Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC)

Glasl, Sarah; Papatheodorou, L.; Baretton, Gustavo; Jung, Ch.; Gross, M.

doi:10.1002/1098-1004(200007)16:1<91::aid-humu22>3.0.co;2-a

Cited by 4 publications

(1 citation statement)

References 10 publications

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“…Several groups have found that DHPLC is effective and has advantages over other methods such as DGGE, SSCP, and PTT assays for mutation screening in different genes. [37][38][39][40][41][42][43][44][45][46] The disadvantages for SSCP and PTT assays include that the results are dependent on the quality of the blood sample, transcript stability, and extraction method, whereas DGGE involves use of labeled primers; and all of these techniques are labor intensive. 22,34,39,42 Furthermore, a high percentage of the mutations reported in MLH1, MSH2, and MSH6 are missense mutations Human Genome Mutation Database; InSIGHT [http://www.…”

Section: Discussionmentioning

confidence: 99%

Assay Validation for Identification of Hereditary Nonpolyposis Colon Cancer-Causing Mutations in Mismatch Repair Genes MLH1, MSH2, and MSH6

Hegde

Blazo

Chong

et al. 2005

The Journal of Molecular Diagnostics

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Hereditary nonpolyposis colon cancer (HNPCC, Online Mendelian Inheritance in Man (OMIM) 114500) is an autosomal dominant disorder that is genetically heterogeneous because of underlying mutations in mismatch repair genes, primarily MLH1, MSH2, and MSH6. One challenge to correctly diagnosing HNPCC is that the large size of the causative genes makes identification of mutations both labor intensive and expensive. We evaluated the usefulness of denaturing high performance liquid chromatography (DHPLC) for scanning mismatch repair genes (MLH1, MSH2, and MSH6) for point mutations, small deletions, and insertions. Our assay consisted of 51 sets of primers designed to amplify all exons of these genes. All polymerase chain reaction reactions were amplified simultaneously using the same reaction conditions in a 96-well format. The amplified products were analyzed by DHPLC across a range of optimum temperatures for partial fragment denaturation based on the melting profile of each specific fragment. DNA specimens from 23 previously studied HNPCC patients were analyzed by DHPLC, and all mutations were correctly identified and confirmed by sequence analysis. Here, we present our validation studies of the DHPLC platform for HNPCC mutation analysis and compare its merits with other scanning technologies. This approach provides greater sensitivity and more directed molecular analysis for clinical testing in HNPCC.

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Section: Discussionmentioning

confidence: 99%

Assay Validation for Identification of Hereditary Nonpolyposis Colon Cancer-Causing Mutations in Mismatch Repair Genes MLH1, MSH2, and MSH6

Hegde

Blazo

Chong

et al. 2005

The Journal of Molecular Diagnostics

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Mutation spectrum in HNPCC in the Israeli population

et al. 2008

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Hereditary non-polyposis colon cancer is caused by mutations in DNA mismatch repair genes. The mutation spectrum in the Israeli population is poorly documented except for the c.1906G>C Ashkenazi founder mutation in the hMSH2 gene. To report our experience in HNPCC screening, the mutations detected and the clinical features among a cohort of Israeli patients. Diagnostic work-up was done in a multi-step process guided by clinical and ethnic information. Tumors of suspected patients were tested for microsatellite instability and immunohistochemistry. Based on tumor analyses, we proceeded to mutation screening by DHPLC followed by sequence analysis and multiplex ligase dependent probe amplification. Ashkenazi Jews were first tested for the c.1906G>C founder mutation. Of the 240 families, 24, including Arabs and Jews from different ethnic origins, were tested positive. All tumors that lost expression of mismatch repair proteins also showed microsatellite instability. There was evidence for involvement of hMSH2 (15) hMLH1 (6) and hMSH6 (3) genes. Mutations were identified in 17/24 (71%) patients: 6 Ashkenazi families harbored the c.1906G>C mutation. Eleven other mutations (2 nonsense, 3 splice site and 6 small deletions) were detected. Three of the mutations are novel. No gross deletions or insertions were detected. This is the first report that characterizes the profile of HNPCC in a cohort of patients in Israel. Tumor testing indicated that the 3 main MMR genes are involved, and that mutation spectrum is broad.

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Lynch Syndrome in high risk Ashkenazi Jews in Israel

Goldberg

Kedar

Kariiv³

et al. 2013

Familial Cancer

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Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.

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Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC)

Cited by 4 publications

References 10 publications

Assay Validation for Identification of Hereditary Nonpolyposis Colon Cancer-Causing Mutations in Mismatch Repair Genes MLH1, MSH2, and MSH6

Assay Validation for Identification of Hereditary Nonpolyposis Colon Cancer-Causing Mutations in Mismatch Repair Genes MLH1, MSH2, and MSH6

Mutation spectrum in HNPCC in the Israeli population

Lynch Syndrome in high risk Ashkenazi Jews in Israel

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