Meta-Analysis of<i>MSH6</i>Gene Mutation Frequency in Colorectal and Endometrial Cancers

Zhao, Yashuang; Hu, Fulan; Wang, Fan; Han, Bing; Li, Dandan; Li, Xiangwei; Zhu, Shuang

doi:10.1080/15287390902841003

Cited by 19 publications

(14 citation statements)

References 35 publications

(32 reference statements)

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“…The carrier shows a late-onset endometrial cancer with the absence of any staining of the MSH6 protein and MSS tumor. Similar results have been reported in several studies (19). The higher rate of mutations in this study appears in the MSH2 gene (nearly double that in MLH1); this is probably because of the high number of recurrent mutations in this gene.…”

Section: Discussionsupporting

confidence: 92%

Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype

Pérez-Cabornero

Flores²,

Infante³

et al. 2011

Cancer Prevention Research

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It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancerrelated phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.

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Section: Discussionsupporting

confidence: 92%

Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype

Pérez-Cabornero

Flores²,

Infante³

et al. 2011

Cancer Prevention Research

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“…6) in the present study. Previous studies from Western countries reported that mean age at the diagnosis of endometrial cancer was ~48 years in MLH1 or MSH2 mutation carriers (9,30,31) and 56.5 years in MSH6 mutation carriers (32). Thus, the endometrial carcinoma in MSH6 mutation carriers was generally diagnosed at an older age (~5 years later) Table IV.…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, MSI testing for all CRC cases would be a useful screening method for high-risk individuals with an MSH6 mutation. However, some MSH6 mutation carriers developed MSI-L or MSS tumors (32). While, an IHC analysis is another potential screening strategy for LS, a recent study reported that ~30% of colon tumors in carriers of pathogenic MSH6 mutations still showed MSH6 protein expression (33).…”

Section: Polyphen-2 C -----------------------------------------------mentioning

confidence: 99%

Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients

et al. 2013

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The MSH6 gene is one of the mismatch repair genes involved in Lynch syndrome and its mutations account for 10-20% of Lynch syndrome. Although previous studies suggested that the difference of the geographical region affects the clinical phenotype of Lynch syndrome, there has been no report on the detailed features of Japanese Lynch syndrome patients carrying an MSH6 mutation. The aim of the present study was to investigate the clinical and molecular features of MSH6 mutation carriers in Japan. Surgically resected 1720 colorectal carcinoma specimens were screened by microsatellite instability (MSI) testing and the MSI-high cases were subjected to a germline mutation analysis of the mismatch repair genes MLH1, MSH2 and MSH6. We investigated the clinical and molecular features of the MSH6 variants, such as the family cancer history, pathological findings, immunohistochemistry, methylation status of the MLH1 promoter and BRAF mutation in the colorectal tumor. Furthermore, the impact of the missense variants on MSH6 protein was predicted by using in silico tools. We identified nine novel pathogenic mutations and eight unclassified missense variants. Among the eight missense variants, three were suspected pathogenic by in silico analysis. We also found that most colorectal cancers in the MSH6 mutation carrier were diagnosed after the age of 50 and were localized distally. Furthermore, the mean age at diagnosis of endometrial cancer in Japanese MSH6 mutation carriers (49.2 years) was earlier than previous reports from Western countries (56.5 years). These results may improve the surveillance program for Japanese MSH6 mutation carriers.

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“…Lynch syndrome is defined by the presence of a germline mutation in one of the mismatch repair genes [Boland, 2005]. Although the majority of these mutations occur in either MLH1 or MSH2, the contribution of mutations in MSH6 or PMS2 (MIM] 600259) is not insignificant [Truninger et al, 2005;Zhao et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Clinical analysis ofPMS2: mutation detection and avoidance of pseudogenes

et al. 2010

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Germline mutation detection in PMS2, one of four mismatch repair genes associated with Lynch syndrome, is greatly complicated by the presence of numerous pseudogenes. We used a modification of a long-range PCR method to evaluate PMS2 in 145 clinical samples. This modification avoids potential interference from the pseudogene PMS2CL by utilizing a long-range product spanning exons 11-15, with the forward primer anchored in exon 10, an exon not shared by PMS2CL. Large deletions were identified by MLPA. Pathogenic PMS2 mutations were identified in 22 of 59 patients whose tumors showed isolated loss of PMS2 by immunohistochemistry (IHC), the IHC profile most commonly associated with a germline PMS2 mutation. Three additional patients with pathogenic mutations were identified from 53 samples without IHC data. Thirty-seven percent of the identified mutations were large deletions encompassing one or more exons. In 27 patients whose tumors showed absence of either another protein or combination of proteins, no pathogenic mutations were identified. We conclude that modified long-range PCR can be used to preferentially amplify the PMS2 gene and avoid pseudogene interference, thus providing a clinically useful germline analysis of PMS2. Our data also support the use of IHC screening to direct germline testing of PMS2.

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Meta-Analysis ofMSH6Gene Mutation Frequency in Colorectal and Endometrial Cancers

Cited by 19 publications

References 35 publications

Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype

Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype

Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients

Clinical analysis ofPMS2: mutation detection and avoidance of pseudogenes

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