<i>MLH1 </i>germline epimutations in selected patients with early‐onset non‐polyposis colorectal cancer

Valle, Laura; Carbonell, Pablo; Fernández, Victoria; Dotor, AM; Sanz, María Jesús Mardomingo; Benı́tez, Javier; Urioste, Miguel

doi:10.1111/j.1399-0004.2007.00751.x

Cited by 56 publications

(48 citation statements)

References 21 publications

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“…In previous reports, MLH1 epimutations were detected in 8-13% of patients with tumors showing MLH1 loss of expression. 13,17,20,22 We have detected this alteration in 2 out of 30 patients with MLH1-methylated CRC meeting Bethesda or Amsterdam criteria (6.7%) and in 2 of 14 patients with an age of onset below 50 years (14.2%), in whom no germline MLH1 mutation was identified. This is in line with the prevalence reported by van Roon et al 23 in patients with MLH1-methylated tumors enriched for cases with an early age of onset.…”

Section: Discussionmentioning

confidence: 89%

“…8 Approximately 40 index cases of constitutional MLH1 methylation have been reported. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] However, the prevalence of MLH1 constitutional epimutations is still unknown. Most studies addressing this issue have enriched their sampling with patients affected with CRC showing loss of MLH1 protein expression.…”

Section: Introductionmentioning

confidence: 99%

“…Most studies addressing this issue have enriched their sampling with patients affected with CRC showing loss of MLH1 protein expression. 13,17,20,22 In other cases, series were enriched for patients with CRC at an age of onset below 50 years. 9,14,17,23 In a very few cases genetic alterations in cis (gross rearrangements and variants in the promoter region) have been identified as responsible for the methylation.…”

Section: Introductionmentioning

confidence: 99%

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MLH1 methylation screening is effective in identifying epimutation carriers

et al. 2012

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Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MLH1 methylation screening is effective in identifying epimutation carriers

et al. 2012

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“…Heritable DNA methylation abnormalities have been identified in two Lynch syndrome-associated genes, MLH1 [33][34][35][36][37][38][39][40] and MSH2. 22,31,32,41,42 Heritable MLH1 promoter hypermethylation appears to be a relatively rare event, and the mechanism for this alteration has not yet been determined.…”

Section: 32mentioning

confidence: 99%

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

Rumilla

Schowalter

Lindor

et al. 2011

The Journal of Molecular Diagnostics

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Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ϳ80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3= EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation. Lynch syndrome is an autosomal dominant predisposition syndrome in which patients have a propensity to develop colorectal adenocarcinoma, endometrial carcinoma, sebaceous neoplasms, upper urinary tract urothelial carcinomas, central nervous system neoplasms, and ovarian and hepatobiliary neoplasms.1-4 The underlying genetic basis for this syndrome is the presence of a mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. [5][6][7][8][9][10] The defining phenotype of tumors from these patients is the presence of tumor microsatellite instability [11][12][13] and loss of protein expression of the affected enzyme in the tumor nuclei as detected by immunohistochemical staining.14 -16 The spectrum of mu-

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“…Patients with a tumour with MSI and somatic hypermethylation of the MLH1 promoter rarely carry a germline mutation in the MMR system, although rare exceptions have been reported. A few families have been described in which Lynch syndrome patients display hypermethylation of the MLH1 promoter in tumour as well as in non-tumour tissue (Gazzoli et al, 2002;Miyakura et al, 2004;Suter et al, 2004;Hitchins et al, 2005;Valle et al, 2007a). In addition, a family was recently described in which the susceptibility to tumours is caused by germline methylation of the MSH2 promoter (Chan et al, 2006).…”

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confidence: 99%

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer

et al. 2007

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The cancer risk is unknown for those families in which a microsatellite instable tumour is neither explained by MLH1 promoter methylation nor by a germline mutation in a mismatch repair (MMR) gene. Such information is essential for genetic counselling. Families suspected of Lynch syndrome (n ¼ 614) were analysed for microsatellite instability, MLH1 promoter methylation and/or germline mutations in MLH1, MSH2, MSH6, and PMS2. Characteristics of the 76 families with a germline mutation (24 MLH1, 2 PMS2, 32 MSH2, and 18 MSH6) were compared with those of 18 families with an unexplained microsatellite instable tumour. The mean age at diagnosis of the index patients in both groups was comparable at 44 years. Immunohistochemistry confirmed the loss of an MMR protein. Together this suggests germline inactivation of a known gene. The Amsterdam II criteria were fulfilled in 50/75 families (66%) that carried a germline mutation in an MMR gene and in only 2/18 families (11%) with an unexplained microsatellite instable tumour (Po0.0001). Current diagnostic strategies can detect almost all highly penetrant MMR gene mutations. Patients with an as yet unexplained microsatellite instable tumour likely carry a different type of mutation that confers a lower risk of cancer for relatives.

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MLH1 germline epimutations in selected patients with early‐onset non‐polyposis colorectal cancer

Cited by 56 publications

References 21 publications

MLH1 methylation screening is effective in identifying epimutation carriers

MLH1 methylation screening is effective in identifying epimutation carriers

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer

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