Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
J Transl Med. 2023 Apr 26;21(1):282. doi: 10.1186/s12967-023-04143-1.
Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
对结直肠癌（CRC）、子宫内膜癌（EC）和皮脂腺肿瘤（SST）进行 DNA 错配修复（MMR）缺陷（dMMR）的常规筛查，导致相当一部分未解决的病例被归类为疑似林奇综合征（SLS）。SLS 病例（n=135）是从澳大利亚和新西兰的家族癌症诊所招募的。对肿瘤（n=137；80 例 CRC、33 例 EC 和 24 例 SST）和匹配的血液衍生 DNA 进行靶向面板测序，以评估微卫星不稳定性状态、肿瘤突变负担、COSMIC 肿瘤突变特征，并识别种系和体细胞 MMR 基因变异。重复进行 MMR 免疫组化（IHC）和 MLH1 启动子甲基化检测。总共，137 例 SLS 肿瘤中有 86.9%可以被分为已建立的亚型。对于这些已解决的 SLS 病例中的 22.6%，鉴定出了主要 MLH1 表观突变（2.2%）以及先前未检测到的种系 MMR 致病性变异（1.5%）、肿瘤 MLH1 甲基化（13.1%）或假阳性 dMMR IHC（5.8%）结果。双重体细胞 MMR 基因突变是每种肿瘤类型中 dMMR 的主要原因（73.9%的已解决病例，总体为 64.2%，CRC 为 70%，ECs 为 45.5%，SSTs 为 70.8%）。未解决的 SLS 肿瘤（13.1%）包括仅存在单个体细胞（7.3%）或无体细胞（5.8%）MMR 基因突变的肿瘤。肿瘤为重点的检测方法将 86.9%的 SLS 重新分类为林奇综合征、散发性 dMMR 或 MMR 功能健全的病例。这些发现支持将肿瘤测序和替代 MLH1 甲基化检测纳入临床诊断，以减少 SLS 患者数量，并提供更适当的监测和筛查建议。
