FaCD Online Syndrome Fact Sheet

Last updated: 31 Oct 2011

Name: Ovarian Cancer, Familial Clustering of

Synonym: incl.: Ovarian Germ Cell Tumors, Familial Clustering of

Mode of Inheritance: multifact?

OMIM number: 604370  

Genes

BRIP1, mapped to 17q23.2
RAD51D, mapped to 17q11

Tumor features

breast cancer
colorectal cancer
endometrial cancer
gastric cancer
ovarian cancer (i.e. epithelial origin)
ovarian chorionic carcinoma
ovarian dysgerminoma
ovarian endodermal sinus tumor
ovarian granulosa cell tumor
ovarian teratoma
pancreatic adenocarcinoma
prostate cancer

Tumor features (possible)

multiple myeloma (Kahler's disease)
non-Hodgkin lymphoma
testicular germ cell tumor

Non-tumor features (possible)

oligodontia / hypodontia

Comment

A family history of ovarian cancer has been documented in 1-7% of patients with this tumor[1]. The estimations of the proportion of hereditary cases range between less than 1% and up to 20%[1-5], although 5-10% is probably the most realistic educated guess.

First-degree relatives of ovarian cancer patients have a relative risk (RR) of developing this tumor of approximately 3-5[6-11], although RR's as high as 11-18 have been calculated in some studies[12,13]. Second degree relatives have a RR of 2-3, and third degree relatives of affected patients have a RR of approximately 1.5 to develop ovarian cancer[3,8]. A study in the Swedish population calculated SIRs for all invasive ovarian cancer of 2.7 (95% CI 2.2-3.2) by ovarian cancer in mother, 2.9 (1.4-5.9) by an affected sister and 24.0 (6.1-74.5) by both an affected mother and sister[32]. A cumulative life-time risk of developing ovarian cancer of 5-6% has been estimated for first-degree relatives and 4-5% for second degree relatives of affected women[1]. Additional affected relatives further increase the risk: having two or three affected relatives is associated with a risk of approximately 7-11%[1,14], although some suggest that the percentage in case of two affected first-degree relatives should rather be estimated at 20%[15].

A decrease in age at diagnosis in the index case is associated with an increase in risk for relatives [6,9]. However, this dependence on age at diagnosis has not been observed in all studies[2,16]. A population-based study performed by Stratton et al.[17] of 101 women with invasive ovarian cancer diagnosed <30 years failed to detect any BRCA1/2 mutations and detected 2 hMLH1 mutations (2%). Histology differed from those diagnosed at a later age in that both borderline and mucinous types were more frequent. This observation is consistent with the fact that ovarian cancer <30 years is very rare in known BRCA1/2 and Lynch syndrome families and, at least in BRCA1-associated ovarian cancer, the mucinous and borderline types are underrepresented. The authors also studied the occurrence of cancer in the relatives of their (diagnosis <30) patients and found that first-degree relatives had an increased risk to develop ovarian cancer (RR = 4.8), non-Hodgkin lymphoma (RR = 7) and myeloma (RR = 10). In terms of absolute/cumulative cancer risks, the authors concluded that, in the absence of a convincing family cancer history, early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives. An Italian study showed that a family history of ovarian/breast cancer was associated with the risk of all ovarian cancer types, except mucinous ones[34].Lynch syndrome syndrome is a rare cause of <40 years ovarian cancer[35]. It has been suggested that 2% of all ovarian cancer is caused by Lynch syndrome[36].

A family history of cancer of the endometrium, pancreas or breast has been associated with increased risk of ovarian cancer[3,18,19,33] and the same applies to a family history of cancer of the colon, rectum, prostate or stomach[10,13]. Compared to breast cancer, bilaterality of ovarian cancer probably is not as strong an indicator of genetic predisposition[20]. All histological types of ovarian tumors have been observed in familial clusters, including small cell carcinomas, dysgerminomas and fibromas[21-24]. However, in familial ovarian cancer, serous cystadenocarcinomas are overrepresented and mucinous adenocarcinomas are underrepresented, compared with sporadic cases[2,21]. Some studies have indicated an association between a family history of breast or endometrial cancer and the occurrence of, in particular, endometrioid ovarian cancer[19]. Risk to develop endometroid type ovarian cancer is particularly increased for daughters of women with endometrial cancer[33]. Whether borderline ovarian cancer is a familial risk factor for ovarian cancer is as yet unclear[2,21,25].

A few rare cases of familial ovarian germ cell tumors have been reported[26] and some of these families include males with germ cell tumors[27,28,37]. Ovarian cancer associated with teratomas in male relatives have been observed as well[29,37]. In a study of the families of 78 women with an ovarian germ cell malignancy, Shulman et al.[30] did not observe an increased risk for this tumor type in first- and second-degree relatives. Interestingly, hypodontia has been reported as a risk factor for epithelial ovarian cancer[31].

RAD51D germline mutations increase the risk to develop ovarian cancer 6-fold[38] and BRIP1 8-fold[39].

References

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[2] Narod SA, Madlensky L, Bradley L, Cole D, Tonin P, Rosen B, Risch HA. Hereditary and familial ovarian cancer in southern Ontario. Cancer 1994; 74:2341-2346.
[3] Kerber RA, Slattery ML. The impact of family history on ovarian cancer risk: The Utah population database. Arch Intern Med 1995; 155:905-912.
[4] Claus EB, Schwartz PE. Familial ovarian cancer: Update and clinical applications. Cancer 1995; 76:1998-2003.
[5] Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 77[11], 2318-2324. 1996.
[6] Auranen A, Pukkala E, Makinen J, Sankila R, Grenman S, Salmi T. Cancer incidence in the first-degree relatives of ovarian cancer patients. Br J Cancer 74[2], 280-284. 1996.
[7] Purdie D, Green A, Bain C, Siskind V, Ward B, Hacker N, Quinn M, Wright G, Russell P, Susil B. Reproductive and other factors and risk of epithelial ovarian cancer: An Australian case-control study. Int J Cancer 1995; 62:678-684.
[8] Schildkraut JM, Thompson WD. Familial ovarian cancer: a population-based case-control study. Am J Epidemiol 1988; 3:456-466.
[9] La Vecchia C, Parazzini F, Negri E, Del Pino D, Franceschi S. Family history and risk of ovarian cancer. Int J Cancer 67[6], 903-904. 1996.
[10] Houlston R, Path MRC, Bourne TH, Davies A, Whitehead MI, Campbell S, Collins WP, Slack J. Use of family history in a screening clinic for familial ovarian cancer. Gynecol Oncol 1992; 47:247-252.
[11] Amos CI, Struewing JP. Genetic epidemiology of epithelial ovarian cancer. Cancer 1993; 71:566-572.
[12] Hildreth NG, Kelsey JL, Livolsi VA, Fischer DB, Holford TR, Mostow ED, Schwartz PE, White C. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981; 114(3):398-405.
[13] Cramer DW, Hutchison GB, Welch WR, Scully RE, Ryan KJ. Determinants of ovarian cancer risk. I. Reproductive experiences and family history. J Natl Cancer Inst 1983; 71(4):711-716.
[14] Sutcliffe S, Pharoah PD, Easton DF, Ponder BAJ. Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. Int J Cancer 2000; 87(1):110-117.
[15] Foulkes WD, Narod SA. Ovarian cancer risk and family history. Lancet 349[9055], 878. 1997.
[16] Amos CI, Shaw GL, Tucker MA, Hartge P. Age at onset for familial epithelial ovarian cancer. JAMA 1992; 268:1896-1899.
[17] 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.
[18] Schildkraut JM, Risch N, Thompson WD. Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship. Am J Hum Genet 1989; 45:521-529.
[19] Schildkraut JM, Thompson WD. Relationship of epithelial ovarian cancer to other malignancies within families. Genet Epidemiol 1988; 5:355-367.
[20] Narod SA. Genetics of breast and ovarian cancer. Br Med Bull 1994; 50:656-676.
[21] Piver MS, Baker TR, Jishi MF, Sandecki AM, Tsukada Y, Natarajan N, Mettlin CJ, Blake CA. Familial ovarian cancer. A report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 1993; 71:582-588.
[22] Longy M, Toulouse C, Mage P, Chauvergne M, Trojani M. Familial cluster of ovarian small cell carcinoma: A new mendelian entity? J Med Genet 33[4], 333-335. 1996.
[23] Jackson SM. Ovarian dysgerminoma in three generations? J Med Genet 1967; 4:112-113.
[24] Dumont-Herskowitz RA, Safaii HS, Senior B. Ovarian fibromata in four successive generations. J Pediat 1978; 4:621-624.
[25] Shushan A, Paltiel O, Gordon L, Schenker JG. Ovarian cancer of low malignant potential is not associated with positive familial history. Am J Obstet Gynecol 175[2], 507-508. 1996.
[26] Simon A, Ohel G, Neri A, Schenker JG. To the point: familial occurrence of mature ovarian teratomas. Obstet Gynecol 1985; 66:278-279.
[27] Stettner AR, Hartenbach EM, Schink JC, Huddart R, Becker J, Pauli R, Long R, Laxova R. Familial ovarian cell cancer: report and review. Am J Med Genet 84, 43-46. 1999.
[28] DiBella NJ. Familial gonadal neoplasms. N Engl J Med 1983; 309(22):1389.
[29] Tischkowitz M, Pilz D, Harper PS. Familial gonadal tumours. J Med Genet 1998; 35:84.
[30] Shulman LP, Muram D, Marina N, Jones C, Portera JC, Wachtel SS, Simpson JL, Elias S. Lack of heritability in ovarian germ cell malignancies. Am J Obstet Gynecol 1994; 170(6):1803-1805.
[31] Chalothorn LA, Beeman CS, Ebersole JL, Kluemper GT, Hicks EP, Kryscio RJ, DeSimone CP, Modesitt SC. Hypodontia as a risk marker for epithelial ovarian cancer: a case-controlled study. Journal of the American Dental Association 2008; 139(2):163-9.
[32] Hemminki K, Granström C. Familial invasive and borderline ovarian tumors by proband status, age and histology. International journal of cancer 2003; 105(5):701-5.
[33] Hemminki K, Granström C. Familial clustering of ovarian and endometrial cancers. European journal of cancer 2004; 40(1):90-5.
[34] Chiaffarino F, Parazzini F, Bosetti C, Franceschi S, Talamini R, Canzonieri V, Montella M, Ramazzotti V, Franceschi S, La Vecchia C. Risk factors for ovarian cancer histotypes. European journal of cancer 2007; 43(7):1208-13.
[35] Domanska K, Malander S, Måsbäck A, Nilbert M. Ovarian cancer at young age: the contribution of mismatch-repair defects in a population-based series of epithelial ovarian cancer before age 40. International journal of gynecological cancer 2007 Jul-Aug; 17(4):789-93.
[36] Malander S, Rambech E, Kristoffersson U, Halvarsson B, Ridderheim M, Borg A, Nilbert M. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecologic oncology 2006; 101(2):238-43.
[37] Giambartolomei C, Mueller CM, Greene MH, Korde LA. A mini-review of familial ovarian germ cell tumors: an additional manifestation of the familial testicular germ cell tumor syndrome. Cancer Epidemiol. 2009 Jul;33(1):31-6.
[38] Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L; Breast Cancer Susceptibility Collaboration (UK), Eccles D, Evans DG, Renwick A, Seal S, Lord CJ, Ashworth A, Reis-Filho JS, Antoniou AC, Rahman N. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011 Aug 7. [Epub ahead of print]
[39] Rafnar T et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nature genetics 2011; 43:1104-7.