SUMMARY 摘要

Wepresent the largest whole-genome sequencing (WGS) study of non-small cell lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled with 23,049 individuals genotyped by SNP array. We construct a high-quality haplotype reference panel for imputation and identify 20 common and low-frequency loci (minor allele frequency [MAF]R0.5%), including five loci that have never been reported before. For rare loss-of-function (LoF) variants (MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also have a substantial effect on NSCLC risk, and their prevalence is comparable with BRCA2 LoF variants. The associations are validated in an independent casecontrol study including 4,410 individuals and a prospective cohort study including 23,826 individuals. Our findings not only provide a high-quality reference panel for future array-based association studies but depict the whole picture of rare pathogenic variants for NSCLC.

我们进行了迄今为止最大规模的非小细胞肺癌(NSCLC)全基因组测序(WGS)研究，研究对象包括6004名中国个体，以及23,049名通过SNP阵列进行基因分型的个体。我们构建了一个高质量的单倍型参考面板，并识别了20个常见和低频位点(次等位基因频率[MAF]≥0.5%)，其中包括5个以前从未报道过的位点。对于罕见的功能丧失(LoF)突变(MAF < 0.5%)，我们发现BRCA2和18个其他癌症易感性基因影响了5.29%的非小细胞肺癌个体，98.91%(181/183)的LoF突变之前没有与非小细胞肺癌风险联系起来。BRCA2的启动子突变对NSCLC风险也有显著影响，其患病率与BRCA2 LoF突变相当。这些关联在一项包括4,410人的独立病例对照研究和一项包括23,826人的前瞻性队列研究中得到验证。我们的研究结果不仅为未来基于阵列的关联研究提供了高质量的参考面板，而且描绘了NSCLC罕见致病变异的全貌。

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