Abstract
BackgroundThe spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history.MethodsThe study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2).DiscussionWe found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component.This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-1-20) contains supplementary material, which is available to authorized users.
Highlights
Hereditary breast cancer accounts for 5-10% of all Breast cancer (BC) cases [1] and is characterized by dominant inheritance, premenopausal diagnosis, more severe course, bilaterality and frequent association with ovarian cancer (OC) [2]
Breast-ovarian cancer (BOC)-causing mutations and other genetic variants are distributed along the entire coding and non-coding regions of BRCA1 and BRCA2, and more than 3400 gene variants have been described in the Breast Cancer Information Core (BIC) [7]
We describe for the first time in Argentina the results of BRCA1/BRCA2 germline analysis in 134 BOC probands selected either for diagnosis within 40 years of age (37 cases) or for family history (FH) (97 cases) (Tables 1 and 2)
Summary
Hereditary breast cancer accounts for 5-10% of all BC cases [1] and is characterized by dominant inheritance, premenopausal diagnosis, more severe course, bilaterality and frequent association with ovarian cancer (OC) [2]. The prevalences of BRCA1/BRCA2 mutations in BOC patients with early onset (EO) and/or BOC family history (FH) appear to be similar across race/ethnicity, but there is evidence of important racial and/or geographic differences in the spectrum of BRCA1/2 genetic variation, including pathogenic mutations and variants of uncertain significance. These differences may reflect population history and genetic drifts, and could have a significant impact on genetic counselling, genetic testing, and follow-up care [8]. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history
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