Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer

Plaschke, Jens; Kruppa, Christian; Tischler, René; Bocker, T.; Pistorius, Steffen; Dralle, Henning; Rüschoff, Josef; Saeger, H. D.; Fishel, Richard; Schackert, Hans K.

doi:10.1002/(sici)1097-0215(20000301)85:5<606::aid-ijc2>3.0.co;2-b

Cited by 58 publications

(46 citation statements)

References 20 publications

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“…The coding sequence of MSH6 was amplified and sequenced from genomic DNA as described previously. 24,25 Microsatellite analysis Analysis for microsatellite instability (MSI) had been performed on matched pairs of tumour DNA and normal DNA using the National Cancer Institute/International Collaborative Group on HNPCC (NCI/ICG-HNPCC) reference marker panel for the evaluation of MSI in colorectal cancer (BAT25, BAT26, D2S123, D5S346 and D17S250). Tumours were scored as highly unstable (MSI-H) if two or more of these five markers exhibited additional alleles, and as stable (MSS) if none of the five markers showed instability.…”

Section: Dna Extractionmentioning

confidence: 99%

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

et al. 2008

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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumour predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. In contrast to MLH1 and MSH2, germline mutations in MSH6 are associated with a milder and particularly variable phenotype. Based on the reported interaction of the MMR complex and the base excision repair protein MUTYH, it was hypothesised that MUTYH mutations serve as phenotypical modifiers in HNPCC families. Recently, a significantly higher frequency of heterozygosity for MUTYH mutations among MSH6 mutation carriers was reported. We examined 64 MSH6 mutation carriers (42 truncating mutations, 19 missense mutations and 3 silent mutations) of the German HNPCC Consortium for MUTYH mutations by sequencing the whole coding region of the gene. Monoallelic MUTYH mutations were identified in 2 of the 64 patients (3.1%), no biallelic MUTYH mutation carrier was found. The frequency of MUTYH mutations was not significantly higher than that in healthy controls, neither in the whole patient group (P ¼ 0.30) nor in different subgroups regarding mutation type. Our results do not support the association between MSH6 mutations and heterozygosity for MUTYH mutations.

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Section: Dna Extractionmentioning

confidence: 99%

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

et al. 2008

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“…Most HNPCC kindreds that fulfill the Amsterdam diagnostic criteria (23) have mutations in either MSH2 or MLH1. Although germ-line MSH6 defects are relatively uncommon in HNPCC, a modest number of mutations have been identified in families with atypical HNPCC or in individuals with suspected inherited cancer susceptibility (1,4,5,7,(24)(25)(26). MSH6 mutations appear to confer a particular risk for endometrial cancer (1, 2, 4).…”

Section: Msh6 Promoter Methylationmentioning

confidence: 99%

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Goodfellow

Buttin

Herzog

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

211

142

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Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P ‫؍‬ 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.T he link between defective DNA mismatch repair and the development of tumors has been firmly established. Inherited mutations in DNA mismatch repair genes are associated with the autosomal dominant cancer susceptibility syndrome, hereditary nonpolyposis colorectal cancer (HNPCC). Patients with HNPCC are at high risk for colorectal and endometrial cancer and a variety of other malignancies. Tumors from HNPCC patients frequently show mutations in repetitive sequences, giving rise to a molecular phenotype referred to as microsatellite instability (MSI). Not surprisingly, a significant fraction of sporadic colorectal and endometrial cancers also show MSI.Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2. MSH6 mutations appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer (1-4). The age of onset of cancers in HNPCC kindreds with MSH6 mutations is higher than in MSH2 or MLH1 mutation carriers, and it has been reported that tumors from affected family members are less likely to have high MSI than tumors from MSH2 or MLH1 mutation carriers (5).The estimated frequency of MSH6 mutation in patients with colorectal cancer ranges between 0% based on a tumor immunohistochemistry study ...

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“…Analysis for microsatellite instability was performed by applying 5 mononucleotide (BAT26, BAT40, TGF␤RIIpA, GTMSIN5, GTMSIN9), 6 dinucleotide (D2S123, D3S1300, D3S1619, D5S346, D17S250, D18S58) and 1 tetranucleotide (MycL1) repeat markers 12,17 by multiplex amplification in 4 panels. The panels include 5 markers indicated for MSI analysis due to their high sensitivity.…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

“…9,10 Mutations of hMSH6 in cell lines and tumors are accompanied by MSI primarily at mononucleotide repeats. 6,11,12 The overlapping substrate specificities for IDLs of mutS␣ and mutS␤ and the microsatellite stable (MSS) phenotype of the tumors developed in Msh6 knockout mice 13 suggest that hMSH6-deficient colorectal tumors may evolve without showing MSI. There have been mixed results on whether hMSH6 participates in colorectal tumors with a low level of MSI (MSI-L; instability in up to 30%).…”

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confidence: 99%

Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation

Plaschke

Krüger

Pistorius

et al. 2001

Intl Journal of Cancer

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Germline mutations in human mismatch repair (MMR) genes yield a predisposition for the hereditary nonpolyposis colon cancer (HNPCC) syndrome. In contrast to hMLH1 and hMSH2, little is known about the overall involvement of hMSH6 in colorectal cancer. We investigated 82 tumors from patients who fulfilled the Bethesda guidelines for HNPCC as well as 146 sporadic tumors, analyzing microsatellite instability and expression of the 4 MMR proteins hMSH6, hMSH2, hMLH1 and hPMS2. Four tumors with lost expression and 1 tumor with cytoplasmic expression of hMSH6 were identified. Sequence analysis revealed germline mutations in 4 of the 5 patients, including 1 patient with sporadic disease. The lost or reduced expression of hMSH2 and hMLH1 was always identical to its heterodimerization partners, hMSH6 and hPMS2, respectively. Furthermore, hMSH2 expression was reduced upon hMSH6 deficiency. HNPCC is a high-penetrance, autosomal dominant cancer-susceptibility syndrome. Affected individuals are at increased risk for developing endometrial, small bowel, gastric, ovarian, ureteral and hepatobiliary carcinoma besides colorectal cancer. 1 A hallmark of most of these malignancies is contraction/expansion of simple sequence motifs, 2,3 which is termed microsatellite instability (MSI). Germline mutations in the human mismatch repair genes hMSH2, hMLH1, hPMS1 and hPMS2 have been found in HNPCC, with mutations in hMSH2 and hMLH1 accounting for the vast majority of genetic predispositions (reviewed in ref. 4). Moreover, about 10 -15% of sporadic colorectal cancers show MSI, 3 mostly based on epigenetic silencing of hMLH1 by hypermethylation of the promoter region. 5 Recently, germline mutations in another mismatch repair gene, hMSH6, have been included in the genetic predisposition of HNPCC or HNPCC-like cases. 6 The average age at onset of the disease has been shown to be about 10 years later than in hMSH2 and hMLH1 germline mutations carriers, which might reflect a lower penetrance of hMSH6 mutations. 7,8 Biochemical studies have revealed that the hMSH6 protein functions as a heterodimer complexed with hMSH2 (hMutS␣) in the recognition of base-base mispairs and small insertion-deletion loops (IDLs). For the repair of IDLs there is a functional overlap with the hMSH2-hMSH3 (hMutS␤) complex. 9,10 Mutations of hMSH6 in cell lines and tumors are accompanied by MSI primarily at mononucleotide repeats. 6,11,12 The overlapping substrate specificities for IDLs of mutS␣ and mutS␤ and the microsatellite stable (MSS) phenotype of the tumors developed in Msh6 knockout mice 13 suggest that hMSH6-deficient colorectal tumors may evolve without showing MSI. There have been mixed results on whether hMSH6 participates in colorectal tumors with a low level of MSI (MSI-L; instability in up to 30%). 14,15 Finally, little is known about the involvement of hMSH6 in colorectal tumors of patients not fulfilling the Bethesda guidelines.We thus investigated the frequency at which abolished hMSH6 protein expression is involved with the generation of colorectal c...

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Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer

Cited by 58 publications

References 20 publications

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation

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