Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.
Chronic Diseases Research Centre (CEDOC), Universidade Nova de Lisboa, Lisboa, Portugal.
Endocrine. 2021 Sep;73(3):588-597. doi: 10.1007/s12020-021-02660-x. Epub 2021 Mar 8.
Germline mutations in DNA repair-related genes have been recently reported in cases with familial non-medullary thyroid carcinoma (FNMTC). A Portuguese family from the Roma ethnic group with four members affected with papillary thyroid carcinoma (PTC), and three members with multinodular goiter (MNG) was identified. The aim of this study was to investigate the involvement of DNA repair-related genes in the etiology of FNMTC in this family and in the Roma ethnic group.
Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing. Sanger sequencing was used for variant confirmation and screening. Twelve polymorphic markers were genotyped for haplotype analysis in the CHEK2 locus.
A germline pathogenic frameshift variant in the CHEK2 gene [c.596dupA, p.(Tyr199Ter)] was detected in homozygosity in the proband (PTC) and in his brother (MNG), being heterozygous in his mother (PTC), two sisters (PTC), and one nephew (MNG). This variant was absent in 100 general population controls. The screening of the CHEK2 variant was extended to other Roma individuals, being detected in 2/33 Roma patients with thyroid cancer, and in 1/15 Roma controls. Haplotype segregation analysis identified a common ancestral core haplotype (Hcac), covering 10 Mb in the CHEK2 locus, shared by affected CHEK2 variant carriers. Analysis of 62 individuals CHEK2 wild-type indicated that none presented the Hcac haplotype. The estimated age for this variant suggested that it was transmitted by a relatively recent common ancestor.
We identified a founder CHEK2 pathogenic variant, which is likely to underlie thyroid cancer and other cancer manifestations in the Roma population.
DNA 修复相关基因中的种系突变最近在家族性非髓样甲状腺癌（FNMTC）病例中被报道。一个来自罗姆族的葡萄牙家庭，有四名成员患有甲状腺乳头状癌（PTC），三名成员患有多结节性甲状腺肿（MNG）。本研究旨在探讨 DNA 修复相关基因在该家族和罗姆族中 FNMTC 病因中的作用。
通过下一代测序分析了 94 个遗传性癌症易感性基因。对变异进行了 Sanger 测序确认和筛选。在 CHEK2 基因座中对 12 个多态性标记进行了基因型分析以进行单体型分析。
在先证者（PTC）和他的兄弟（MNG）中发现 CHEK2 基因的纯合胚系致病性移码变异[c.596dupA，p.（Tyr199Ter）]，在他的母亲（PTC）、两个姐妹（PTC）和一个侄子（MNG）中为杂合子。该变体在 100 名普通人群对照中不存在。对 CHEK2 变体的筛查扩展到其他罗姆人，在 33 名患有甲状腺癌的罗姆人中检测到 2 例，在 15 名罗姆对照中检测到 1 例。单体型分离分析确定了一个常见的祖先核心单体型（Hcac），在 CHEK2 基因座上覆盖了 10 Mb，受影响的 CHEK2 变体携带者共享该单体型。对 62 名 CHEK2 野生型个体的分析表明，没有一个个体具有 Hcac 单体型。该变体的估计年龄表明，它是由一个相对较近的共同祖先传递的。
我们发现了一个可能导致罗姆人群中甲状腺癌和其他癌症表现的创始 CHEK2 致病性变体。
