Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.
نویسندگان
چکیده
BACKGROUND Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. METHODS Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. RESULTS Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. CONCLUSION Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with MSI-negative tumors.
منابع مشابه
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome: Surveillance and Diagnostic strategies
Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominant genetic disease. The disease is caused by a mutation in one of four genes of the DNA mismatch repair system and increases the risk for various cancers, especially the uterine and colon cancers. The prevalence of this disease in the general population is about 1 in 500 and it causes about 2-3...
متن کاملThe genetics of hereditary colon cancer.
The genetic basis of sporadic colorectal cancer has illuminated our knowledge of human cancer genetics. This has been facilitated and catalyzed by an appreciation and deep understanding of the forms of colorectal cancer that harbor an inherited predisposition, including familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, the hamartomatous p...
متن کاملThe Lynch Syndrome: Melding Natural History and Molecular Genetics to Genetic Counseling and Cancer Control.
Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndromes I and II, is an autosomal, dominantly inherited disorder that accounts for approximately 5% of all colorectal cancers. While colorectal cancer is the most frequently occurring malignancy in HNPCC, other types of cancer occur with increased statistical significance. A better understanding of its natural histor...
متن کاملUnderstanding Lynch syndrome: implications for nursing.
Colorectal cancer (CRC) is the second-leading cause of cancer-related death in the United States. Approximately 10% of CRC is hereditary, and hereditary nonpolyposis CRC (HNPCC), or Lynch syndrome I, is the most common form. Lynch syndrome I is characterized by onset at an early age, poor differentiation, predominance of proximal tumors, and an excess of synchronous and metachronous tumors. In ...
متن کاملEvaluation of MLH1 and MSH2 Gene Mutations in a Subset of Iranian Families with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
متن کامل
Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.
A significant fraction of hereditary nonpolyposis colorectal cancer cases with defective mismatch repair (ie, Lynch syndrome) have large genomic deletions or duplications in the mismatch repair genes, hMLH1 and hMSH2, which can be challenging to detect by traditional methods. For this study, we developed and validated a novel Southern blot analysis method that allows for ascertainment of the ex...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of the National Cancer Institute
دوره 99 4 شماره
صفحات -
تاریخ انتشار 2007