Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

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Genetic risk factors for familial ovarian cancer

Menopause International ◽

10.1258/136218002100321776 ◽

2002 ◽

Vol 8 (3) ◽

pp. 92-97

Author(s):

Elmar Stickeler ◽

Ingo B Runnebaum

Keyword(s):

Ovarian Cancer ◽

Family History ◽

Cancer Risk ◽

Brca2 Mutation ◽

Individual Risk ◽

Ovarian Cancer Risk ◽

Cancer Syndrome ◽

Brca1 And Brca2 ◽

Ovarian Cancers ◽

Mutation Carriers

In Europe ovarian cancer represents the third most common cancer of the female genital tract, with 30,000 newly diagnosed patients per year. Family history is the most significant risk factor. Lifetime risk for ovarian cancer increases from 1.4% for women with a negative family history to 14.6-32.2% in women from affected families. About 5-10% of ovarian cancers are hereditary and supposed to occur in three different forms: hereditary breast and ovarian cancer syndrome (HBOC), site-specific hereditary ovarian cancer (HOC) and hereditary nonpolyposis colorectal cancer syndrome (HNPCC). HBOC and HOC account for 80-90% of the cases and are associated with inactivating germline mutations of the BRCA1 and BRCA2 genes. For BRCA1 and BRCA2 mutation carriers the cumulative risk by age 70 of developing ovarian cancer is 45-60% and 25-30%, respectively. Approximately 10-15% of familial ovarian cancers are related to the HNPCC syndrome with a cumulative ovarian cancer risk of 9% by age 70. Germline polymorphisms may further modify ovarian cancer risk. Bilateral prophylactic oophorectomy reduces the risk of developing ovarian cancer in HBOC and HOC families by 50%. Tubal ligation also significantly reduces the risk in BRCA1 mutation carriers (odds ratio 0.39). Knowledge of the genetic background provides an objective basis for individual risk assessment and prevention.

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Management of hereditary ovarian cancer

Orvosi Hetilap ◽

10.1556/oh.2011.29218 ◽

2011 ◽

Vol 152 (40) ◽

pp. 1596-1608 ◽

Cited By ~ 2

Author(s):

József Gábor Joó ◽

Szabolcs Ládi ◽

B. Zsolt Nagy ◽

Zoltán Langmár

Keyword(s):

Ovarian Cancer ◽

Hereditary Ovarian Cancer ◽

Brca1 And Brca2 ◽

Ovarian Cancers ◽

Brca2 Mutations ◽

Histological Phenotype ◽

Brca1 Brca2 ◽

Brca1 And Brca2 Mutations ◽

High Level ◽

Associated Tumors

Mutations in BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. Approximately 10% of cases of ovarian cancer are due to germline mutations in BRCA1 and BRCA2. Ovarian cancer associated with BRCA1 and BRCA2 mutations has a distinct histological phenotype. This type of cancer is predominantly of serous or endometrioid histology and is high grade. Patients with BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 40 years, or when childbearing is complete. Nowadays there are no differences between the treatments provided for sporadic and hereditary ovarian cancer, although there are indications that targeted therapy is effective in women with BRCA1/BRCA2-associated tumors. Retrospective studies reveal a high level of sensitivity to platinum agents in BRCA-associated tumors and initial trials show good efficacy and tolerability for polyADP-ribose polymerase inhibitors in mutation carriers with advanced ovarian cancers. These agents might also potentially be used in chemoprevention. Authors review the current management of hereditary ovarian cancer. Orv. Hetil., 2011, 152, 1596–1608.

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Psychological and Behavioral Implications of Screening for Breast or Ovarian Cancer Predisposition Genes BRCA1 and BRCA2

Baylor University Medical Center Proceedings ◽

10.1080/08998280.1999.11930150 ◽

1999 ◽

Vol 12 (2) ◽

pp. 87-92

Author(s):

Karen T. Lesniak ◽

Tonya G. Callaway ◽

Becky Althaus ◽

Charles A. Guarnaccia ◽

Joanne L. Blum

Keyword(s):

Ovarian Cancer ◽

Cancer Predisposition ◽

Brca1 And Brca2 ◽

Predisposition Genes

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Association between contemporary hormonal contraception and ovarian cancer in women of reproductive age in Denmark: prospective, nationwide cohort study

BMJ ◽

10.1136/bmj.k3609 ◽

2018 ◽

pp. k3609 ◽

Cited By ~ 14

Author(s):

Lisa Iversen ◽

Shona Fielding ◽

Øjvind Lidegaard ◽

Lina S Mørch ◽

Charlotte W Skovlund ◽

...

Keyword(s):

Ovarian Cancer ◽

Relative Risk ◽

Hormonal Contraception ◽

Reproductive Age ◽

Hormonal Contraceptives ◽

Ovarian Cancer Risk ◽

Women Of Reproductive Age ◽

Ovarian Cancers ◽

Study Population ◽

Combined Hormonal Contraceptives

AbstractObjectivesTo investigate the association between contemporary combined hormonal contraceptives (including progestogen types in combined preparations and all progestogen-only products) and overall and specific types of ovarian cancer.DesignProspective, nationwide cohort study.SettingDenmark, 1995-2014.ParticipantsAll women aged 15-49 years during 1995-2014 were eligible. Women were excluded if they immigrated after 1995, had cancer (except non-melanoma skin cancer), had venous thrombosis, or were treated for infertility before entry (final study population included 1 879 227 women). Women were categorised as never users (no record of being dispensed hormonal contraception), current or recent users (≤1 year after stopping use), or former users (>1 year after stopping use) of different hormonal contraceptives.Main outcome measuresPoisson regression was used to calculate relative risk of ovarian cancer among users of any contemporary combined hormonal contraceptives and by progestogen type in combined preparations and all progestogen-only products, including non-oral preparations. Separate analyses examined women followed up to their first contraception type switch and those with full contraceptive histories. Duration, time since last use, and tumour histology were examined and the population prevented fraction were calculated.ResultsDuring 21.4 million person years, 1249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13 344 531 person years. Never users had 771 ovarian cancers during 8 150 250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (relative risk 0.58 (95% confidence interval 0.49 to 0.68) and 0.77 (0.66 to 0.91), respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82 (0.59 to 1.12) with ≤1 year use to 0.26 (0.16 to 0.43) with >10 years’ use; P<0.001 for trend). Similar results were achieved among women followed up to their first switch in contraceptive type. Little evidence of major differences in risk estimates by tumour type or progestogen content of combined oral contraceptives was seen. Use of progestogen-only products were not associated with ovarian cancer risk. Among ever users of hormonal contraception, the reduction in the age standardised absolute rate of ovarian cancer was 3.2 per 100 000 person years. Based on the relative risk for the never use versus ever use categories of hormonal contraception (0.66), the population prevented fraction was estimated to be 21%—that is, use of hormonal contraception prevented 21% of ovarian cancers in the study population.ConclusionsUse of contemporary combined hormonal contraceptives is associated with a reduction in ovarian cancer risk in women of reproductive age—an effect related to duration of use, which diminishes after stopping use. These data suggest no protective effect from progestogen-only products.

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