Mutational analysis ofMLH1 andMSH2 in 25 prospectively-acquired RER+ endometrial cancers

Kowalski, Lynn D.; Mutch, David G.; Herzog, Thomas J.; Rader, Janet S.; Goodfellow, Paul J.

doi:10.1002/(sici)1098-2264(199703)18:3<219::aid-gcc8>3.0.co;2-4

Cited by 100 publications

(72 citation statements)

References 34 publications

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“…Tumor MSI analysis was performed as described (9,10 of MSI in colorectal cancer (11), we have analyzed the BAT25, BAT26, D5S346, D2S123, and D17S250 markers to assess MSI in our endometrial cancers. A sample was classified as MSI-high (MSI-H) if two or more markers showed instability, MS-stable (MSS) if no instability was noted, and MSI-low (MSI-L) if a single marker revealed novel bands.…”

Section: Methodsmentioning

confidence: 99%

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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.

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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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Section: Methodsmentioning

confidence: 99%

“…The 10 MSH6 exons were evaluated for sequence alterations by SSCV analysis as described (10). Eighteen PCR assays were devised by using the PRIMER3 program (12).…”

Section: Single-strand Conformational Variant (Sscv) and Direct Sequencementioning

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.

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211

142

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“…No tumoural LOH was seen for Val326Ala and His718Tyr mutations. Kowalski et al found an allele frequency of 0.14 for His718Tyr among an Afro-American population (Kowalski et al, 1997), suggesting that this mutation represents a polymorphism. hMLH1 Val326Ala did not score as a loss-of-function mutation in a functional assay and therefore is likely to be a rare variant (Shimodaira et al, 1998).…”

Section: Tumoural Loh For Validation Of Mis-sense Mutationsmentioning

confidence: 99%

Extensive molecular screening for hereditary non-polyposis colorectal cancer

et al. 2000

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The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFβRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria ( n = 10), families in which at least one of the criteria was not satisfied ( n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 ( n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases. © 2000 Cancer Research Campaign

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“…However, hMSH2 or hMLH1 mutations have been found in less than 10% of UECs with MIϩ. [27][28][29][30] Several studies have described a different pathway for inactivation of hMLH1 in colorectal tumors with MSI associated with silencing of the gene by promoter hypermethylation. [32][33][34][35] These studies demonstrate that hMLH1 promoter hypermethylation is associated with the loss of Supported in part by grant from Asociacion Espanola contra el Cancer and SAF96 -0363, Madrid, Spain and Telemarato-Fundacio Pi i Sunyer (29/95), Barcelona, Spain.…”

Section: -19mentioning

confidence: 99%

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

Esteller¹,

Catasús

Matías‐Guiu

et al. 1999

The American Journal of Pathology

281

177

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It has recently been suggested that silencing of the hMLH1 gene by promoter hypermethylation is the mechanism underlying the presence of the microsatellite instability (MSI) phenotype in sporadic colon and endometrial carcinomas. To determine whether hMLH1 promoter hypermethylation is a relatively early event in endometrial tumorigenesis we evaluated endometrial hyperplasia (EH) characterized as simple , complex , and atypical (the direct precursor of endometrial carcinoma) for hMLH1 aberrant methylation. In addition , we studied the hMLH1 , hMSH2, hMSH3, and hMSH6 promoter methylation and MSI status of those endometrial carcinomas with synchronous hyperplasias and those without them. We found that 11 of 12 (91%) cases of endometrial carcinoma (EC) displaying MSI had hMLH1 promoter hypermethylation , whereas aberrant methylation of any of the other mismatch repair genes was not observed. All 15 cases of EC without MSI were unmethylated at hMLH1. Abnormal methylation of hMLH1 was also present in 8 of 116 (7%) cases of EH and was restricted primarily to the atypical endometrial hyperplasia (AEH) type with coexisting endometrial carcinoma. In this set , half of EH methylated at hMLH1 displayed MSI , whereas none of the unmethylated EH had MSI. Our data suggest that hypermethylation of hMLH1 can be an early event in the pathogenesis of EC, preceding the development of an apparent MSI phenotype in a subset of cases. (Am J Pathol 1999, 155:1767-1772)Endometrial carcinoma is the most common gynecological malignancy and is the fourth most common cancer of women in the United States.1 Uterine endometrioid carcinoma (UEC) is the most common histological type. UEC often precedes or coexists with endometrial hyperplasias, which have been proposed as possible precursor lesions.2,3 Atypical endometrial hyperplasia (AEH) is most associated with progression to carcinoma, and women with AEH without concurrent invasive carcinoma have a 30% risk of developing UEC.3 UEC and AEH share cytological atypia and a monoclonal pattern, 4,5 but UEC are distinguished by the presence of invasion.3 A spectrum of hyperplasia without atypia, including simple and complex hyperplasia, also exists. These lesions show a low rate of progression to UEC 3 and a putative polyclonal pattern. 4,5Very little is known about the genetic alterations underlying the biology of the precursor lesions of UEC. Only mutations in the oncogene K-ras and the tumor suppressor gene PTEN have been described in AEH.6,7 PTEN mutations may even precede the appearance of an evident atypia in the endometrial hyperplasia.8 However, a subset of AEH displays the microsatellite instability (MSI) phenotype.5,7,9,10 MSI was first detected in tumors from patients with hereditary non-polyposis colorectal carcinoma (HNPCC). In this setting, the cause of MSI has been attributed to germline defects in DNA mismatch repair (MMR) genes, mainly involving hMLH1 and hMSH2. 11-19Other MMR genes identified include hPMS1, hPMS2, hMSH3, and hMSH6. 20 -21 Endometrial carcinoma (EC) is the most com...

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Mutational analysis ofMLH1 andMSH2 in 25 prospectively-acquired RER+ endometrial cancers

Cited by 100 publications

References 34 publications

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

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

Extensive molecular screening for hereditary non-polyposis colorectal cancer

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

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