FaCD Online Syndrome Fact Sheet

Last updated: 16 Aug 2011

Name: Hereditary Breast-Ovarian Cancer, BRCA2 type

Mode of Inheritance: AD

Genes

BRCA2, mapped to 13q12.3

Tumor features

breast cancer
breast cancer, male
fallopian tube cancer
gastric cancer
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma
peritoneal (papillary serous) carcinoma
prostate cancer

Tumor features (possible)

biliary tract cancer (incl. gallbladder)
bone tumor
carcinosarcoma, ovarian
cervical cancer
colon cancer
lymphoma, malignant (Non-Hodgkin and/or Hodgkin)
melanoma, cutaneous
melanoma, uveal (choroidal, ciliary body, iris)/ocular
oropharyngeal cancer
papillary serous cervical cancer
sarcoma

Comment

Approximately 5-10 % of breast cancer and ovarian cancer patients in the general population are estimated to be carriers of a highly penetrant cancer susceptibility gene[1,2]. Presently it is unclear whether hereditary site-specific breast or site-specific ovarian cancer, i.e. disorders with a highly penetrant gene increasing exclusively breast cancer or ovarian cancer risk, exist [3].

Hereditary Breast-Ovarian cancer is often clinically defined as the presence of at least 3 cases of breast and/or ovarian cancer in at least two successive generations, with one affected relative being a first degree relative of the other two (or a second degree relative in case of the apparent transmission of the gene through the paternal line).

Of the hereditary breast cancer families, approximately 45% is contributed to germline mutations in the BRCA2 gene, although some have suggested that this percentage has been overestimated[4]. Compared with BRCA1 mutation families there appears to be an older distribution of ages at onset[5].Most BRCA mutations are observed in successive generations, de novo BRCA1/2 mutations appear to be very rare[48,49].

Breast cancer risk
Cumulative breast cancer risk in women with BRCA2 gene mutations by age 70 was estimated from 37 % up to 84% (95% confidence intervals range from 22% to 95%)[5-7](one study estimated the risk at 28% for the Ashkenazi founding mutations, without giving the confidence interval[8]). In a recent meta-analysis by Chen and Parmigiani [36] mean cumulative cancer risks for mutation carriers at age 70 years was estimated 49% (95% CI, 40% to 57%).

Among BRCA2 mutation carrying women who had already developed breast cancer, the cumulative risk by age 70 of contralateral breast cancer was estimated at 52%[9]. The use of oral contraceptives has been suggested to increase breast cancer risk in BRCA1 and BRCA2 mutation carriers[10]. BRCA1 and 2-associated breast cancer risk appears to increase with the number of births, and early first pregnancy does not reduce this risk[11]. Smoking may reduce breast cancer risk in women with either BRCA1 or 2 mutations, possibly through the postulated anti-estrogenic effect of cigarette smoke[12,13], although more recent studies suggested increased breast cancer risk or no effect on risk[38,39].

Male breast cancer is a typical feature of germline BRCA2 mutations with a cumulative risk by age 70 of 6-7% [14,37]. Germline BRCA2 mutations may be found in male breast cancer patients without a strong family history[15]. However, male breast cancer may also occur in BRCA1 families[6].

It appears that BRCA2-associated breast cancers are much more frequently steroid receptor positive than those associated with BRCA1[21] and generally do not appear to differ clearly from sporadic breast cancer[35]. As in BRCA1, survival in women with breast cancer and germline BRCA2 mutations appears to be similar to that in women with sporadic breast cancer[21,22].

Ovarian cancer
Ovarian cancer appears to be smaller than the risk in BRCA1 mutation carriers[16;17]: 0.4 % by age 50 and 27 % by age 70[6]. In a recent meta-analysis by Chen and Parmigiani [36] the mean cumulative ovarian cancer risks for mutation carriers at age 70 years was estimated at 18% (95% CI, 13% to 23%. Ovarian cancer risk appears to depend on the type of mutation found in this gene[6;18]. Among BRCA2 mutation carrying women who had already developed breast cancer, the cumulative risk by age 70 of ovarian cancer was estimated at 16%[9]
Mean age at diagnosis of ovarian cancer appears to be younger for BRCA1 cases than for BRCA2 cases (54 versus 62 years in one series[19]). A population-based study performed by Stratton et al.[20] of 101 women with invasive ovarian cancer diagnosed <30 years failed to detect any BRCA1/2 mutations.

Surgical and pathological characteristics appear to be similar for BRCA2-associated ovarian cancer and sporadic cases[19]. Compared with sporadic ovarian cancer cases, ovarian cancer associated with BRCA2 mutations appears to have a better survival[19]. Mucinous ovarian cancer is underrepresented in familial ovarian cancer and the same might be true for BRCA1/2 associated ovarian cancer. Overall, however, histology of BRCA1/2 associated ovarian cancer and sporadic cases appear to be similar[19], although a recent study suggested that BRCA1/2-associated ovarian cancer is biologically distinct and carries a higher risk of visceral metastasis than sporadic cases do[50]. Ovarian carcinosarcoma has been reported in a few patients[50].

Other tumors
The tumor spectrum associated with germline BRCA2 mutations appears to be more extended than that associated with BRCA1 mutations[40]. In addition to an increased risk to develop breast and ovarian cancer, there is evidence for an increased risk to develop pancreatic cancer[9;23-25,47], prostate cancer[9;24;26;27], colorectal cancer[26,28], gastric cancer[9,25,26], invasive cervical cancer[27], gallbladder and bile duct cancer[9], (only ocular?) malignant melanoma[9,29,30], bone[41], pharyngeal cancer[41] and sarcoma[42,43]. However, the association with colorectal cancer has been disputed[9,31,32]. As in BRCA1 families, fallopian tube cancer may develop in BRCA2 families as well[33].
Cumulative prostate cancer risk by age 60 and 70 has been estimated at 1.6% and 19.8%, respectively[9]. Prostate cancer shows relatively rapid progression in BRCA2 mutation carriers<46>.
The cumulative risks for pancreatic cancer by these ages were 1% and 3.2% in males and 0.7% and 1.5% in females, respectively[9]. In families with breast and/or ovarian cancer, the occurrence of pancreatic cancer should strongly raise the suspicion of an unrecognized BRCA1/2 mutation[45].
An increased risk for lymphoma was calculated for Ashkenazi BRCA2 founder mutation carriers[28]. Childhood cancer appears to be more prevalent in BRCA2 families than in the general population[44].
Kaplan et al.[34] reported a family with a history of breast cancer and papillary serous cancer of the ovary, peritoneum and cervix. Testing for possible underlying BRCA1/2 mutations was declined by the family.

Links

Breast Cancer Linkage Consortium 18 1 08

References

[1] Lynch HT, Lynch JF. Breast cancer genetics in an oncology clinic: 328 consecutive patients. Cancer Genet Cytogenet 1986; 22:369-371.
[2] Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 77[11], 2318-2324. 1996.
[3] Liede A, Tonin PN, Sun CC, Serruya C, Daly MB, Narod SA, Foulkes WD. Is hereditary site-specific ovarian cancer a distinct genetic condition? Am J Med Genet 75[1], 55-58. 1998.
[4] Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, Ghadirian P, Perret C, Moslehi R, Dion F, Faucher MC, Dole K, Karimi S, Foulkes W, Lounis H, Warner E, Goss P, Anderson D, Larsson C, Narod SA, Futreal PA. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 13[1], 120-122. 1996.
[5] Schubert EK, Lee MK, Mefford HC, Argonza RH, Morrow JE, Hull J, Dann JL, King MC. BRCA2 in American families with four or more cases of breast or ovarian cancer: Recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet 60[5], 1031-1040. 1997.
[6] Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H, Seitz S, Cannon-Albright LA, Schofield A, Zelada-Hedman M. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62[3], 676-689. 1998.
[7] Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjord JE. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352[9137], 1337-1339. 1998.
[8] Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, Ozcelik H, Goss P, Allingham Hawkins D, Hamel N, Di Prospero L, Contiga V, Serruya C, Klein M, Moslehi R, Honeyford J, Liede A, Glendon G, Brunet JS, Narod S. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 1999; 91(14):1241-1247.
[9] Easton D, Thompson D, McGuffog L, et.al. Cancer risks in BRCA2 mutation carriers: the breast cancer linkage consortium. J Natl Cancer Inst 1999; 91(15):1310-1316.
[10] Ursin G, Henderson BE, Haile RW, Pike MC, Zhou NM, Diep A, Bernstein L. Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57[17], 3678-3681. 1997.
[11] Jernström H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, Daly M, Olopade OI, Foulkes WD, Warner E, Brunet JS, Narod SA. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 1999; 354(9193):1846-1850.
[12] Brunet JS, Ghadirian P, Rebbeck TR, Lerman C, Garber JE, Tonin PN, Abrahamson J, Foulkes WD, Daly M, Wagner-Costalas J, Godwin A, Olopade OI, Moslehi R, Liede A, Futreal PA, Weber BL, Lenoir GM, Lynch HT, Narod SA. Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90[10], 761-766. 1998.
[13] Baron JA, Haile RW. Protective effect of cigarette smoking on breast cancer risk in women with BRCA1 or BRCA2 mutations??? J Natl Cancer Inst 90[10], 726-727. 1998.
[14] Easton DF, Steele L, Fields P, Ormiston W, Averill D, Daly PA, Mcmanus R, Neuhausen SL, Ford D, Wooster R, Cannon-Albright LA, Stratton MR, Goldgar DE. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet 61[1], 120-128. 1997.
[15] Csokay B, Udvarhelyi N, Sulyok Z, Besznyak I, Ramus S, Ponder B, Olah E. High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. Cancer Res 59[5], 995-998. 1999.
[16] Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod S, Lenoir GM, Lynch H, Feunteun J, Devilee P, Cornelisse CJ, Menko FH, Daly PA, Ormiston W, Mcmanus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994; 265:2088-2090.
[17] Ford D, Easton DF. The genetics of breast and ovarian cancer. Br J Cancer 1995; 72:805-812.
[18] Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BAJ, Stratton MR, Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15[1], 103-105. 1997.
[19] Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, Saigo PE, Almadrones LA, Barakat RR, Brown CL, Chi DS, Curtin JP, Poynor EA, Hoskins WJ. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000; 283(17):2260-2265.
[20] Stratton JF, Thompson D, Bobrow L, Dalal N, Gore M, Bishop DT, Scott I, Evans G, Daly P, Easton DF, Ponder BAJ. The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study. Am J Hum Genet 1999; 65(6):1725-1732.
[21] Verhoog LC, Brekelmans CTM, Seynaeve C, Dahmen G, van Geel AN, Bartels CC, Tilanus-Linthorst MM, Wagner A, Devilee P, Halley DJJ, van den Ouweland AMW, Meijers-Heijboer EJ, Klijn JGM. Survival in hereditary breast cancer associated with germline mutations of BRCA2 [see comments]. J Clin Oncol 1999; 17(11):3396-3402.
[22] Loman N, Johannsson O, Bendahl P, Dahl N, Einbeigi Z, Gerdes A, Borg A, Olsson H. Prognosis and clinical presentation of BRCA2-associated breast cancer. Eur J Cancer 2000; 36(11):1365-1373.
[23] Ozcelik H, Schmocker B, DiNicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S, Redston M. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16[1], 17-18. 1997.
[24] Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjord JE. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet 60[5], 1079-1084. 1997.
[25] Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK. A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 56[15], 3409-3414. 1996.
[26] Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13[1], 117-119. 1996.
[27] Johannsson O, Loman N, Möller T, Kristoffersson U, Borg A, Olsson H. Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers. Eur J Cancer 1999; 35(8):1248-1257.
[28] Kadouri L, Hubert A, Rotenberg Y, Hamburger T, Sagi M, Nechushtan C, Abeliovich D, Peretz T. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. Journal of medical genetics 2007; 44(7):467-71.
[29] Sinilnikova OM, Egan KM, Quinn JL, Boutrand L, Lenoir GM, Stoppa-Lyonnet D, Desjardins L, Levy C, Goldgar D, Gragoudas ES. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer 1999; 82(3):325-328.
[30] Houlston RS, Damato BE. Genetic predisposition to ocular melanoma. Eye 13, 43-46. 1999.
[31] Lin KM, Ternent CA, Adams DR, Thorson AG, Blatchford GJ, Christensen MA, Watson P, Lynch HT. Colorectal cancer in hereditary breast cancer kindreds. Dis Colon Rectum 1999; 42(8):1041-1045.
[32] Wacholder S, Hartge P, Struewing JP, Pee D, McAdams M, Brody L, Tucker M. The kin-cohort study for estimating penetrance. Am J Epidemiol 148[7], 623-630. 1998.
[33] Rose PG, Shrigley R, Wiesner GL. Germline BRCA2 mutation in a patient with fallopian tube carcinoma: a case report. Gynecol Oncol 2000; 77(2):319-320.
[34] Kaplan EJ, Caputo TA, Shen PUF, Sassoon RI, Soslow RA. Familial papillary serous carcinoma of the cervix, peritoneum, and ovary: a report of the first case. Gynecol Oncol 70, 289-294. 1998.
[35] Eerola H, Heikkilä P, Tamminen A, Aittomäki K, Blomqvist C, Nevanlinna H. Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families. Breast cancer research : BCR 2005; 7(1):R93-100.
[36] Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007; 25(11):1329-33.
[37] Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute 2007; 99(23):1811-4.
[38] Breast Cancer Family Registry; Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia); Ontario Cancer Genetics Network (Canada). Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years. Breast cancer research and treatment 2008; 109(1):67-75.
[39] Ginsburg O, Ghadirian P, Lubinski J, Cybulski C, Lynch H, Neuhausen S, Kim-Sing C, Robson M, Domchek S, Isaacs C, Klijn J, Armel S, Foulkes WD, Tung N, Moller P, Sun P, Narod SA, . Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update. Breast cancer research and treatment 2008;epub ahead of publication
[40] Cancer risks in BRCA2 mutation carriers.The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999 Aug 4;91(15):1310-6
[41] van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF, Ausems MG, Menko FH, Gomez Garcia EB, Klijn JG, Hogervorst FB, van Houwelingen JC, van't Veer LJ, Rookus MA, van Leeuwen FE, . Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. Journal of medical genetics 2005; 42(9):711-9.
[42] Evans DG, Wu CL, Birch JM. BRCA2: a cause of Li-Fraumeni-like syndrome. Journal of medical genetics 2008; 45(1):62-3.
[43] Manoukian S, Peissel B, Pensotti V, Barile M, Cortesi L, Stacchiotti S, Terenziani M, Barbera F, Pasquini G, Frigerio S, Pierotti MA, Radice P, Della-Torre G. Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families. European journal of cancer 2007; 43(3):601-6.
[44] Magnusson S, Borg A, Kristoffersson U, Nilbert M, Wiebe T, Olsson H. Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes. Familial cancer 2008; .
[45] Hall MJ, Dignam JJ, Olopade OI. Family history of pancreatic cancer in a high-risk cancer clinic: implications for risk assessment. Journal of genetic counseling 2008; 17(4):365-72.
[46] Narod SA, Neuhausen S, Vichodez G, Armel S, Lynch HT, Ghadirian P, Cummings S, Olopade O, Stoppa-Lyonnet D, Couch F, Wagner T, Warner E, Foulkes WD, Saal H, Weitzel J, Tulman A, Poll A, Nam R, Sun P, , Danquah J, Domchek S, Tung N, Ainsworth P, Horsman D, Kim-Sing C, Maugard C, Eisen A, Daly M, McKinnon W, Wood M, Isaacs C, Gilchrist D, Karlan B, Nedelcu R, Meschino W, Garber J, Pasini B, Manoukian S, Bellati C. Rapid progression of prostate cancer in men with a BRCA2 mutation. British journal of cancer 2008; 99(2):371-4.
[47] Kim DH, Crawford B, Ziegler J, Beattie MS. Prevalence and characteristics of pancreatic cancer in families with BRCA1 and BRCA2 mutations. Familial cancer 2008; epub, ahead of print .
[48] Edwards E, Yearwood C, Sillibourne J, Baralle D, Eccles D. Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer. 2009 Jul 21. [Epub ahead of print]
[49] Diez O, Gutiérrez-Enríquez S, Mediano C, Masas M, Saura C, Gadea N, Balmaña J. A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer.Breast Cancer Res Treat. 2009 Aug 1. [Epub ahead of print]
[50] Gourley C, Michie CO, Roxburgh P, Yap TA, Harden S, Paul J, Ragupathy K, Todd R, Petty R, Reed N, Hayward RL, Mitchell P, Rye T, Schellens JH, Lubinski J, Carmichael J, Kaye SB, Mackean M, Ferguson M. Increased Incidence of Visceral Metastases in Scottish Patients With BRCA1/2-Defective Ovarian Cancer: An Extension of the Ovarian BRCAness Phenotype. J Clin Oncol. 2010 Apr 20. [Epub ahead of print]