Novel MLH1 mutations and a novel MSH2 polymorphism identified by SSCP and DHPLC in Portuguese HNPCC families

Isidro, Glória; Matos, Sérgio A.; Gonçalves, Vânia; Cavaleiro, Carla; Antunes, Ofélia; Marinho, Carla; Soares, José; Boavida, Maria Guida

doi:10.1002/humu.9192

Cited by 12 publications

(9 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…c.1529 CAG>CGG was predicted to have no pathogeneity, the pathogeneity of other three novel DNA variants were uncertain. Seven mutations (−28 A>G, c.927 CCC>CCT, IVS13+14 G>A, IVS14-19 A>G, c.1742 CCG>CTG, c.1845_1847 deletion GAA and c.*35_*37 deletion CTT) were previously reported in the InSiGHT database [10], [16], [17], [18], [19], [20], [21]. c.1742 CCG>CTG and c.1845_1847 deletion GAA were reported to be pathologic mutations [21], [22].…”

Section: Resultsmentioning

confidence: 97%

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Wang

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Research on hMLH1 and hMSH2 mutations tend to focus on Lynch syndrome (LS) and LS-like colorectal cancer (CRC). No studies to date have assessed the role of hMLH1 and hMSH2 genes in mass sporadic CRC (without preselection by MSI or early age of onset). We aimed to identify novel hMLH1 and hMSH2 DNA variants, to determine the mutation frequencies and sites in both sporadic and LS CRC and their relationships with clinicopathological characteristics of CRC in Northeast of China. 452 sporadic and 21 LS CRC patients were screened for germline and somatic mutations in hMLH1 and hMSH2 genes with PCR–SSCP sequencing. We identified 11 hMLH1 and seven hMSH2 DNA variants in our study cohort. Six of them were novel: four in hMLH1 gene (IVS8-16 A>T, c.644 GAT>GTT, c.1529 CAG>CGG and c.1831 ATT>TTT) and two in hMSH2 gene (−39 C>T, insertion AACAACA at c.1127 and deletion AAG at c.1129). In sporadic CRC, germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 15.59% and 17.54%, respectively (p = 0.52). Germline mutations present in hMLH1 and hMSH2 genes were 5.28% and 10.78%, respectively (p<0.01). Somatic mutations in hMLH1 and hMSH2 genes were 6.73% and 11.70%, respectively (p = 0.02). In LS CRC, both germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 28.57%. The most prevalent germline mutation site in hMSH2 gene was c.1168 CTT>TTT (3.90%), a polymorphism. Somatic mutation frequency of hMLH1/hMSH2 gene was significantly different in proximal, distal colon and rectal cancer (p = 0.03). Our findings elucidate the mutation spectrum and frequency of hMLH1 and hMSH2 genes in sporadic and LS CRC, and their relationships with clinicopathological characteristics of CRC.

show abstract

Section: Resultsmentioning

confidence: 97%

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Wang

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…23 The independent findings of the two linked (c.-27C>A and c.85G>T) substitutions in three seemingly unrelated Lynch-like families raises the possibility of a founder disease-susceptibility haplotype. We propose that methylation studies on a number of MLH1 promoter SNVs in suspected Lynch syndrome cases 24,25,26 may help resolve their pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry

Ward

Dobbins

Lindor

et al. 2013

Genetics in Medicine

View full text Add to dashboard Cite

Purpose:Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome–associated cancers. This study investigated their frequency and inheritance.Methods:A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals.Results:Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays.Conclusion:Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.

show abstract

“…Several polymorphisms have been reported in the hMSH2 gene (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). It has been suggested that one of these polymorphism, IVS12À6T>C, may predispose to some kind of cancer (27,28,32,52,53).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in thehMSH2Gene and the Risk of Primary Lung Cancer

Jung¹,

Choi²,

Park³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Polymorphisms in the DNA repair genes may be associated with differences in the capacity to repair DNA damage, and so this can influence an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of hMSH2 À118T>C, IVS1+9G>C, IVS10+12A>G, and IVS12À6T>C genotypes and their haplotypes with the risk of lung cancer in a Korean population. The hMSH2 genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency matched for age and gender. The hMSH2 haplotypes were estimated based on a Bayesian algorithm using the Phase program. The presence of at least one IVS10+12G allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the IVS10+12AA genotype [adjusted odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40-0.88; P = 0.01], and the presence of at least one IVS12-6C allele was associated with a significantly increased risk of adenocarcinoma, as compared with the IVS12-6TT genotype (adjusted OR, 1.52; 95% CI, 1.02-2.27; P = 0.04). Consistent with the results of the genotyping analysis, the TGGT haplotype with no risk allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the TCAC haplotype with two risk allele [i.e., IVS10+12A and IVS12-6C allele; adjusted OR, 0.49; 95% CI, 0.30-0.78; P = 0.003 and P c (Bonferroni corrected P value) = 0.012]. The effect of the hMSH2 haplotypes on the risk of adenocarcinoma was statistically significant in the never smokers and younger individuals (adjusted OR, 0.45; 95% CI, 0.27-0.75; P = 0.002 and P c = 0.004; and adjusted OR, 0.44; 95% CI, 0.23-0.85; P = 0.014 and P c = 0.028, respectively) but not in the ever-smokers and older individuals. These results suggest that the hMSH2 polymorphisms and their haplotypes may be an important genetic determinant of adenocarcinoma of the lung, particularly in never smokers. (Cancer Epidemiol Biomarkers Prev 2006;15(4):762-8)

show abstract

Novel MLH1 mutations and a novel MSH2 polymorphism identified by SSCP and DHPLC in Portuguese HNPCC families

Cited by 12 publications

References 11 publications

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry

Polymorphisms in thehMSH2Gene and the Risk of Primary Lung Cancer

Contact Info

Product

Resources

About