Ligtenberg Marjolijn J L, Kuiper Roland P, Chan Tsun Leung, Goossens Monique, Hebeda Konnie M, Voorendt Marsha, Lee Tracy Y H, Bodmer Danielle, Hoenselaar Eveline, Hendriks-Cornelissen Sandra J B, Tsui Wai Yin, Kong Chi Kwan, Brunner Han G, van Kessel Ad Geurts, Yuen Siu Tsan, van Krieken J Han J M, Leung Suet Yi, Hoogerbrugge Nicoline
Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Nat Genet. 2009 Jan;41(1):112-7. doi: 10.1038/ng.283. Epub 2008 Dec 21.
Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.
林奇综合征患者由于错配修复基因（包括MSH2，参考文献1）的种系失活突变，易患结直肠癌和子宫内膜癌。在此，我们描述了来自荷兰和中国家庭的患者，他们患有MSH2缺陷肿瘤，携带TACSTD1最后外显子的杂合种系缺失，TACSTD1是MSH2上游直接编码Ep-CAM的基因。由于这些缺失，TACSTD1的转录延伸到MSH2。在Ep-CAM阳性而非Ep-CAM阴性的正常组织中，与缺失顺式的MSH2启动子发生甲基化，从而揭示了突变的TACSTD1等位基因的活性与相应MSH2等位基因的表观遗传失活之间的相关性。如本文所示，通过相邻基因在正义或反义方向的转录通读导致的基因沉默，可能代表一种普遍的突变机制。根据缺乏正常多聚腺苷酸化信号的相邻基因的表达模式，这可能导致表观遗传失活的普遍或镶嵌模式。
