文章：

一项代表性大家系变异特征分析提示“变异风险簇”对林奇综合征风险易感性存在差异

Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome

原文发布日期：12 August 2023

DOI: 10.3390/cancers15164074

类型: Article

开放获取: 是

英文摘要：

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three “variant risk clusters” shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different “variant risk clusters” can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.

摘要翻译： 

近期，全球范围内年轻成人侵袭性结直肠癌（CRC）的发病率急剧上升。其中被诊断为家族性林奇综合征（LS）相关CRC的病例预后极差。本研究从一个包含12名LS患者的突尼斯大家族系中，探索新的家族性种系变异，以识别与不同LS风险相关的潜在种系变异。通过全基因组测序分析，识别了患病与非患病家族成员间共有的已知及新型种系变异。通过计算分析鉴定了单核苷酸多态性（SNPs）、插入缺失（indels）及结构变异（SVs），并利用遗传关联复杂疾病与障碍数据库、OncoKB及My Cancer Genome数据库预测其肿瘤学影响。在鉴定出的94个具有预测功能影响的家族性种系变异中，28个基因中检测到37个SNPs/indels，其中2个（MLH1和PRH1-TAS2R14）已知与CRC相关，另外4个（PPP1R13B、LAMA5、FTO和NLRP14）已知与非CRC癌症相关。此外，57个已鉴定的SVs中有48个与43个基因重叠，其中3个基因（RELN、IRS2和FOXP1）已知与非CRC消化系统癌症相关，1个基因（RRAS2）已知与非CRC癌症相关。本研究识别出83个新型、预测具有功能影响的种系变异，这些变异被归类为三个“变异风险簇”，分别对应于三个家族相关的LS风险组（高风险、中风险和低风险）。此项变异特征研究表明，大规模家系研究为以下假设提供了重要证据：即使在同一个家系内，不同的“变异风险簇”也可能传递LS-CRC的不同风险机制和致癌机制。

原文链接：

Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome