MLH1 Germline Epimutations as a Factor in Hereditary Nonpolyposis Colorectal Cancer

Hitchins, Megan P.; Williams, Rachel; Cheong, Kayfong; Halani, Nimita; Lin, Vita Ap; Packham, Deborah; Ku, Sue; Buckle, Andrew; Hawkins, Nicholas J.; Burn, John; Gallinger, Steven; Goldblatt, Jack; Kirk, Judy; Tomlinson, Ian; Scott, Rodney J.; Spigelman, Allan D.; Suter, Catherine M.; Martin, David I. K.; Suthers, Graeme; Ward, Robyn L.

doi:10.1053/j.gastro.2005.09.003

Cited by 168 publications

(171 citation statements)

References 18 publications

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“…No methylation was detected in their peripheral blood lymphocytes (data not shown), suggesting that methylation was somatically acquired and localized, as opposed to constitutional, such as that found in carriers of MLH1 epimutations. [34][35][36][37] In the tumours of each of these seven cases, at least one additional gene within 3p22 was concomitantly methylated with MLH1 ( Figure 6). In five cases, the tumours were BRAF V600E mutant and in four the tumours were CIMP þ (Table 6).…”

Section: Association Between Methylation Of Individual 3p22 Genes Rementioning

confidence: 99%

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

et al. 2011

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Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP þ ), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93G4A SNP within the MLH1 promoter, CIMP þ and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of Z3 of five 3p22 genes with CIMP þ and the BRAF V600E mutation (Po0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP þ and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP þ provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.

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Section: Association Between Methylation Of Individual 3p22 Genes Rementioning

confidence: 99%

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

et al. 2011

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“…DNA (1 -2 mg) was converted with sodium bisulphite and the 'A' and 'C' regions of the MLH1 promoter were subject to combined bisulphite restriction analyses (COBRA) as previously described (Hitchins et al, 2005). Samples giving a positive restriction digestion pattern indicative of the presence of methylation were cloned into the pGEMTeasy vector (Promega, Annandale, NSW, Australia), and individual clones were fluorescently sequenced on an ABI 3100 using SP6 and T7 vector primers.…”

Section: Methylation Analysis Of Mlh1 Promotermentioning

confidence: 99%

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

et al. 2006

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Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

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“…11 These cases have tended to be sporadic due to the spontaneous origination of the epimutation in carriers and its subsequent eradication in the germline. [12][13][14][15] However, a handful of familial cases with an MLH1 epimutation have been reported in which transmission of the epimutation between generations has been shown to occur in both non-Mendelian 14 and autosomal dominant patterns, with the latter linked to localized cis-acting genetic anomalies. 16,17 In a Caucasian family from Western Australia (WA Family 16), dominant transmission of a mosaic MLH1 epimutation was demonstrated through three successive generations linked to a particular haplotype bearing two single-nucleotide variants (SNVs) in tandem; promoter substitution c. À27C4A and missense variant c.85G4T (p.A29S) (according to coding reference sequence NM_000249.2).…”

Section: Introductionmentioning

confidence: 99%

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

et al. 2013

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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. À27C4A and c.85G4T, 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 r2.6-r6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal r2.6 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. À27C4A and c.85G4T 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.

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MLH1 Germline Epimutations as a Factor in Hereditary Nonpolyposis Colorectal Cancer

Cited by 168 publications

References 18 publications

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

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