Early life: an important window of susceptibility for colorectal cancer

Incidence rates of colorectal cancer have increased in young adults (age <50 years) in the U.S. 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 persons born in the 1960s.² This so-called “birth cohort effect” implicates exposures in early life as risk factors, consistent with a large literature demonstrating the importance of gestation, infancy, and childhood for several adult cancers.³ Early life, beginning in utero, represents a critical window of susceptibility, and exposures during this time can translate into large effects on risk of cancer in adulthood.

In a recent issue of Gastroenterology, Gausman et al.⁴ explore the early life hypothesis in the U.K. Biobank, a large-scale biomedical database that provides medical and genetic information of over 500,000 volunteer participants. Participants also completed a baseline questionnaire on health history, including early life factors. Gausman et al. examined the associations of breastfeeding in infancy (yes vs. no), maternal smoking (yes vs. no), comparative body size (thinner vs. average vs. plumper) and height (shorter vs. average vs. taller) at age 10 years, age at menarche (women only, <11 vs. 11-13 vs. ≥14 years), and age at first facial hair (men only, younger vs. average vs. older) and colorectal cancer in young adults (diagnosed at age <50 years). There was no association with any of these six early life factors, and the authors conclude that early life factors do not play a meaningful role in colorectal carcinogenesis.

These null results, however, must be interpreted within the context of the study design and several limitations. First, case-control studies of early life factors require now-adult children to recall events and exposures that occurred decades prior, and this often leads to measurement error. About 75% of study participants completed the baseline questionnaire more than 50 years after birth, and many of the early life factors, such as breastfeeding and maternal smoking, may have been near impossible to remember. Although the authors conducted a sensitivity analysis excluding prevalent cases (i.e., those diagnosed prior to the baseline questionnaire), this does not address measurement error or improve the accuracy of information recalled from so long ago. Second, breastfeeding and maternal smoking were operationalized simply as yes vs. no, and the timing and duration may matter most. Third, body size and puberty may be consequences of earlier or in utero exposures that were not measured. It is possible that these childhood and adolescent factors may not directly increase risk of colorectal cancer even if in utero exposures do. Finally, participants comprise a mix of persons from higher- and lower-risk generations–an important consideration when studying early life factors.

In contrast to the findings of Gausman et al., a growing literature supports the importance of in utero exposures for colorectal cancer. Swedish and Norwegian studies report an association between birth size and colorectal cancer,⁵ and a Finnish study identified placental shape and size as a risk factor.⁶ In the U.S., in utero exposure to synthetic hormones, anti-nauseants, and sulfonamides – medications frequently prescribed to pregnant women in the 1960s – increases risk of colorectal cancer by three- to five-fold.⁷ Maternal obesity, pregnancy weight gain, and fetal growth also appear to play a role.⁸ Importantly, these studies have linked prospectively collected information on early life with cancer diagnoses ascertained from population-based registries over 60 or more years; they do not rely on participant-reported information and are not subject to the same methodologic challenges of case-control studies. The U.S. study includes persons born between 1959 and 1967, the generation to first experience increasing incidence rates of colorectal cancer.

To conclude, Gausman et al. used a large database to address an increasingly relevant question, but the null results do not address the role of in utero exposures and should not end our quest to identify other early life factors that increase risk of colorectal cancer. Early life factors, including in utero exposures, are still a relatively new concept in the setting of gastrointestinal disease. The evidence accumulated to date paints a convincing picture about their importance for colorectal cancer, particularly for generations at higher risk. We need to reconsider our long-held notions about the causes of this disease – and across all ages – as higher risk generations age and the burden of colorectal cancer continues to increase.