Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Simchoni, Sharon; Friedman, Eitan; Kaufman, Bella; Gershoni‐Baruch, Ruth; Orr-Urtreger, Avi; Kedar-Barnes, Inbal; Shiri-Sverdlov, Ronit; Dagan, Efrat; Tsabari, Sigal; Shohat, Mordechai; Catane, Raphael; King, Mary Claire; Lahad, Amnon; Levy-Lahad, Ephrat

doi:10.1073/pnas.0511301103

Cited by 81 publications

(51 citation statements)

References 23 publications

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“…breast or ovary or bilateral breast) of the individual that led to the family ascertainment and the method of ascertainment (i.e. through unselected cancer cases or families with multiple affected individuals) [10,11,15]. Such observations are consistent with the hypothesis that factors clustering in families, genetic and ⁄ or environmental, modify cancer risk in mutation carriers (Fig.…”

Section: Introductionsupporting

confidence: 74%

Unravelling modifiers of breast and ovarian cancer risk forBRCA1andBRCA2mutation carriers: update on genetic modifiers

Barnes¹,

Antoniou²

2012

Journal of Internal Medicine

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Abstract. Barnes DR, Antoniou AC (Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK). Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers (Review). J Intern Med 2012;271: 331-343.Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genomewide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genomewide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.

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Section: Introductionsupporting

confidence: 74%

Unravelling modifiers of breast and ovarian cancer risk forBRCA1andBRCA2mutation carriers: update on genetic modifiers

Barnes¹,

Antoniou²

2012

Journal of Internal Medicine

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“…Length of repeat variations in the androgen receptor gene and in the steroid nuclear receptor coactivator AIB1/NCOA3 were reported to affect breast cancer risk (reviewed in Narod, 2002a), but this has not been confirmed (Spurdle et al, 2005(Spurdle et al, , 2006. A noncoding polymorphism in RAD51, which binds BRCA2 in the DNA repair process, has been shown to increase breast cancer risk in BRCA2 carriers (HR ¼ 3.2À5.5) in three independent studies, all performed in AJs (discussed in Simchoni et al, 2006). There has been one report of an HRAS-linked polymorphism affecting ovarian cancer risk in BRCA1 carriers, but no follow-up studies were published (Narod, 2002a).…”

Section: Other Genetic Factors -Genetic Modifiersmentioning

confidence: 99%

“…There is epidemiological evidence for the existence of such modifiers for BRCA1 and BRCA2 mutations, since there is familial clustering of the cancer site: carriers in families with ovarian cancer index cases are at higher risk for ovarian cancer and at lower risk for breast cancer than carriers from families with breast cancer index cases (Easton et al, 1995;Antoniou et al, 2003;Simchoni et al, 2006). In the case of multiple generation families with different environments, familial clustering is likely to represent sharing of genetic modifiers within families.…”

Section: Other Genetic Factors -Genetic Modifiersmentioning

confidence: 99%

Cancer risks among BRCA1 and BRCA2 mutation carriers

2007

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BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction. BRCA1 and BRCA2 were identified as genes mutated in hereditary breast/ovarian cancer by genetic analysis in families with multiple cases of these malignancies. In the following decade, as BRCA1 and BRCA2 testing became more common in patients with a personal or family history of cancer, numerous studies assessed cancer risks in carriers of these mutations. These studies have resulted in variable risk estimates, leading to difficulties in defining risk figures that are clinically applicable to the individual patient. However, they illuminated the complexities that underlie risk prediction even in the context of a single gene with major effects on cancer predisposition. The emerging picture is that breast and ovarian cancer risks in BRCA1 and BRCA2 carriers are substantially higher than in the general population, but that they are considerably affected by nongenetic, environmental factors, and by additional genetic modifiers. BREAST AND OVARIAN CANCER RISK IN WOMENOriginal estimates of breast and ovarian cancer risks in carriers were based on the families used for positional cloning of the BRCA1 and BRCA2 genes, where all carriers had molecular testing, and all cancer diagnoses were validated. These families were chosen because they harboured multiple, early-onset cases, that is, they were essentially selected for high cancer risk. In the Breast Cancer Linkage Consortium (BCLC) families, by age 70 years, BRCA1 carriers had a breast cancer risk of 71% (95% CI 53 -82%) and an ovarian cancer risk of 47 -63% (Easton et al, 1995). BRCA2 carriers had a breast cancer risk of 84% (95% CI 43 -95%), and an ovarian cancer risk of 27% (95% CI, 0 -47%) (Ford et al, 1998). Many subsequent studies were case-based, that is, risk was estimated by analysis of family history in relatives of breast or ovarian cancer patients, often from hospital-based series (Antoniou et al, 2003). The design of these studies partially addressed the ascertainment bias inherent in studying highly selected, multiple-case families, but risk estimates were based on family history, rather than on testing carriers directly and validating their cancer status. With this design, misclassification can result from discrepancies between modelled vs true carrier status, and from errors in cancer reporting by relatives, a particularly common problem for ovarian cancer. In a meta-analysis of such case-based studies, by age 70 years, in BRCA1 carriers breast cancer risk was 65% (95% CI 51 -75%) and ovarian cancer risk was 39% (95% CI 22 -51%), and in BRCA2 carriers breast cancer risk was 45% (95% CI 33 -54%) and ovarian cancer risk was 11% (95% CI 4.1 -18%) (Antoniou et al, 2003). One s...

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“…9 However, the risks of both breast and ovarian cancers have been reported to be slightly modified by the site of the gene mutation and by either genetic or nongenetic modifying factors. 9,13,14 Ovarian cancer risks are low before the age of 40 and 50 years in BRCA1 and BRCA2 mutation carriers, respectively. In addition to the risk of ovarian cancer, there is a low risk of fallopian tube (FTC) and primary peritoneum carcinomas (PPC).…”

mentioning

confidence: 99%

Prophylactic salpingo‐oophorectomy in a series of 89 women carrying a BRCA1 or a BRCA2 mutation

Laki

Kirova

This

et al. 2007

Cancer

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BACKGROUND.Prophylactic salpingo‐oophorectomy (SO), which is recommended in BRCA1/2 mutation carriers, still needs to be reappraised.METHODS.In all, 89 BRCA1/BRCA2 mutation carriers underwent SO between 1994–2004. Past medical and familial history, SO, results and survival after SO were analyzed.RESULTS.The series consisted of 56 BRCA1 and 33 BRCA2 mutation carriers. All but 1 had a family history of breast (BC) and/or ovarian cancer; 42 BRCA1 and 31 BRCA2 had a personal history of BC. The median age at SO was 44 (BRCA1) and 49.5 (BRCA2) years for women without previous BC (not significant) and 48 (BRCA1) and 53 BRCA2) years (P = .03) for women with previous BC. Occult ovarian (n = 2) and/or fallopian (n = 3) carcinomas were found in 4 patients (4.5%): 1 experienced recurrence (4 years), 2 are disease‐free (26 and 38 months of follow‐up), and 1 died from BC (12 months). Among the other 69 patients with previous BC (median follow‐up, 42 months), 14 developed ipsilateral or contralateral BC and 8 developed metastatic disease. Among the 16 patients without previous BC (median follow‐up, 27 months), 3 developed BC. Of the 89 patients, 85 are still alive: 3 died from BC and 1 died from pancreatic cancer. No peritoneal malignancy was observed.CONCLUSIONS.This study shows that prophylactic SO remains an important option for BRCA1/2 mutation carriers as asymptomatic ovarian/fallopian cancers were found in 4.5% of patients. However, a longer follow‐up and larger series are required to more precisely evaluate the benefits of this procedure in terms of BC incidence, peritoneal malignancy, or recurrence. Cancer 2007. © 2007 American Cancer Society.

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Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Cited by 81 publications

References 23 publications

Unravelling modifiers of breast and ovarian cancer risk forBRCA1andBRCA2mutation carriers: update on genetic modifiers

Unravelling modifiers of breast and ovarian cancer risk forBRCA1andBRCA2mutation carriers: update on genetic modifiers

Cancer risks among BRCA1 and BRCA2 mutation carriers

Prophylactic salpingo‐oophorectomy in a series of 89 women carrying a BRCA1 or a BRCA2 mutation

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