Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients

Abstract

). Only 5-10% of breast cancers are associated with mutations in the susceptibility genes BRCA1 and BRCA2. However, in cases associated with strong family history, mutation rates are higher, ranging from 16% to 26% for BRCA1 [1][2][3] and from 7% to 13% for BRCA2.2 3 However, many breast cancer patients with strong family histories have no obvious mutations in BRCA1/2. While there is an active search for other breast cancer susceptibility genes, it is possible that the true contributions of BRCA1 and BRCA2 to early onset breast cancer have been underestimated. Indeed, one study has shown that only 63% of breast cancer families linked to BRCA1 are associated with detectable mutations in BRCA1. 4Several reasons for this discrepancy are possible. For example, mutations in BRCA1 promoter sequences might be undetectable by current detection techniques. Additionally, inherited genomic rearrangements that inactivate BRCA1 and BRCA2 but cannot be detected by conventional polymerase chain reaction (PCR) based assays have been reported. 5-10Finally, it is possible that some genetic variants previously dismissed as ''unclassified variants'' or ''polymorphisms'' may have hitherto underappreciated effects on protein synthesis or function.Most studies of BRCA1 and BRCA2 associated breast cancers have focused on white populations, yet several observations suggest that there might be a genetic component to breast cancer susceptibility in families of African ancestry.11 Breast cancer is less common in African populations than in other populations but, when it does occur, it is characterised by an early age of onset and a higher mortality.12-14 Additionally, histopathological studies have revealed striking similarities between breast tumours that occur in BRCA1 mutation carriers and patients of African descent, including a higher likelihood of being high grade, hormone receptor negative, and showing increased S-phase and nuclear atypia. 15-21Thus it is important to know whether BRCA1 and/or BRCA2 mutations play any role in the early onset breast cancers that disproportionately affect patients of African ancestry. We previously described the first analysis of truncating BRCA1 and BRCA2 alleles in a population of Nigerian breast cancer patients aged 40 years or younger. 22 This study showed that, while protein truncating alleles are surprisingly less frequent in the Nigerian cohort than other populations studied, the total level of genetic variability in these genes was very high. In the present study, we examine whether non-truncating alleles of BRCA1 or BRCA2 are associated with breast cancers in a similar cohort. Specifically, we addressed whether BRCA1/2 sequence variations are more frequent in African breast cancer populations than in other populations; whether there is a distinctive spectrum of BRCA1/2 sequence variations in African patients that may identify functionally critical protein domains; and whether there are founder mutations that occur frequently in breast cancer populations of African descent. Key pointsN Breast ...

DNA-repair genetic polymorphisms and risk of breast cancer in Cyprus

“…This variant has been found in many individuals with a family history of breast cancer and has been classified as a variant of no clinical significance in the Breast Cancer Information Core Database (BIC) [16]. On the other hand, in silico prediction methods suggest that this is a nontolerated amino acid substitution within the limits of confidence in the alignments [17]. Therefore, until functional data become available, the pathogenicity of this variant cannot be excluded, and it may be a variant that increases risk moderately, but is indeed, not highly penetrant.…”

Prevalence of Pathogenic BRCA1 Mutation Carriers in 5 US Racial/Ethnic Groups

“…In contrast, 1 large series of high-risk patients estimated a similar prevalence in patients of African or European ancestry. 12 Other studies in African American women 12,[25][26][27][28][29][30][31][32] or Nigerian women 33,34 did not include other racial/ethnic groups for direct comparison.…”

Young breast cancer patients in the developing world: incidence, choice of surgical treatment and genetic factors

“…4,6 Mutation rates are higher in patients with a strong family history ranging from 16-26% in BRCA 1 and 7-13% in BRCA 2. 4 In patients with BRCA 1 mutation, there is a 50% chance of developing breast cancer by age 50, and an 80% chance by 70 years of age. 13 The lifetime risk for ovarian cancer in these patients is 1 in 2.…”

“…Fackenthal et al analysed 39 young Nigerian breast cancer patients and found that 74% carried at least one BRCA 1 and 2 variation with 69% having sequence variation in BRCA 2, representing a higher frequency of BRCA 2 variants compared to a previously studied white cohort. 4 It is proposed that the significant genetic variation in BRCA 1 and 2 may contribute to breast cancer risk. No founder mutation was identified in this study.…”

“…The extent of the contribution of BRCA 1 and 2 to the breast cancer burden in Africa is uncertain. 5,15,4 Another 15-20% of breast cancers in young women are associated with gene polimorphisms and environmental factors, and the rest of the remaining breast cancer cases are thought to be sporadic. 6 There are other rare genetic causes that predispose young women to breast cancer.…”