Epidemiology and biology of early onset colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in men or women in the United States. Average-risk screening that begins at age 50 years has reduced incidence and mortality of CRC in those over 50 years of age, whereas CRC incidence in those under age 50 years (early onset colorectal cancer (eoCRC)) has recently and dramatically increased. In this review, we summarize the recent literature including risk factors for eoCRC, differences in clinicopathologic presentation and outcomes in eoCRC, and emerging evidence regarding the molecular pathways that are altered in eoCRC compared to later onset CRC (loCRC). Epidemiologic studies of eoCRC show predominance in distal colon and rectum, and association with several modifiable risk factors, including diabetes, obesity, diet, sedentary time, alcohol consumption and smoking. Data regarding potential risk factors of prior antibiotic exposure and microbiome alterations or direct carcinogen exposure are still emerging. Aggressive clinicopathologic features of eoCRC at presentation may be due to delay in diagnosis or more aggressive tumor biology. EoCRC outcomes are similar to loCRC when matched for stage, but overall mortality is greater due to higher frequency of advanced disease at a younger presentation, with more life-years lost. There are only few molecular evaluations of eoCRC to date, with findings of potential increase in TP53 and CTNNB1 somatic mutation and decrease in APC, KRAS and BRAF somatic mutation, compared to loCRC. Other findings include LINE-1 hypomethylation, absence of microsatellite instability (MSI-H), presence of chromosomal instability (CIN) or microsatellite and chromosomal stability (MACS). These studies are only now emerging and have not yet identified a specific molecular signature defining eoCRC. Further research evaluating genetic and molecular differences as well as environmental triggers for eoCRCs should provide a clearer understanding to inform targeted screening for pre-symptomatic at-risk younger individuals.