Dominantly Inherited Constitutional Epigenetic Silencing of MLH1 in a Cancer-Affected Family Is Linked to a Single Nucleotide Variant within the 5′UTR
Dominantly Inherited Constitutional Epigenetic Silencing of MLH1 in a Cancer-Affected Family Is Linked to a Single Nucleotide Variant within the 5′UTR
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DOI：
10.1016/j.ccr.2011.07.003
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发表时间：
2011-08-16
期刊：
影响因子：
50.3
通讯作者：
Ward, Robyn L.
中科院分区：
文献类型：
--
作者：
Hitchins, Megan P.;Rapkins, Robert W.;Ward, Robyn L.
肿瘤抑制基因的表型突变表现为启动子甲基化和单个等位基因在正常体细胞组织中的转录沉默，从而诱发癌症。宪法MLH 1表突变发生在个人与复发性癌症，并证明非孟德尔遗传通过其逆转生殖系。我们报告了一个受癌症影响的家族，该家族表现出与特定遗传单倍型相关的胞体范围高度嵌合MLH 1甲基化和转录抑制的显性传播。表突变在精子中消失，但在下一代的体细胞中恢复。受影响的单倍型具有两个串联的单核苷酸取代; c. 27 C> A位于转录起始位点附近，c.85G > T。C. 27 C> A变体在报告基因测定中显著降低转录活性，并且是该表位突变的可能原因。
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.