Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Research Group Human Genomics, Department of Biomedicine, University of Basel, Basel, Switzerland.
Mol Genet Genomic Med. 2024 Jan;12(1):e2360. doi: 10.1002/mgg3.2360.
Lynch syndrome represents one of the most common cancer predispositions worldwide and is caused by germline pathogenic variants (PV) in DNA mismatch repair (MMR) genes. We repeatedly identified a PV in the MMR gene PMS2, c.1831dup, accounting for 27% of all Swiss PMS2 PV index patients identified. Notably, 2/18 index patients had been diagnosed with colorectal cancer (CRC) before age 30.
In this study, we investigated if this PV could (i) represent a founder variant by haplotype analysis and (ii) be associated with a more severe clinical phenotype.
Haplotype analysis identified a shared common region of about 0.7 Mb/1.3 cM in 13 (81%) out of 16 index patients. Genotype-phenotype correlations, combining data from the 18 Swiss and 18 literature-derived PMS2 c.1831dup PV index patients and comparing them to 43 Swiss index patients carrying other PMS2 PVs, indicate that the PMS2 c.1831dup variant may be associated with earlier (<50 y) age at CRC diagnosis (55% vs. 29%, respectively; p = 0.047). Notably, 30% (9/30) of cancers from c.1831dup carriers displayed atypical MMR protein expression patterns on immunohistochemistry.
Our results suggest that the PMS2 c.1831dup PV represents a, probably ancient, founder mutation and is possibly associated with an earlier CRC diagnosis compared to other PMS2 PVs.
林奇综合征是全球最常见的癌症遗传易感性之一，由 DNA 错配修复 (MMR) 基因中的种系致病性变异 (PV) 引起。我们反复在 MMR 基因 PMS2 中发现一个 PV，c.1831dup，占所有瑞士 PMS2 PV 索引患者的 27%。值得注意的是，18 名索引患者中有 2 名在 30 岁之前被诊断患有结直肠癌 (CRC)。
在这项研究中，我们研究了该 PV 是否可以 (i) 通过单倍型分析代表一个创始人变体，以及 (ii) 与更严重的临床表型相关。
单倍型分析确定了 16 名索引患者中的 13 名（81%）共享一个约 0.7Mb/1.3cM 的共同区域。结合来自 18 名瑞士和 18 名文献来源的 PMS2 c.1831dup PV 索引患者的数据进行的基因型-表型相关性分析，并将其与携带其他 PMS2 PV 的 43 名瑞士索引患者进行比较，表明 PMS2 c.1831dup 变体可能与更年轻 (<50 岁) 的 CRC 诊断年龄相关（分别为 55% 和 29%；p=0.047）。值得注意的是，30%（9/30）的 c.1831dup 携带者的癌症在免疫组织化学上显示出非典型的 MMR 蛋白表达模式。
我们的结果表明，PMS2 c.1831dup PV 代表一个可能古老的创始人突变，与其他 PMS2 PV 相比，可能与更早的 CRC 诊断相关。
