Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families
Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families
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DOI：
10.1007/s10689-012-9540-8
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发表时间：
2012-09-01
期刊：
影响因子：
2.2
通讯作者：
Peterlongo, Paolo
中科院分区：
文献类型：
--
作者：
Catucci, Irene;Milgrom, Roni;Peterlongo, Paolo
BRCA1和BRCA2的种系突变占遗传性乳腺癌的30%。基于BRIP1和PALB2在维持细胞完整性方面的作用，它们可能是乳腺癌易感性的基因。事实上，在种族多样化的乳腺癌家族中，这两个基因的致病性种系突变很少被报道。在犹太高危家庭中，关于这两种基因对遗传性乳腺癌的假定贡献的数据很少。通过变性梯度凝胶电泳、高分辨率熔融和测序相结合的方法筛选brp1种系突变的高危犹太妇女，她们都不是BRCA1/BRCA2主要犹太突变的携带者。外显子和侧翼内含子序列直接测序用于PALB2突变分析。总的来说，149名女性，所有的高风险，易患癌症的德系犹太人家族，被分型为BRIP1突变：127人患有乳腺癌，22人患有卵巢癌。没有发现截断突变，检测到一个新的（p.a ala745thr）和两个先前描述的错义突变。PALB2中，93名德系犹太人（n = 32）和非德系犹太人（n = 32）的女性被基因分型（87名患有乳腺癌）。共检测到15个序列变异，其中没有截断，4个以前未报道，根据PolyPhen2蛋白预测算法，2个（p.Asp871Gly和p.Leu1119Pro）似乎具有致病性。在113名健康的德系犹太人和109名无癌症对照的摩洛哥人中，没有检测到这些错义突变。综上所述，BRIP1和PALB2的种系突变对不同种族的犹太高危家庭的乳腺癌易感性有轻微影响。
Germline mutations in BRCA1 and BRCA2 account for similar to 30 % of inherited breast cancer. BRIP1 and PALB2 are likely genes for breast cancer susceptibility, based on their roles in maintaining cellular integrity. Indeed, few pathogenic germline mutations in both genes are reported in ethnically diverse breast cancer families. There is a paucity of data on the putative contribution of both genes to inherited breast cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were screened for BRIP1 germline mutations by combined denaturing gradient gel electrophoresis, high resolution melting and sequencing. Direct sequencing of exons and flanking intronic sequences was used for PALB2 mutational analysis. Overall, 149 women, all of high risk, cancer prone families of Ashkenazi origin, were genotyped for BRIP1 mutations: 127 with breast cancer, 22 with ovarian cancer. No truncating mutations were noted and one novel (p.Ala745Thr) and two previously described missense mutations were detected. For PALB2, 93 women were genotyped (87 with breast cancer) of Ashkenazi (n = 32) and non Ashkenazi Jewish origin. Fifteen sequence variants were detected, of these, none was truncating, four were not previously reported, and two (p.Asp871Gly and p.Leu1119Pro) were seemingly pathogenic based on the PolyPhen2 protein prediction algorithm. These missense mutations were not detected in any of 113 healthy Ashkenazi and 109 Moroccan, cancer free controls. In conclusion, germline mutations in BRIP1 and PALB2 contribute marginally to breast cancer susceptibility in ethnically diverse, Jewish high risk families.