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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• 作者：Megan  ; P. Hitchins¹ ; Robert  ; W. Rapkins¹ ; Chau-To Kwok¹ ; SameerSrivastava¹ ; Justin  ; J.L. Wong¹ ; Levon  ; M. Khachigian² ; Patsie Polly³ ; Jack Goldblatt⁴ ; Robyn  ; L. Ward¹ ; ^{robyn@unsw.edu.au" rel="nofollow}
• 刊名：Cancer Cell
• 出版年：2011
• 出版时间：16 August 2011
• 年：2011
• 卷：20
• 期：2
• 页码：200-213
• 全文大小：1660 K

文摘

Summary

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.