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美国和尼日利亚非洲裔和欧洲裔人群乳腺癌的种系变异和体细胞突变特征。

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.

机构信息

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Center for Clinical Cancer Genetics & Global Health, Department of Medicine, University of Chicago, Chicago, IL.

出版信息

Int J Cancer. 2019 Dec 15;145(12):3321-3333. doi: 10.1002/ijc.32498. Epub 2019 Jun 27.

Abstract

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 (h = 0.575, p = 0.010) and the combined APOBEC signatures (h = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were 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 in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10 ). 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.

摘要

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痕迹。很少有研究全面检查它们与种系变异的关联,也没有在非洲本土人群中进行研究。SomaticSignatures 被用于从乳腺癌女性患者的全基因组或全外显子组测序数据中提取突变特征(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。推断出九个稳定的特征,其中四个特征(APOBEC C>T、APOBEC C>G、衰老和同源重组缺陷)与已知的 COSMIC 特征高度相似,并解释了大部分(60-85%)特征的贡献。APOBEC C>T 特征(h = 0.575,p = 0.010)和 APOBEC 特征的组合存在与遗传相关的显著成分(h = 0.432,p = 0.042)。在 TCGA 数据集,GNB5 内或附近的七个常见 SNP 与 APOBEC 特征贡献比例的增加显著相关(beta = 0.33,95%CI = 0.21-0.45),而 MTCL1 中的罕见种系突变也与该特征的更高贡献显著相关(p = 6.1×10-8)。这是第一项在不同人群和地理范围内识别种系变异与乳腺癌突变模式之间关联的研究。这些发现为种系遗传风险变异与致癌作用之间的因果关系提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03f8/6851589/f0d8dd0723db/IJC-145-3321-g001.jpg

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