Kwok Chau-To, Vogelaar Ingrid P, van Zelst-Stams Wendy A, Mensenkamp Arjen R, Ligtenberg Marjolijn J, Rapkins Robert W, Ward Robyn L, Chun Nicolette, Ford James M, Ladabaum Uri, McKinnon Wendy C, Greenblatt Marc S, Hitchins Megan P
Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Eur J Hum Genet. 2014 May;22(5):617-24. doi: 10.1038/ejhg.2013.200. Epub 2013 Oct 2.
Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.
DNA错配修复基因MLH1、MSH2、MSH6或PMS2的种系突变，以及影响与MSH2相邻的EPCAM基因的缺失，是林奇综合征的病因，会使人易患早发性结直肠癌、子宫内膜癌和其他癌症。林奇综合征的另一种罕见病因是MLH1的体质性表观突变，即一个等位基因在所有正常组织中都发生启动子甲基化和转录沉默。在西澳大利亚一个患有林奇综合征的白种人家庭中，一种显性遗传的体质性MLH1表观突变与一个携带两个单核苷酸变体（NM_000249.2:c.-27C>A和c.85G>T）的MLH1单倍型相关。随后，又报道了第二例表面上无关联的澳大利亚白种人病例，其具有相同的MLH1单倍型和伴随的表观突变。我们现在描述另外三个表面上无关联的、有欧洲血统且受癌症影响的家庭，他们具有这种与体质性表观突变相关的MLH1单倍型，使报告的索引病例数达到五例。对其中四个家庭进行的基于阵列的基因分型显示，各个家庭之间存在共享单倍型，这些单倍型延伸至3号染色体短臂上≤2.6 - ≤6.4兆碱基区域，表明有共同的祖先。确定了所有四个家庭共有的最小≤2.6兆碱基的奠基者单倍型，它包含MLH1和其他侧翼基因，并在每个家庭中与MLH1表观突变一起分离。我们的研究结果表明，MLH1 c.-27C>A和c.85G>T变体存在于欧洲祖先单倍型上，并通过正常组织中MLH1的表观遗传沉默机制为其致病性提供了确凿证据。可能还存在携带这种奠基者单倍型的其他后代，他们也有患林奇综合征相关癌症的高风险。
