Olkinuora Alisa, Gylling Annette, Almusa Henrikki, Eldfors Samuli, Lepistö Anna, Mecklin Jukka-Pekka, Nieminen Taina Tuulikki, Peltomäki Päivi
Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
Cancers (Basel). 2020 Jul 9;12(7):1853. doi: 10.3390/cancers12071853.
Some 10-50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics ( = 55) or research ( = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in . Individuals with isolated absence of MSH6 are routinely screened for mutations alone; we found a predisposing mutation in in 1/7 such cases (14%). Somatic deletion of the - region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both and should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of warrant consideration.
在免疫组化（IHC）染色异常的疑似林奇综合征病例中，约10%-50%未发现任何可识别的DNA错配修复（MMR）基因种系突变。MMR蛋白形成异二聚体复合物，突变时会产生不同的IHC模式。未发现种系突变的潜在原因包括IHC模式未预测到的MMR基因受累、易感性的表观遗传机制、另一个DNA修复或复制相关基因的原发性突变以及双体细胞MMR基因突变。我们通过对60例经诊断（n = 55）或研究（n = 5）确定的疑似林奇综合征病例进行种系和肿瘤研究，探讨了这些可能性。所有病例肿瘤中MMR蛋白染色均异常，但种系中疑似MMR基因无点突变或大片段重排。在诊断实践中，MSH2/MSH6（MutS同源物2/MutS同源物6）缺陷会促使进行MLH1突变筛查；在我们的研究中，3/11（27%）具有这种IHC模式的索引个体在MLH1中发现了致病性种系突变。单独MSH6缺失的个体常规仅筛查MLH1突变；我们在1/7（14%）的此类病例中发现了MLH1中的易感突变。EPCAM区域的体细胞缺失、MSH6和MSH3（MutS同源物3）蛋白的联合缺失以及MSH2/MSH6二聚化受阻，为误导性的IHC模式提供了解释。在MSH2和/或MSH6缺陷病例以及38例MLH1（MutL同源物1）缺陷肿瘤病例中探讨了遗传性表观突变假说；在1例MLH1缺陷肿瘤病例中鉴定出原发性EPCAM表观突变。我们得出结论，在MSH2/6缺陷和MSH6缺陷病例中应同时筛查MLH1和EPCAM。在MLH1缺陷病例中，EPCAM的遗传性表观突变值得考虑。
