The epidemiology and molecular characterization of colorectal cancer in eastern Newfoundland

Background: Hereditary Non-Polyposis Colon Cancer (HNPCC) is a dominantly inherited disorder caused by germ-line defects of mismatch repair (MMR) genes. HNPCC can be diagnosed using clinical and genetic criteria. Few population-based studies have been undertaken to determine the genetic basis of CRC. The purpose of this pilot project was to determine the proportion of hereditary vs. sporadic CRC cases on the Avalon Peninsula (AP) of Newfoundland and to determine the genetic basis of disease in hereditary cases. -- Methods: The population studied was identified through the Newfoundland Cancer Treatment and Research Foundation (NCTRF) registry, the meditech system (a hospital reporting tool), and pathology reports. One hundred and sixty-eight potential probands were identified, diagnosed in either 1997 or 1998, between the ages of 20-69, and residing on the AP. Probands, or an appropriate next of kin if a proband was deceased, were interviewed to determine family history of cancer. Contact was made with 158 eligible participants of which one hundred and six (67%) agreed to participate in the study. The final number of study subjects was 79, which was 74.5% of those who agreed to participate. The NCTRF registry and a review of medical charts were used for the collection of baseline characteristics which included demographic and clinical data. -- Probands were classified by their family history using the Amsterdam Criteria (AC), Amsterdam II Criteria, and several other criteria to identify familial risk of HNPCC. Microsatellite analysis (n= 74) and immunohistochemistry analysis (n= 71) for hMLH1, hMSH2, and hMSH6 was completed on proband's normal and tumour DNA. We also examined the diagnostic utility of microsatellite analysis and of protein expression to identify High Risk (HR) families, in comparison to Low Risk (LR) families. -- Results: Twenty-two (28.2%) families were considered HR with 6 families fulfilling the AC I, 1 family fulfilling the AC II, and 15 families fulfilling our Age and Cancer Modified AC (youngest cancer ≤ 60 rather than 50). Twenty-two (28.2%) families were Intermediate Risk (IR), and 34 (43.6%) families were (LR) for HNPCC. However 13 of the LR families had an uninformative family structure. All Amsterdam Criteria families had previously been referred to the Newfoundland Medical Genetics program. -- Sixteen cases (21.6%) had high frequency microsatellite instability (MSI-H) tumours. Sixteen cases (22.5%) had absence of protein expression for at least one of three proteins. For the HR group 6 (31.6%) had MSI-H tumours and all showed absence of protein expression. Fourteen (68.4%) of the HR group had microsatellite stable (MSS) tumours of which 13 (92.9%) expressed all the proteins. For their group 4 (22.2%) had MSI-H tumours and all showed absence of protein expression. Fourteen (77.8%) of the IR group had MSS tumours and all expressed the proteins. For the LR group 4 (12.5%) had MSI-H tumours and 3 (9.4%) of these showed absence of protein expression. Twenty-eight (87.5%) of the LR group had MSS tumours of which 27 (96.4%) expressed all proteins. -- The sensitivity of the laboratory methods used in predicting cases that are high risk for HNPCC was 35.0% and the specificity of the methods in predicting cases that do not have HNPCC was 78.9%. -- Conclusions: We conclude that in the Eastern Newfoundland population the risk for HNPCC is high. Twenty-eight percent of families with CRC are at high risk for HNPCC. Furthermore the prevalence of MSS tumours in the HR group was high. It is likely that novel genes predisposing to HNPCC occur in the Newfoundland population. The utility of testing for MSI and MMR protein expression for the diagnosis of HNPCC in this population was poor.

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