High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes
Autor: | John R. McLaughlin, Susan Stuckless, Steven S. Gallinger, Amanda Careen, Aaron Pollett, Marina E. Croitoru, Bharati Bapat, Jason A.W. Chaulk, Jegan Jegathesan, J. Desmond Robb, H. Banfield Younghusband, Patrick S. Parfrey, Angela Hyde, Fiona Curtis, Roger C. Green, Michael O. Woods, Jane Green |
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Rok vydání: | 2005 |
Předmět: |
Oncology
Male Cancer Research Pathology Time Factors DNA Repair Colorectal cancer Base Pair Mismatch Genetic Linkage Cohort Studies Promoter Regions Genetic education.field_of_study Age Factors Nuclear Proteins Middle Aged Immunohistochemistry DNA-Binding Proteins MutS Homolog 2 Protein Medical genetics Female Colorectal Neoplasms MutL Protein Homolog 1 Adult medicine.medical_specialty Newfoundland and Labrador Population MLH1 Internal medicine medicine Humans Genetic Predisposition to Disease education Adaptor Proteins Signal Transducing Aged Models Genetic business.industry Microsatellite instability Cancer Genetic Variation Sequence Analysis DNA DNA Methylation medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis MSH6 MSH2 Mutation business Carrier Proteins Microsatellite Repeats |
Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 11(19 Pt 1) |
ISSN: | 1078-0432 |
Popis: | Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland. Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer–like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1. Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings. Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families. |
Databáze: | OpenAIRE |
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