Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

Toledano, Helen; Goldberg, Yael; Kedar-Barnes, Inbal; Baris, Hagit N.; Porat, Rinnat M.; Shochat, Chen; Bercovich, Dani; Pikarsky, Eli; Lerer, Israela; Yaniv, Isaac; Abeliovich, Dvorah; Peretz, Tamar

doi:10.1007/s10689-008-9227-3

Cited by 26 publications

(17 citation statements)

References 27 publications

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“…Breast and prostate cancer were observed in 23% of the MSH6 families, while ovarian cancer was observed in 17% of the families. Both ovarian and prostate cancer were expected to be observed in Lynch syndrome families [34] but the inclusion of breast cancer in the cancer spectrum in Lynch syndrome is controversial [35-39]. The high incidence of breast cancer in these families may genuinely reflect an increased risk of breast cancer, or it may indicate the high incidence of breast cancer in the general population (1 in 9 woman in Australia [40]).…”

Section: Discussionmentioning

confidence: 99%

“…Currently the general consensus is that MSH6 mutations in HNPCC are under-diagnosed [25,35,41]. This is thought to be due to MSH6 not being routinely tested in most laboratories and that the presence of MSH6 mutations is under-estimated due to a more atypical presentation of disease, making the patients less likely to fulfil diagnostic criteria.…”

Section: Discussionmentioning

confidence: 99%

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MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Talseth‐Palmer

McPhillips

Groombridge

et al. 2010

Hered Cancer Clin Pract

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BackgroundApproximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families.MethodsA total of 78 participants (from 29 families) with a mutation in MSH6 and 7 participants (from 6 families) with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis.ResultsMSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females) and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females.ConclusionNovel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Talseth‐Palmer

McPhillips

Groombridge

et al. 2010

Hered Cancer Clin Pract

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“…A high percentage of the published CMMRD patients developed adenomas of the gastrointestinal tract, which are considered the premalignant lesions from which gastrointestinal cancers develop. Adenomas of the colon and rectum were reported in 52 (36%) of the patients, and many of them developed multiple synchronous adenomas ranging from a few to up to 100 polyps22 reminiscent of (attenuated) FAP 23 24. In eight patients, adenomas of the small bowel were reported.…”

Section: The Clinical Phenotype Of Cmmrd As Deduced From the Known Casesmentioning

confidence: 99%

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)

et al. 2014

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“…We and others [7,8], have detected this mutation in 18-33% of Ashkenazi AC positive families. Lately we reported of an Ashkenazi family with childhood cancer syndrome (CCS) due to homozygosity of this mutation [20].…”

Section: Introductionmentioning

confidence: 99%

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

et al. 2009

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Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.

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Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

Cited by 26 publications

References 27 publications

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

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