Walker Romy, Mahmood Khalid, Joo Jihoon E, Clendenning Mark, Georgeson Peter, Como Julia, Joseland Sharelle, Preston Susan G, Antill Yoland, Austin Rachel, Boussioutas Alex, Bowman Michelle, Burke Jo, Campbell Ainsley, Daneshvar Simin, Edwards Emma, Gleeson Margaret, Goodwin Annabel, Harris Marion T, Henderson Alex, Higgins Megan, Hopper John L, Hutchinson Ryan A, Ip Emilia, Isbister Joanne, Kasem Kais, Marfan Helen, Milnes Di, Ng Annabelle, Nichols Cassandra, O'Connell Shona, Pachter Nicholas, Pope Bernard J, Poplawski Nicola, Ragunathan Abiramy, Smyth Courtney, Spigelman Allan, Storey Kirsty, Susman Rachel, Taylor Jessica A, Warwick Linda, Wilding Mathilda, Williams Rachel, Win Aung K, Walsh Michael D, Macrae Finlay A, Jenkins Mark A, Rosty Christophe, Winship Ingrid M, Buchanan Daniel D
Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Parkville, VIC 3010, Australia.
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC 3010, Australia.
medRxiv. 2023 Mar 1:2023.02.27.23285541. doi: 10.1101/2023.02.27.23285541.
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; 80xCRCs, 33xECs 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 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 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor 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 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，会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）来自澳大利亚和新西兰各地的家庭癌症诊所。对肿瘤样本（n = 137；80例CRC、33例EC和24例SST）及其匹配的血液来源DNA进行靶向测序，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免疫组织化学（IHC）和启动子甲基化检测。在137例SLS肿瘤中，总共86.9%的病例可被明确分类为已确定的亚型。在这些已明确分类的SLS病例中，22.6%的病例被发现存在原发性表观突变（2.2%）、先前未检测到的种系MMR致病变异（1.5%）、肿瘤甲基化（13.1%）或假阳性dMMR IHC结果（5.8%）。双体细胞MMR基因突变是每种肿瘤类型中dMMR的主要原因（已解决病例的73.9%，总体为64.2%，CRC为70%，EC为45.5%，SST为70.8%）。未解决的SLS肿瘤（13.1%）包括仅具有单个体细胞MMR基因突变（7.3%）或无体细胞MMR基因突变（5.8%）的肿瘤。以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功能正常的病例。这些发现支持将肿瘤测序和替代甲基化检测纳入临床诊断，以减少SLS患者数量，并提供更合适的监测和筛查建议。
