Evidence for an ancient BRCA1 pathogenic variant in inherited breast cancer patients from Senegal.,npj Genomic Medicine

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Evidence for an ancient BRCA1 pathogenic variant in inherited breast cancer patients from Senegal.
npj Genomic Medicine ( IF 4.7 ) Pub Date : 2020-01-31 , DOI: 10.1038/s41525-020-0114-7
Rokhaya Ndiaye _{1,

2,

3} , Jean Pascal Demba Diop ₁ , Violaine Bourdon-Huguenin ₄ , Ahmadou Dem ₅ , Doudou Diouf ₅ , Mamadou Moustapha Dieng ₅ , Pape Saloum Diop ₂ , Serigne Modou Kane Gueye ₂ , Seydi Abdoul Ba ₁ , Yacouba Dia ₁ , Sidy Ka ₅ , Babacar Mbengue ₂ , Alassane Thiam ₆ , Maguette Sylla Niang ₂ , Papa Madieye Gueye ₂ , Oumar Faye ₁ , Philomene Lopez Sall ₂ , Aynina Cisse ₂ , Papa Amadou Diop ₂ , Hagay Sobol ₄ , Alioune Dieye ₂

Affiliation

BRCA1 and BRCA2 are the most incriminated genes in inherited breast/ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in sub-Saharan Africa. The objectives of this study were to identify pathogenic variants of the BRCA genes involved in hereditary breast cancer in Senegal and to search for a founder effect. We recruited after free informed consent, 27 unrelated index cases diagnosed with breast cancer and each having a family history. Mutation screening of the genes identified a duplication of ten nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) (NM_007294.3) located in exon 11 of BRCA1 gene, in 15 index cases (allelic frequency 27.7%). The pathogenic variant has been previously reported in African Americans as a founder mutation of West African origin. Haplotypes analysis of seven microsatellites surrounding the BRCA1 gene highlights a shared haplotype encompassing ~400 kb between D17S855 and D17S1325. This haplotype was not detected in none of 15 healthy controls. Estimation of the age of the pathogenic variant suggested that it occurred ~1400 years ago. Our study identified a founder pathogenic variant of BRCA1 predisposing to breast cancer and enabled the establishment of an affordable genetic test as a mean of prevention for Senegalese women at risk.

中文翻译：

来自塞内加尔的遗传性乳腺癌患者中古代BRCA1致病变异的证据。

在遗传性乳腺癌/卵巢癌中，BRCA1和BRCA2是最关键的基因。这些基因的几种致病变异赋予了遗传易感性，已经在不同人群中进行了描述，但在撒哈拉以南非洲却很少。这项研究的目的是确定与塞内加尔遗传性乳腺癌有关的BRCA基因的致病变异，并寻找建立者的作用。在征得自由知情同意后，我们招募了27例不相关的索引病例，这些病例被诊断出患有乳腺癌，每个都有家族病史。在15个索引病例中（等位基因频率为27.7％），对基因的突变筛选确定了位于BRCA1基因第11外显子的十个核苷酸c.815_824dupAGCCATGTGG（p.Thr276Alafs）（NM_007294.3）的重复。先前已在非裔美国人中报告了这种致病性变异，是西非血统的创始人突变。围绕BRCA1基因的七个微卫星的单倍型分析突出显示了在D17S855和D17S1325之间包含约400 kb的共享单倍型。15个健康对照者均未检测到此单倍型。对病原体变体年龄的估计表明它发生在大约1400年前。我们的研究确定了BRCA1的创始人致病性变异体易患乳腺癌，并使人们能够建立起负担得起的基因检测手段，以预防处于危险中的塞内加尔妇女。对病原体变体年龄的估计表明它发生在大约1400年前。我们的研究确定了BRCA1的创始人致病性变异体易患乳腺癌，并使人们能够建立起负担得起的基因检测手段，以预防处于危险中的塞内加尔妇女。对病原体变体年龄的估计表明它发生在大约1400年前。我们的研究确定了BRCA1的创始人致病性变异体易患乳腺癌，并使人们能够建立起负担得起的基因检测手段，以预防处于危险中的塞内加尔妇女。

更新日期：2020-01-31

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