林奇综合征患者中不同遗传性癌症综合征种系致病性变异的共同发生。

Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome.

机构信息

Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Elche, 032303, Spain.

Molecular Genetics Unit. Elche University Hospital, Elche, 032303, Spain.

出版信息

Cancer Commun (Lond). 2021 Mar;41(3):218-228. doi: 10.1002/cac2.12134. Epub 2021 Feb 25.

DOI:10.1002/cac2.12134

PMID:33630411

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7968885/

Abstract

BACKGROUND

Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.

METHODS

A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing.

RESULTS

We identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes: [MLH1-BRCA2-NBN], [MLH1-BRCA1], [MSH2-ATM], [MSH6-NF1], and [MLH1-FANCA]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [MLH1-BRCA2-NBN] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.

CONCLUSIONS

Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

摘要

背景

林奇综合征（LS）是一种遗传性疾病，其特征是结直肠癌、子宫内膜癌和其他与 DNA 错配修复基因种系改变相关的肿瘤的风险较高。LS 的经典遗传诊断策略包括对与可疑综合征相关的基因进行 Sanger 测序。下一代测序（NGS）可实现大量遗传性癌症基因的同时测序。在此，我们旨在研究 LS 患者是否存在其他种系致病性的遗传性癌症基因变异。

方法

通过杂交捕获对 84 名经 Sanger 测序先前诊断为 LS 的先证者进行了 94 个遗传性癌症基因商业面板的 NGS 重新分析。使用美国医学遗传学与基因组学学院的标准对变异的临床意义进行分类。通过 Sanger 测序对 NGS 的发现进行了验证。在可能的情况下，还对先证者亲属中的新发现进行了 Sanger 测序的遗传分析。

结果

我们发现，在 84 个家系中，有 5 个家系（6%）存在至少两种种系致病性变异，这些变异分别位于不同的显性癌症易感基因中，其致病变异风险为高或中度：[MLH1-BRCA2-NBN]、[MLH1-BRCA1]、[MSH2-ATM]、[MSH6-NF1]和[MLH1-FANCA]。有趣的是，这 5 个家系中只有 1 个家系的临床表现与新的致病性变异相关。携带[MLH1-BRCA2-NBN]基因三种致病性变异的家系表现出与 LS 和乳腺癌/卵巢癌综合征相关的肿瘤高度聚集。