Department of Molecular Medicine and Medical Biotechnologies and CEINGE Advanced Biotechnologies Scarl, "Francesco Salvatore" Napoli, University of Naples Federico II, 80131 Naples, Italy.
Endoscopy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semola, 80131 Naples, Italy.
Int J Mol Sci. 2023 Mar 22;24(6):5970. doi: 10.3390/ijms24065970.
Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer.
林奇综合征（LS）是一种常染色体显性遗传疾病，主要使个体易患结直肠癌和子宫内膜癌。它与 DNA 错配修复（MMR）基因的致病性变异有关。在这项研究中，我们报告了一例 16 岁男孩的病例，他患有癌前结肠病变，并伴有 LS 的临床怀疑。该先证者被发现存在体细胞 MSI-H 状态。通过 Sanger 测序对 MLH1 和 MSH2 基因的编码序列和侧翼内含子进行分析，导致鉴定出 MLH1 基因中的意义不明的变体，即 c.589-9_589-6delGTTT。进一步的研究表明，该变体可能是致病性的。随后的下一代测序面板分析显示，ATM 基因中存在两个意义不明的变体。我们的结论是，我们的索引病例的表型可能是这些已鉴定变体协同作用的结果。未来的研究将使我们能够了解不同结直肠癌易感基因中的风险等位基因如何相互作用，从而增加个体患癌症的风险。
