Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine at the University of New South Wales, NSW 2052, Australia.
Cancer Cell. 2011 Aug 16;20(2):200-13. doi: 10.1016/j.ccr.2011.07.003.
Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem; c.-27C > A located near the transcription initiation site and c.85G > T. The c.-27C > A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
抑癌基因的结构突变表现为正常体细胞中单等位基因的启动子甲基化和转录沉默，从而易患癌症。MLH1 结构突变发生在发病年龄较早的癌症患者中，并通过在生殖系中逆转表现出非孟德尔遗传。我们报告了一个受癌症影响的家族，该家族表现出广泛的体细胞高度镶嵌 MLH1 甲基化和转录抑制的显性遗传，与特定的遗传单倍型相关。该结构突变在精子中被抹去，但在下一代的体细胞中重新出现。受影响的单倍型串联存在两个单核苷酸替换；c.-27C > A 位于转录起始位点附近，c.85G > T。c.-27C > A 变体显著降低了报告基因检测中的转录活性，可能是这种结构突变的原因。
