Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Genome Med. 2021 Sep 9;13(1):147. doi: 10.1186/s13073-021-00964-1.
DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear.
We analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers.
The affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay.
Our results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations.
DNA 测序越来越多地纳入癌症患者的常规护理中，其中许多患者还携带与其他疾病相关的遗传的、中等/高外显率变体。然而，此类变体的普遍性和后果仍不清楚。
我们分析了 TCGA 队列中 10389 例成年癌症病例的种系基因组，鉴定了常染色体显性基因、常染色体隐性基因和美国分子遗传学学院（即 ACMG59 基因）精心筛选的 59 个可治疗基因中的致病性/可能致病性变体。我们还分析了携带者中的变体和基因水平的表达后果。
受影响的基因表现出不同的全种族和特定人群的模式，总体而言，欧洲人群显示出最高的致病性/可能致病性变体频率。我们进一步确定了表现出支持变体功能的表达后果的基因，包括通过大规模平行剪接分析确定的基因表达改变、等位基因特异性表达和错剪接。
我们的结果表明，在相当一部分病例中发现了改变表达的变体，并说明了对不同人群的多种疾病进行基因组风险评估的效果。
