Mutation Frequencies in Patients With Early-Onset Colorectal Cancer

To the Editor The recent study by Pearlman et al raises concerns. The hypothesis of the article is laudable, that is, genetic susceptibility forms a significant part of the risk in patients with early-onset (defined as younger than 50 years) colorectal cancer (CRC). However, the data reported in the article do not correlate with what is known as being relevant in the disease mechanism of CRC. The authors report mutations in "nontraditional" CRC genes such as BRCA1/2, CDKN2A, PALB2, and CHEK2 in 32 of 72 patients, all of which are associated with hereditary breast cancer. In fact, given that CRC is a phenomenon driven primarily by dysfunctional Wnt signaling, it is difficult to understand how these germline drivers in cell cycle and DNA repair genes (which have been extensively investigated previously, in vitro and in vivo, as potential driver genes in CRC) have any relevance to this topic; they merely inflate the relevant germline variation rate reported in this study. What the article should in fact report is that a detection rate of 10% for patients with Lynch syndrome was observed, which is above what has previously been reported in other population studies and is likely to be enriched by the selection for early-onset cancer. The observed APC mutation (APC c.3920T>A, p.I1307K mutation) is almost uniquely associated with Ashkenazi Jewish ancestry, being associated with a multiple-tumor phenotype; it is not low penetrance and unlikely to be common outside the group of patients. In conclusion, this type of study is useful in that it highlights the role of genetic testing in early onset-cancer cases, but it should not be used to argue that there is a hidden pool of patients with relevant germline drivers. It is likely that further information from population-based whole-genome sequencing studies (eg, the UK 100 000 Genomes project) will reveal the complex landscape of rare, highly penetrant CRC driver genes.

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