Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.
Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.
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美国和尼日利亚非洲和欧洲血统人群乳腺癌的种系变异和体细胞突变特征。
DOI：
10.1002/ijc.32498
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发表时间：
2019
影响因子：
6.4
通讯作者：
Ogundira
中科院分区：
文献类型：
--
作者：
Wang,Shengfeng;Pitt,JasonJ;Zheng,Yonglan;Yoshimatsu,ToshioF;Gao,Guimin;Sanni,Ayodele;Oluwasola,Olayiwola;Ajani,Mustapha;Fitzgerald,Dominic;Odetunde,Abayomi;Khramtsova,Galina;Hurley,Ian;Popoola,Abiodun;Falusi,Adeyinka;Ogundira
体细胞突变特征可能代表导致不同癌症的遗传和环境暴露的足迹。很少有研究全面研究它们与种系变异的关系，也没有在非洲土著人群中进行研究。 SomaticSignatures 用于根据女性乳腺癌患者的全基因组或全外显子组测序数据提取突变特征（TCGA，训练集，n= 1,011；尼日利亚样本，验证集，n= 170），并估计每个样本中特征的贡献。使用线性回归检查体细胞特征与常见单核苷酸多态性 (SNP) 或罕见有害变异之间的关联。推断出九个稳定的签名，其中四个签名（APOBEC C>T、APOBEC C>G、老化和同源重组缺陷）与已知的 COSMIC 签名高度相似，并解释了大部分（60-85%）的签名贡献。存在与 APOBEC C>T 特征（h2= 0.575，p= 0.010）和组合 APOBEC 特征（h2= 0.432，p= 0.042）相关的显着遗传成分。在 TCGA 数据集中，GNB5 内或附近的 7 个常见 SNP 与全基因组范围内 APOBEC 特征贡献比例的增加（β = 0.33，95% CI = 0.21–0.45）显着相关，而 MTCL1 中罕见的种系突变也与该特征的较高贡献显着相关（p= 6.1 × 10−6）。这是第一项确定不同人群和地域乳腺癌种系变异与突变模式之间关联的研究。这些发现提供了证据来证实种系遗传风险变异与致癌之间的因果关系。
Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole‐genome or whole‐exome sequencing data from female patients with breast cancer (TCGA, training set,n= 1,011; Nigerian samples, validation set,n= 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60–85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2= 0.575,p= 0.010) and the combined APOBEC signatures (h2= 0.432,p= 0.042). In TCGA dataset, seven common SNPs within or nearGNB5were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21–0.45) of APOBEC signature contribution at genome‐wide significance, while rare germline mutations inMTCL1was also significantly associated with a higher contribution of this signature (p= 6.1 × 10−6). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.