Deletions Account for 17% of Pathogenic Germline Alterations in <i>MLH1</i> and <i>MSH2</i> in Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Families

Grabowski, Monika; Mueller-Koch, Yvonne; Grasbon-Frodl, E. M.; Koehler, Udo; Keller, Gisela; Vogelsang, H.; Dietmaier, Wolfgang; Kopp, Reinhard; Siebers, U; Schmitt, Wolfgang; Neitzel, Birgit; Gruber, Maria; Doerner, Christa; Kerker, Brigitte; Ruemmele, Petra; Henke, Gabriele; Holinski‐Feder, Elke

doi:10.1089/gte.2005.9.138

Cited by 51 publications

(29 citation statements)

References 35 publications

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“…Grabowski et al [20] reported that large fragment deletion in hMLH1 and hMSH2 accounts for 17% of all pathogenic mutations, which is almost consistent with the results of our study. The three types of large fragment deletion are in line with the findings reported by Nakagawa et al [21] .…”

Section: Discussionsupporting

confidence: 93%

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Sheng

Zhang²,

Ji³

et al. 2009

WJG

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AIM:To study the characteristics of mismatch repair gene mutation of Chinese hereditary non-polyposis colorectal cancer (HNPCC) and hMLH1 gene promoter methylation, and to improve the screening strategy and explore the pertinent test methods. METHODS:A systematic analysis of 30 probands from HNPCC families in the north of China was performed by immunohistochemistry, microsatellite instability (MSI), gene mutation and methylation detection. RESULTS:High frequency microsatellite instability occurred in 25 probands (83.3%) of HNPCC family. Loss of hMLH1 and hMSH2 protein expression accounted for 88% of all microsatellite instability. Pathogenic mutation occurred in 14 samples and 3 novel mutational sites were discovered. Deletion of exons 1-6, 1-7 and 8 of hMSH2 was detected in 3 samples and no large fragment deletion was found in hMLH1. Of the 30 probands, hMLH1 gene promoter methylation occurred in 3 probands. The rate of gene micromutation detection combined with large fragment deletion detection was 46.7%-56.7%. The rate of the two methods in combination with methylation detection was 63.3%. CONCLUSION:Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC.

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Section: Discussionsupporting

confidence: 93%

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Sheng

Zhang²,

Ji³

et al. 2009

WJG

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“…The present frequency of large genomic deletions, 27%, which is already in the upper range of deletion rates reported for comparable series in the literature 14,[32][33][34] does not include a prevalent founder mutation (Mutation 1 21 ) that had been excluded at the outset. Among the original 81 families from which the present research cohort of 11 families originated, 29 are known to harbor Mutation 1; additionally, 1 family has a genomic deletion of MLH1 Exons 3-5 19 that was independently diagnosed in another member of the same family as part of the present clinic-based cohort.…”

Section: Discussionmentioning

confidence: 48%

Large genomic rearrangements and germline epimutations in Lynch syndrome

Gylling

Ridanpää

Vierimaa

et al. 2009

Intl Journal of Cancer

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In one-third of families fulfilling the Amsterdam criteria for hereditary nonpolyposis colorectal cancer/Lynch syndrome, and a majority of those not fulfilling these criteria point mutations in DNA mismatch repair (MMR) genes are not found. The role of large genomic rearrangements and germline epimutations in MLH1, MSH2 and MSH6 was evaluated in 2 such cohorts. All 45 index patients were mutation-negative by genomic sequencing and testing for a prevalent population-specific founder mutation, and selectively lacked MMR protein expression in tumor tissue. Eleven patients (''research cohort'') represented 11 mutation-negative families among 81 verified or putative Lynch syndrome families from the nation-wide Hereditary Colorectal Cancer Registry of Finland. Thirty-four patients from 33 families (''clinic-based cohort'') represented suspected Lynch syndrome patients tested for MMR gene mutations in a diagnostic laboratory during [2004][2005][2006][2007]. Multiplex ligation-dependent probe amplification (MLPA) and methylation-specific (MS)-MLPA were used to detect rearrangements and epimutations, respectively. Large genomic deletions occurred in 12/45 patients (27%), being present in 3/25 (12%), 9/16 (56%) and 0/4 (0%) among index patients lacking MLH1, MSH2 or MSH6 expression, respectively. Germline epimutations of MLH1, one of which coexisted with a genomic deletion, occurred in 2 patients (4%) and were accompanied by monoallelic expression in mRNA. Large genomic deletions (mainly MSH2) and germline epimutations (MLH1) together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of such families.

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“…Deletion or duplication analysis of the MLH1 and MSH2 gene with an MLPA assay was published previously. 32 The MLH1 core promoter is located between c.1-300 and c.1-140 bp. 15,16,33 For amplification and sequencing of the region including c.1 -667 to c.1 -26 bp (Figure 1a and Supplementary Table 1), a standard touchdown PCR protocol 34 was performed.…”

Section: Patients and Materialsmentioning

confidence: 99%

Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC

et al. 2008

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Germline mutations in mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression are the hallmarks of HNPCC (Lynch syndrome). While somatic MLH1 promoter hypermethylation is generally accepted in the tumorigenesis of sporadic tumours, abnormal MLH1 promoter methylation in normal body cells is controversially discussed as a mechanism predisposing patients to HNPCC. In all 94 patients suspected of HNPCC-syndrome with a mean age of onset of 45.5 years, MLH1-deficiency in their tumours but no germline mutation, underwent methylation-specific PCRscreening for MLH1 promoter methylation. In peripheral blood cells of 12 patients an MLH1 promoter methylation, in seven informative cases allele-specific, was found. Normal colonic tissue, buccal mucosa, and tumour tissue available from three patients also presented abnormal methylation in the MLH1 promoter. The heredity of aberrant methylation is questionable. Pro: MLH1 promoter methylation was found in a patient and his mother giving evidence for a familial predisposition for an epimutation in MLH1. Contra: a de novo set-up of methylation in one patient, a mosaic or incomplete methylation pattern in six patients, and no evidence for inheritance of MLH1 promoter methylation in the remaining families. Our findings provide strong evidence that MLH1 promoter methylation in normal body cells mimics HNPCC and constitutes a pathogenic pre-lesion in MLH1. The identification of hypermethylation as an epigenetic defect has important implications for surveillance recommendations, as these patients should be treated like Lynch syndrome patients, whereas the heritability of methylation is still under investigation.

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Deletions Account for 17% of Pathogenic Germline Alterations in MLH1 and MSH2 in Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Families

Cited by 51 publications

References 35 publications

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Large genomic rearrangements and germline epimutations in Lynch syndrome

Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC

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