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Abstract

We appreciate the opportunity to respond to the concerns raised in Murphy and Cohn’s letter.1Murphy C.C. Cohn B.A. Gastroenterology. 2022; 163: 532-533Abstract Full Text Full Text PDF Scopus (1) Google Scholar We thank Murphy and Cohn for their interest and knowledgeable comments regarding our study. The first concern they raise is that because of our null results, we concluded “that early-life factors do not play a meaningful role in colorectal carcinogenesis.” We agree it is important to study early-life factors as potential explanatory risk factors for the rising incidence in early-onset colorectal cancer, and this was the primary motivation for conducting our large cohort study. Although we did not find an association between the 6 early-life factors we assessed from the UK Biobank database and early-onset colorectal cancer, we did not conclude that early-life factors in general do not play a meaningful role.2Gausman V. et al.Gastroenterology. 2022; 162: 981-983.e3Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Rather, we concluded that although the 6 early-life factors we studied are unlikely to substantially contribute to the observed increased incidence of early-onset colorectal cancer, further studies are needed to elucidate other early-life factors that may drive this disease. Their second concern was with regard to the limitations of our study. We agree with Murphy and Cohn’s comments1Murphy C.C. Cohn B.A. Gastroenterology. 2022; 163: 532-533Abstract Full Text Full Text PDF Scopus (1) Google Scholar on our limitations (namely, recall bias and missing data on additional early-life factors), and we acknowledge that our findings need to be interpreted in the context of these limitations. Although we did not specifically examine differences between “higher- and lower-risk generations,” we did conduct sensitivity analyses stratifying cases by year and age at diagnosis. As we briefly mention in the article, these did not affect our results. A third concern centered on other recent literature, which, unlike our study, observed associations between several early-life exposures and early-onset colorectal cancer. The literature cited by Murphy and Cohn1Murphy C.C. Cohn B.A. Gastroenterology. 2022; 163: 532-533Abstract Full Text Full Text PDF Scopus (1) Google Scholar supports our hypothesis that early-life factors may contribute to colorectal carcinogenesis, but these studies examined a set of early-life factors that are unavailable in the UK Biobank (eg, birth size, placenta size and shape, in utero exposure to certain medications, pregnancy weight gain, and fetal growth). Notably, the majority of these were in utero factors, whereas the factors we assessed were related to infancy and childhood. Thus, these results can be viewed as complementary rather than contradictory. In summary, we believe that our null results are important because they will help the research community direct its attention to potentially more meaningful early-life factors, with the ultimate goal of improved risk stratification for early-onset colorectal cancer. The null associations were specific to the 6 early-life factors we studied, and we invite and welcome further studies to both confirm and extend our findings. Early Life: An Important Window of Susceptibility for Colorectal CancerGastroenterologyVol. 163Issue 2PreviewIncidence rates of colorectal cancer have increased in young adults (age <50 years) in the US since the early 1990s, and more recently, incidence rates have increased in adults in their early 50s.1 The shifting epidemiology of colorectal cancer has forced researchers to reconsider what we know about the causes of this disease. Importantly, incidence rates of colorectal cancer have increased across generations or birth cohorts, starting with those born in the 1960s.2 This so-called “birth cohort effect” implicates exposures in early life as risk factors, consistently with a large literature demonstrating the importance of gestation, infancy, and childhood for several adult cancers. Full-Text PDF