Germline mutation analysis ofhPMS2gene in Chinese families with hereditary nonpolyposis colorectal cancer

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

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Is there a role for prophylactic subtotal colectomy among hereditary nonpolyposis colorectal cancer germline mutation carriers?

Diseases of the Colon & Rectum ◽

10.1007/bf02048279 ◽

1996 ◽

Vol 39 (1) ◽

pp. 109-110 ◽

Cited By ~ 75

Author(s):

Henry T. Lynch

Keyword(s):

Colorectal Cancer ◽

Germline Mutation ◽

Subtotal Colectomy ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Mutation Carriers ◽

Hereditary Nonpolyposis ◽

Cancer Germline

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Population-Based Molecular Detection of Hereditary Nonpolyposis Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.11.2193 ◽

2000 ◽

Vol 18 (11) ◽

pp. 2193-2200 ◽

Cited By ~ 326

Author(s):

Reijo Salovaara ◽

Anu Loukola ◽

Paula Kristo ◽

Helena Kääriäinen ◽

Heikki Ahtola ◽

...

Keyword(s):

Colorectal Cancer ◽

Endometrial Cancer ◽

Mutation Analysis ◽

Large Scale ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Germline Mutations ◽

Population Based ◽

Degree Relative ◽

Efficient Manner ◽

Hereditary Nonpolyposis

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

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