Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics.
Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics.
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DOI：
10.1038/s41698-023-00354-3
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发表时间：
2023-01-27
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
--
作者：
最近的研究表明，某些基因中的罕见有害变异（RDV）是遗传性癌症风险的关键决定因素。为了更全面地了解RDV，我们在一项多癌症关联研究的病例对照环境中进行了迄今为止最大的种系变异识别分析，该研究来自20，789名参与者的全外显子组测序数据，分为发现和验证队列。我们证实并扩展了癌症风险与特定基因组中生殖系RDV之间的已知关联，包括DNA修复（OR = 1.50; p值= 8.30e-07; 95% CI：1.28-1.77），癌症易感性（OR = 1.51; p值= 4.58e-08; 95%CI：1.30-1.75）和体细胞癌驱动因素（OR = 1.46; p值= 4.04e-06; 95%CI：1.24-1.72）。此外，这些基因组中的个体RDV负荷与风险增加、发病年龄更小、肿瘤中M1巨噬细胞增加以及特定癌症中肿瘤突变负荷增加相关。我们的研究结果可用于识别高风险个体，然后这些个体可以从增加监测，早期筛查和利用其肿瘤特征的治疗中受益，从而改善预后。
Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28–1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30–1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24–1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis.
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影响因子：
64.8
作者：
Li X;Kim Y;Tsang EK;Davis JR;Damani FN;Chiang C;Hess GT;Zappala Z;Strober BJ;Scott AJ;Li A;Ganna A;Bassik MC;Merker JD;GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Hall IM;Battle A;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
16.6
作者：
Buscher K;Ehinger E;Gupta P;Pramod AB;Wolf D;Tweet G;Pan C;Mills CD;Lusis AJ;Ley K
通讯作者：
Ley K
影响因子：
50.3
作者：
Berger AC;Korkut A;Kanchi RS;Hegde AM;Lenoir W;Liu W;Liu Y;Fan H;Shen H;Ravikumar V;Rao A;Schultz A;Li X;Sumazin P;Williams C;Mestdagh P;Gunaratne PH;Yau C;Bowlby R;Robertson AG;Tiezzi DG;Wang C;Cherniack AD;Godwin AK;Kuderer NM;Rader JS;Zuna RE;Sood AK;Lazar AJ;Ojesina AI;Adebamowo C;Adebamowo SN;Baggerly KA;Chen TW;Chiu HS;Lefever S;Liu L;MacKenzie K;Orsulic S;Roszik J;Shelley CS;Song Q;Vellano CP;Wentzensen N;Cancer Genome Atlas Research Network;Weinstein JN;Mills GB;Levine DA;Akbani R
通讯作者：
Akbani R
影响因子：
64.5
作者：
Belbin, Gillian M.;Cullina, Sinead;Kenny, Eimear E.
通讯作者：
Kenny, Eimear E.
影响因子：
4.6
作者：
Hall, Evan T.;Parikh, Divya;Kurian, Allison W.
通讯作者：
Kurian, Allison W.