How Helpful Is Age at Colorectal Cancer Onset in Finding HNPCC?

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At least 1% to 3% of all colorectal cancers (CRCs) are known to be due to mutations in one of the mismatch repair (MMR) genes responsible for hereditary nonpolyposis colorectal cancer (HNPCC, or “Lynch syndrome”).1 Although it is uncommon, the presence of HNPCC carries significant clinical management implications for the affected individual and for his or her relatives. However, the ability to detect the presence of HNPCC is relatively new, technically demanding, and complicated. These considerations make undertaking the detection of HNPCC challenging to the point of being off-putting to many clinical gastroenterologists and other providers.In this issue of Diseases of the Colon & Rectum, Wright and colleagues2 describe their strategy for detecting HNPCC in the setting of a clinically oriented program in the medium-sized metropolitan area of Auckland, New Zealand. Between 2001 and 2007, pathologists at the 3 major hospitals evaluated incident CRCs by means of immunohistochemical (IHC) staining for protein associated with the mismatch repair genes of HNPCC. Attention was limited to the 214 patients aged 50 and younger, a group traditionally considered most likely to manifest HNPCC. About three-fourths of cases were subjected to IHC for all 4 major MMR-associated proteins (MLH1, MSH2, MSH6, and PMS2), while the remaining cases were only evaluated for MLH1 and MSH2, during the earliest years of the investigation. Loss of protein expression was found in 33 of 243 (13.6%) cases. No significant demographic difference existed between those who did and those who did not have loss of protein expression, although cases with abnormal IHC results were more likely to be right-sided tumors. Of the 33 patients with abnormalities, 26 were referred for genetic assessment. Of the 22 actually undergoing germline mutation testing, 10 (45%) had mutations based on analyses of the hMLH1, hMSH2, hMSH6, and hPMS2 genes (details of the mutational testing process were not described in any detail).Family history was not a selection factor in this study, and indeed few details of family history were provided, although it is implied that a large proportion did not have striking family histories that would have otherwise provided an independent basis for IHC testing or mutational testing.The overall findings of the Wright study are consistent with those of other population-based investigations, in particular, those targeting younger patients. This study was a bit different in that it emphasized the uptake of tumor-based testing strategies in the community, with a reasonably comprehensive outcome measure.So what are the useful messages in this study? First, at least within the manageable confines of one metropolitan area, a comprehensive tumor-testing–driven program can be implemented. When carefully linked to a genetic counseling program and mutational testing capability, clinically relevant molecular diagnoses can be made without major disruption to clinical practice patterns.That more than 20% of cases with IHC abnormalities were not referred for genetic counseling underscores the challenges of following through with referrals. It could not be determined what proportion of missed cases were because of the practitioner not being aware of the abnormal test results, what fraction was due to other provider characteristics, or how many were because of patient nonadherence to recommendations. These are important distinctions when undertaking the improvement of a system of implementing new diagnostics into existing clinical practice. Wright and colleagues note that the (economic) barriers to follow-through are minimal in New Zealand. The presence and nature of barriers to diagnostic evaluation have been subjected to considerable scrutiny, although not so much so in the area of genetic testing and counseling.

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