Genetics of ovarian cancer

Genetics of ovarian cancer

Reviews in Gynaecological Practice 4 (2004) 27–31 Genetics of ovarian cancer Suchitra N. Pandit∗ , Sejal P. Desai1 Department of Obstetrics and Gynec...

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Reviews in Gynaecological Practice 4 (2004) 27–31

Genetics of ovarian cancer Suchitra N. Pandit∗ , Sejal P. Desai1 Department of Obstetrics and Gynecology, LTMM College and Hospital, Sion, Mumbai, India Received 1 May 2003; accepted 1 June 2003

Abstract Genetic testing has become an integral part of medicine and incredible progress has been made in understanding the molecular basis of various diseases. Gynecological cancers are no exception. Though most cases of ovarian cancer are sporadic 50% of patients with ovarian cancer demonstrate a familial inheritance pattern. Genes that cause cancer are either oncogenes or tumor suppressor genes. Mutations in proto-oncogenes are dominant in their action and mutations in tumor suppressor genes are recessive. Two genetic loci associated with inherited predisposition to ovarian cancer are BRCA1 and BRCA2. They are believed to be tumor suppressor genes. Women who carry mutations in the MSH2 gene have an approximately 12% lifetime risk for developing ovarian cancer. Risk assessment of an individual would involve detailed family history. Three distinct clinical patterns of familial cancer have been identified. 1. Families with ‘site-specific’ ovarian cancer. 2. Families in whom both breast and ovarian cancer predominate. 3. Families characterised by cases of ovarian cancer, in addition to cases of colon and uterine cancer. Calculating best estimates of the risk of ovarian cancer for a specific individual within a family pedigree usually requires a Bayesian analysis. Recommendations for ovarian cancer surveillance include transvaginal ultrasound with color Doppler flow once or twice a year and measurement of serum CA-125 levels. For high risk families screening from about the age of 25–30 years and continuing until at least 70 years of age has been recommended. Administration of oral contraceptives to patients with history of ovarian/breast cancer in the family has been studied. The effect is still controversial and more over it may increase the risk of breast cancer in these women. It has been proposed that tubal ligation provides significant protection against development of ovarian cancer in women who carry mutation in BRCA genes. In women with history of familial ovarian syndromes, prophylactic oophorectomy has been suggested as a primary procedure but is not 100% effective in preventing primary peritoneal carcinomatosis. Though, prophylactic oophorectomy has the added benefit of reducing the risk of breast cancer. © 2003 Elsevier B.V. All rights reserved. Keywords: Genes; Mutations; Chromosomes; Inheritance; Pedigree

1. Molecular biology The Human Genome Mapping project is on the verge of completion and it will have a tremendous impact on the application of knowledge of genetics in all specialties ∗ Corresponding author. Present address: 6, Little Star Society, R.K. Mission Marg, Santacruz (West), Mumbai 400056, India. E-mail addresses: [email protected] (S.N. Pandit), [email protected] (S.P. Desai). 1 Present address: Avni, Dadiseth Road, Malad (West), Mumbai 400064, India.

1471-7697/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/S1471-7697(03)00066-2

of medicine. The carcinogenesis of gynaecological cancer has imbibed new interests due to better understanding of the molecular basis of the disease. Amongst the gynaecological cancers, ovarian and endometrial cancer can occur as components of familial cancer syndromes owing to germ line inheritance of predisposing genetic abnormalities. The various other factors implicated in the origin of ovarian cancer are geographical distribution, diet, exposure to certain industrial agents like talc and asbestos, the proposed ‘incessant ovulation theory’ and the use of fertility drugs.

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Most causes of ovarian cancer are sporadic. However, a growing body of evidence indicates that about 5% of patients with ovarian cancer demonstrate a familial inheritance pattern [1]. Patient with family histories of ovarian cancer and breast and/or colon cancer appear to be at a substantially increased risk for developing the disease. Genes that cause cancer are of two district types—oncogenes and tumor suppressor genes. Most oncogenes are proto-oncogenes which promote growth. The tumor suppressor gene presents malignant transformation and leads to malignancy only if function of both alleles is lost. The three syndromes identified are given further. 1.1. Site-specific familial ovarian cancer The pattern of recurrence seen in some families as well as formal genetic analysis of ovarian cancer pedigrees, provide evidence for the existence of one or more rare autosomal dominant genes, which confers an increased risk for ovarian cancer in some families. Thus, syndrome is characterised by the presence of two or more first degree relatives or first and second degree relatives who have epithelial ovarian cancer. In case of ‘site-specific’ ovarian cancer, the risk of ovarian cancer by the age of 70 for a women with one first degree relative is about 5%. This is about three times the general population risk of 1.4%. The lifetime risk of ovarian cancer by the age of 70 for a woman with two or more affected first degree relatives has been estimated to range from 7 to 30% [2]. 1.2. Breast–ovarian cancer syndrome This syndrome consists of those families with two or more cases of early onset breast cancer and two or more cases of ovarian cancer. It includes almost all families with breast and ovarian cancer resulting from mutations to the BRCA1 gene. Two genetic loci associated with inherited predisposition to ovarian cancer are BRCA1 and BRCA2. BRCA1 is located on 2cM region on long arm of chromosome 17 and BRCA2 on chromosome 13. BRCA1 functions as a tumor suppressor gene. In order for ovarian (or breast) cancer to develop, mutations must be present in both copies of the gene or the chromosome with the non-mutated form of the BRCA gene must be lost. A woman with an inherited susceptibility already has one mutation and therefore must only acquire one more mutation for cancer to develop. Approximately 8% of women in whom ovarian cancer is diagnosed before the age of 70 years carry a mutation in BRCA1 [3]. Both men and women who carry a mutation in either BRCA1 or BRCA2 have a 50% chance of passing the mutation on to their children and therefore several generations in a family [3]. The BRCA1 mutation 185delAG, which occurs with a carrier frequency of 1% is estimated to account for 39% of ovarian cancer cases prior to the age of 50 years in women of Ashkenazi decent [4].

The approximate lifetime risk for developing ovarian cancer associated with a mutation in BRCA1 or BRCA2 ranges between 60 [5] and 27% [6], respectively. 1.3. Lynch II syndrome The Lynch II syndrome, i.e. hereditary non-polyposis colon cancer or HNPPC which includes multiple adenocarcinomas, involves a combination of familial colon cancer and a high rate of ovarian, endometrial and breast cancers and other malignancies of the gastrointestinal and genitourinary systems. The risk that a woman who is a member of one of these families will develop epithelial ovarian cancer depends on the frequency of this disease in first and second degree relatives, although these women seem to have at least three times the relative risk of the general population. Thus, approximately 10% of all epithelial ovarian carcinomas are associated with autosomal dominant genetic predisposition primarily by inherited mutations [7,8]. Women who carry mutations in the MSH2 gene have an approximately 12% lifetime risk for developing ovarian cancer [9]. • Invasive serous and undifferentiated ovarian carcinomas are characterised by TP53 mutations and TP53 protein accumulation loss of genetic material from chromosome 17 is also common [10]. • Over expression of BCL2 is seen in most endometrioid carcinomas (90%). These tumors can also show micro satellite instability [10]. • KRSA mutations are characteristic for mucinous carcinomas (40–50%). In mucinous tumors with low malignant potential KRAS mutations are less frequent [10]. Table 1 Mutated genes Gene

Location

CTNNB1(CTNNB) PIK3CA SPARC(ON,OSN,BM-40) CDKN1A(P21,WAF1,CIP1) TFAP2A(AP2,AP2TF) ST8(OVCS) IL6(IFNB2) HSPB1(HSP27) MGMT HRAS FOLR1(MOv18,FOLR,FBP) KRAS2(Ki-ras,KRAS,K-RAS) CDKN1B(KIP1,P27) MDM2 BRCA2 LRP(MVP) TP53(p53,P53) ERBB2(HER2,NEU) BRCA1 M17S2(CA-125,NBR1) BCL2 KLK3(PSA,APS) AKT2

3p22-p21.3 3q26.3 5q31.3-q32 6q21.2 6p24 6q26-q27 7q21 7q 10q26 11p15.5 11q13.3-q13.5 12p12.1 12p13 12q13-q14 13q12.3 16p13.1-p11.2 17p13.1 17q11.2-q12 17q21 17q21.1 18q21.3 19q13 19q13.1-q13.2

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• The various other mutated genes and abnormal protein expression are as shown in Table 1 [11]. For the nonepithelial ovarian carcinoma limited evidence exists to support an inherited etiology with two exceptions-benign cystic teratoma and ovarian stroma neoplasias. 1.3.1. Other hereditary syndromes predisposing to ovarian cancer Several genetic conditions are associated with an increased risk of ovarian cancer. • • • • •

Basal cell nevus syndrome XY females (gonadal dysgenesis) Gorlin syndrome Osteochondromatosis Peutz–Jeghers syndrome

2. Risk assessment Women at risk benefit from a thorough pedigree analysis. Testing to determine whether there is a mutation in the BRCA1 gene locus is likely to play an important role. A geneticist should evaluate the family pedigree for at least three generations. There is no specific genetic testing available for families with ‘site-specific’ ovarian cancer other than testing for mutations of BRCA2 or MSH2. The protocol for managing individuals with suspected genetic susceptibility to cancer includes following steps.

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• A negative test result in an unaffected patient when testing of an affected relative is not possible may be falsely reassuring. Prior to undertaking any genetic testing, it is essential that the value and implications of the test results should be thoroughly discussed with the patient.

3. Screening for high risk patients In view of the high risk of ovarian cancer in patient with a family history, it is reasonable to commence screening for this cancer at an early age. There has been evaluation of various screening methods which are aimed at increasing early detection rates. In essence, three techniques are available: history and physical examination, transvaginal ultrasonography and tumor markers—CA-125 levels. For high risk families screening from about the age of 25–30 years and continuing until at least 70 year of age has been recommended [13].

4. Prevention of ovarian cancer Currently the means of preventing ovarian cancer is controversial. 4.1. Oral contraceptives

a. Performing a pedigree analysis to determine if a genetic disorder exists in a family. b. Counselling and education to arrive at a decision whether the individual wishes to undergo genetic testing. c. Genetic testing. d. Disclosure of results by a multidisciplinary team. e. Determination of cancer risk for both carries and non carriers. f. Discussion of options for management. g. Psychological counseling with regard to carrier status. h. Follow up counseling.

Several case-control studies have estimated that the use of oral contraceptives by women in the general population reduces the risk of ovarian cancer by approximately 40% [14]. It is not clear whether this protection applies to women at high risk for developing ovarian cancer due to family history and/or genetic mutations. A recent study by Prentice and Thomas suggested that women who carry BRCA mutations who took oral contraceptive for at least 6 years had a 50% reduction in ovarian cancer risk [15]. The benefits against ovarian and endometrial cancer may be offset by an increased risk of breast cancer in these women.

2.1. Genetic testing for BRCA genes or MSH2 genes

4.2. Tubal ligation

• It is ideal to first test a relative who has had cancer in order to determine that the cancers in the family are associated with a mutation. In many families with familial cancer, the affected relative may be decreased and alternative strategies apply. • Since three specific mutations sites account for 95% of the BRCA mutations in Ashkenazi Jews, an option is to undergo genetic testing for these three mutations, even through an affected member is not available. Studies suggest that as many as 2–2.5% of Ashkenazi Jewish women carry one of these mutations, regardless of their personal or family history of cancer [12]

A recent multinational, retrospective, case-control study showed that tubal ligation provides significant protection against the development of ovarian cancer in women who carry mutations in the BRCA genes. The data suggest that for women who carry BRCA mutations and have completed child bearing tubal ligation is a feasible option to reduce the risk of ovarian cancer [16]. 4.3. Prophylactic oophorectomy Prophylactic oophorectomy is an alternative to ovarian cancer screening for women at high risk of developing

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ovarian cancer. Recent studies suggest that prophylactic oophorectomy in women who carry BRCA mutations reduces the risk of developing ovarian cancer by 90%. The younger the woman was at the time of oophorectomy, the greater benefit she received in terms of life years gained [17,18]. Unfortunately, prophylactic oophorectomy is not 100% effective in preventing primary peritoneal carcinomatosis, which histologically resembles ovarian cancer. The peritoneum shares a common embryonic origin with the epithelium of the ovary and therefore a prophylactic oophorectomy does not remove all the cells in the peritoneum that are at risk for malignant transformation [19,20]. Prophylactic oophorectomy has the added benefit of reducing the risk of breast cancer and in women who carry BRCA mutations this reduction in risk may be as much as 50%. The current recommendations of the committee on Gynaecological practice of the American College of Obstetricians and Gynecologists are summarized below [21]. 1. Women who wish to preserve their reproductive capacity should undergo periodic screening by transvaginal ultrasonography every 6 months and should consider prophylactic oophorectomy when child bearing is completed. 2. Women with familial ovarian or hereditary breast/ovarian cancer syndrome who do not wish to maintain their fertility should be offered prophylactic bilateral salpingooophorectomy. The role of BRCA1 testing in these women is being evaluated. Women with documented Lynch II syndrome should be treated in the same manner as women with familial breast/ovarian cancer syndrome but in addition, they should undergo periodic screening mammography, colonoscopy and endometrial biopsy.

5. Practice points • Ovarian cancer do demonstrate a familial inheritance pattern. • TWO genetic loci are associated with inherited predisposition to ovarian cancer are BRCA1 and BRCA2. • Recommendation for ovarian cancer surveillance include transvaginal ultrasound with color doppler and measurement of CA-125 levels. • Prophylactic oophorectomy is an alternative ovarian cancer screening for high risk women. • The means for prevention of ovarian cancer are controversial.

6. Research directions Site-specific familial ovarian cancer was rarely reported before 1970. A series of reports in that decade spurred the interest of researches at Roswell Park Cancer Institute, with the

resultant establishment of the Gilda Radner Familial Ovarian Cancer Registry. As of 1994, the registry had assessed 1146 families comprising some 2600 cases and 25,000 relatives. More such cancer registries should be set up and all patients having histories of familial cancers should be registered. Such cancer registries encourage research in this field and they provide a strong support group for patients. Also the BRCA1 and BRCA2 genes are larger and the vast numbers of mutations are not localized to specific locations, analysis of these genes for mutations is not yet feasible in the clinical setting. References [1] Piver MS, Hempling RE. Ovarian cancer: screening, prophylactic oopherectomy and surgery—TeLinde’s operative gynaecology. 8th ed., vol. 51. Philadelphia: Lippincort-Raven. p. 1557–68. [2] Claus EB, Schwartz PE. Familial ovarian cancer. Update and clinical applications. Cancer 1995;76(Suppl 10):1998–2003. [3] Lynch HT, Fitzsimmons ML, Conway TA, Bewtra C, Lynch J. Hereditary carcinoma of the ovary and associated cancers: a study of two families. Gynecol Oncol 1990;36(1):48–55. [4] Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60(3):505–14. [5] Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343(8899):692–5. [6] Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62(3):676–89. [7] Boyd J. Molecular genetics of hereditary ovarian cancer. Oncology (Huntingt). 1998 Mar;12(3):399–406; discussion 409–10, 413. [8] Diebold J. Molecular genetics of ovarian carcinomas. Histol Histopathol 1999;14(1):269–77. [9] Brown GJ, St John DJ, Macrae FA, Aittomaki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol 2001;80(3):346–9. [10] Pieretti M, Cavalieri C, Conway PS, Gallion HH, Powell DE, Turker MS. Genetic alterations distinguish different types of ovarian tumors. Int J Cancer 1995;64(6):434–40. [11] Mutated genes and abnormal protein expression. Cancer-genetics. Org. [12] Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 1996;14(2):188–90. [13] Tonin P, Weber B, Offit K, Couch F, Rebbeck TR, Neuhausen S, et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 1996;2(11):1179–83. [14] Hensley ML, Castiel M, Robson ME. Screening for ovarian cancer: what we know, what we need to know. Oncology (Huntingt). 2000 Nov;14(11):1601–7, discussion 1608, 1613–6. [15] Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987;49:285–401. [16] Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998;339(7):424–8. [17] Narod SA, Sun P, Ghadirian P, Lynch H, Isaacs C, Garber J, et al. Tubal ligation and risk of ovarian cancer in carriers of BRCA1

S.N. Pandit, S.P. Desai / Reviews in Gynaecological Practice 4 (2004) 27–31 or BRCA2 mutations: a case-control study. Lancet 2001;357(9267): 1467–70. [18] Schrag D, Kuntz KM, Garber JE, Weeks JC. Decision analysis— effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 1997;336(20):1465–71. [19] Schrag D, Kuntz KM, Garber JE, Weeks JC. Life expectancy gains from cancer prevention strategies for women with breast can-

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cer and BRCA1 or BRCA2 mutations. JAMA 2000;283(5):617– 24. [20] Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni Jr JF. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 1982;2(8302):795–7. [21] Chen KT, Schooley JL, Flam MS. Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome. Obstet Gynecol 1985;66(Suppl 3):93S–4S.