Malone et al. found that, compared with noncarriers, BRCA1 and BRCA2 mutation carriers had a 4.5-fold and 3.4-fold increased risk of contralateral breast cancer, respectively.13 The relative risk of developing CBC in BRCA1 mutation carriers compared to noncarriers increased with younger age at first diagnosis with an 11-fold increased CBC risk among women diagnosed before 35, a 4-fold increased risk for women diagnosed from 35-44, and a 2.6-fold increased risk for women diagnosed 45-54 years. Data regarding BRCA2 mutation carriers did not show a clear age-related trend. Data indicate that the 10-year risk for ovarian cancer AFTER a breast cancer in BRCA1 and BRCA2 mutation carriers is 12.7% and 6.8%, respectively.8 Other studies have shown that the risk for ovarian cancer AFTER a breast cancer diagnosis on BRCA2 mutation carriers is 16%9 and women with a BRCA1 or BRCA2 mutation have a 10-fold increased risk compared to women who do not have a BRCA1/2 mutation.10 Due to the ineffectiveness to screen for ovarian cancer, the National Comprehensive Cancer Network (NCCN) and the Society of Gynecologic Oncology (SGO)have recommended that mutation positive women have a prophylactic bilateral salpingo-oophorectomy after child-bearing.11,12ReferencesFrank TS, et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. JCO. 1998;16:2417-2425.Ford D, et al. Risks of cancer in BRCA1-mutation carriers. Lancet. 1994;343: 692-695. The Breast Cancer Linkage Consortium: Cancer Risks in BRCA2 Mutation Carriers. JNCI. 1999;15:1310-1316.Verhoog LC, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998;351:316-321.Metcalfe K, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. JCO. 2004;22:2328-2335.Chen Y, et al. Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev. 1999 Oct;8(10):855-61.Graeser MK, et al. Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. J Clin Oncol. 2009 Dec 10;27(35):5862-4.Metcalfe KA, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol. 2005 Jan;96(1):222-6.The Breast Cancer Linkage Consortium: Cancer Risks in BRCA2 Mutation Carriers. JNCI. 1999;15:1310-1316. Frank TS, et al. Sequence analysis of BRCA1 and BRCA2: Correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 16:2417-2425. NCCN Clinical Practice Guidelines in Oncology v.1.2011 Genetic/Familial High-Risk Assessment: Breast and Ovarian. Accessed at www.nccn.orgSociety of Gynecologic Oncologists Clinical Practice Committee Statement on Prophylactic Salpingo-oophorectomy. Gynecol Oncol. 2005 Aug;98(2)179-81.Malone et al. Population-Based Study of the Risk of Second Primary Cohntralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2. J Clin Onc. 2010 May 10;28(14):2404-10.
- Risks in Men with a BRCA Mutation To date, fewer men than women have undergone hereditary cancer testing for BRCA1 and BRCA2 mutations, in part because of misinformation about male cancer risks.1 However, men who carry BRCA1 or BRCA2 mutations have a significantly increased risk of cancer, with BRCA2 the more important gene for cancer susceptibility in men. In a study of BRCA2 families, the cumulative risk of all BRCA-associated cancers in men was 32% by age 70, compared with 90% for women.2 For BRCA2 mutation carriers, the lifetime risk of male breast cancer is approximately 7-8%.4,7 This is compared to a risk of 0.1% (1 in 1000) for male breast cancer in the general population.6The risk of male breast cancer in BRCA1 families is less characterized, but may be up to 1.8% by age 80.7 Mutations in BRCA2 also are associated with an increased risk of invasive prostate cancer (20% by age 80).2 In a case-control study of Ashkenazi Jewish men, BRCA2 mutation carriers had a nearly 5-fold increased risk of prostate cancer.3 A recent study found that prostate cancer in BRCA2 mutation carriers is associated with more aggressive disease and poorer overall survival. The authors of this study suggest that, compared to prostate cancers in men without BRCA mutations, the prostate cancer in men who also have germline BRCA mutations should not be managed with active surviellance.8 A modestly increased risk of prostate cancer was reported in men under age 65 with BRCA1 mutations.5References:Liede A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the literature. JCO. 2004;22:735-42.The Breast Cancer Linkage Consortium: Cancer risks in BRCA2 mutation carriers. JNCI. 1999;15:1310-1316.Kirchhoff T, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clinical Cancer Research. 2004;10:2918-2.Thompson D, Easton D; Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001 Feb;68(2):410-9. Thompson D, et al. Cancer incidence in BRCA1 mutation carriers. JNCI. 2002 Sep 18;94 (18):1358-65.DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0. Statistical Research and Applications Branch, National Cancer Institute, 2005. http://srab.cancer.gov/devcan. Accessed May, 2011.Tai YC, et al. Breast cancer risk among male BRCA1 and BRCA2mutation carriers. JNCI. 2007 Dec 5;99(23):1811-4. Edwards SM, et al. Prostate Cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010; 103(6):918-924.
- Risks of Other Cancers Both men and women with mutations in BRCA1 or BRCA2 have an elevated risk of pancreatic cancer compared to the general population.1,2,5,9-13 However, BRCA2 mutation carriers , with a risk of pancreatic cancer of up to 7% by age 80, appear to be at higher risk than BRCA1 mutation carriers.5 An increased risk of colorectal cancer among BRCA mutation carriers, compared to the general population, has been described. Specifically, a two-fold increased risk was observed among BRCA1 carriers,2,3 and a three-fold increased risk was observed among BRCA2 carriers.6 However, additional studies have not observed this increased risk, so a true association remains unclear.1,4,5 An increased risk of melanoma has been described in BRCA2 mutation carriers with a 2.5 increase in relative risk compared to the general population.1 An increased risk of melanoma in BRCA1 mutation carriers has not been observed. At this time, there are no professional/societal recommendations for increased screening for pancreatic cancer, colon cancer, and melanoma, in mutation-positive individuals; however, experts agree that BRCA positive families in which there is a history of pancreatic cancer should be offered regular surveillance using peer-reviewed protocols at experienced medical centers.7,8 For male-associated cancers, the NCCN has specific guidelines outlined elsewhere in this presentation.References:The Breast Cancer Linkage Consortium: Cancer Risks in BRCA2 Mutation Carriers. JNCI. 1999;15:1310-1316.Thompson D, et al. Cancer Incidence in BRCA1 mutation carriers. JNCI. 2002;94:1358-65.Brose MS, et al. Cancer Risk Estimates for BRCA1 Mutation Carriers Identified in a Risk Evaluation Program. JNCI. 2002;94 1365-72.Lin KM, et al. Colorectal cancer in hereditary breast cancer kindreds. Diseases of the Colon and Rectum 1999;42:1041-1045. Van Asperen CJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005 Sep;42(9):711-9. Risch HA, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. Brand RE, et al. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007 Oct;56(10):1460-9. Canto MI, et al. Screening and surveillance approaches in familial pancreatic cancer. Gastrointest Endosc Clin N Am. 2008 Jul;18(3):535-53.DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0. Statistical Research and Applications Branch, National Cancer Institute, 2005. http://srab.cancer.gov/devcan. Accessed May, 2011.Lynch HT, et al. BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet. 2005 Apr 15;158(2):119-25. Hahn SA, et al. BRCA2 germline mutations in familial pancreatic carcinoma. JNCI. 2003 Feb 5;95(3):214-21. Lal G, et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res. 2000 Jan 15;60(2):409-16. Murphy KM, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002 Jul 1;62(13):3789-93.