Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany.
Exp Mol Pathol. 2021 Oct;122:104668. doi: 10.1016/j.yexmp.2021.104668. Epub 2021 Jul 22.
Lynch syndrome (LS) is caused by a pathogenic heterozygous germline variant in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. LS-associated colorectal carcinomas (CRCs) are characterized by MMR deficiency and by accumulation of multiple insertions/deletions at coding microsatellites (cMS). MMR deficiency-induced variants at defined cMS loci have a driver function and promote tumorigenesis. Notably, PMS2 variant carriers face only a slightly increased risk of developing CRC. Here, we investigate whether this lower penetrance is also reflected by differences in molecular features and cMS variant patterns. Tumor DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue cores or sections (n = 90). Tumors originated from genetically proven germline pathogenic MMR variant carriers (including 14 PMS2-deficient tumors). The mutational spectrum was analyzed using fluorescently labeled primers specific for 18 cMS previously described as mutational targets in MMR-deficient tumors. Immune cell infiltration was analyzed by immunohistochemical detection of T-cells on FFPE tissue sections. The cMS spectrum of PMS2-deficient CRCs did not show any significant differences from MLH1/MSH2-deficient CRCs. PMS2-deficient tumors, however, displayed lower CD3-positive T-cell infiltration compared to other MMR-deficient cancers (28.00 vs. 55.00 per 0.1 mm, p = 0.0025). Our study demonstrates that the spectrum of potentially immunogenic cMS variants in CRCs from PMS2 gene variant carriers is similar to that observed in CRCs from other MMR gene variant carriers. Lower immune cell infiltration observed in PMS2-deficient CRCs could be the result of alternative mechanisms of immune evasion or immune cell exclusion, similar to those seen in MMR-proficient tumors.
林奇综合征（LS）是由 DNA 错配修复（MMR）基因之一的种系致病性杂合变体引起的：MLH1、MSH2、MSH6 或 PMS2。LS 相关的结直肠癌（CRC）的特征是 MMR 缺陷和编码微卫星（cMS）的多个插入/缺失的积累。在特定的 cMS 基因座上，MMR 缺陷诱导的变异具有驱动功能，并促进肿瘤发生。值得注意的是，PMS2 变异携带者仅面临稍高的 CRC 发病风险。在这里，我们研究这种较低的外显率是否也反映在分子特征和 cMS 变异模式上的差异。从福尔马林固定石蜡包埋（FFPE）组织芯或切片中提取肿瘤 DNA（n=90）。肿瘤来源于经遗传证实的种系致病性 MMR 变异携带者（包括 14 例 PMS2 缺陷型肿瘤）。使用先前描述的针对 18 个 cMS 的荧光标记引物分析突变谱，这些 cMS 是 MMR 缺陷型肿瘤中的突变靶标。使用针对 FFPE 组织切片中 T 细胞的免疫组织化学检测分析免疫细胞浸润。与 MLH1/MSH2 缺陷型 CRC 相比，PMS2 缺陷型 CRC 的 cMS 谱没有显示出任何显著差异。然而，与其他 MMR 缺陷型癌症相比，PMS2 缺陷型肿瘤的 CD3 阳性 T 细胞浸润较低（28.00 与 0.1mm 中的 55.00 相比，p=0.0025）。我们的研究表明，PMS2 基因变异携带者的 CRC 中潜在免疫原性 cMS 变异的谱与其他 MMR 基因变异携带者的 CRC 中观察到的谱相似。在 PMS2 缺陷型 CRC 中观察到的较低的免疫细胞浸润可能是由于替代的免疫逃逸或免疫细胞排斥机制的结果，类似于 MMR 功能正常的肿瘤中观察到的机制。
