Multifactorial causation of early onset colorectal cancer.

The multiple-hit hypothesis of cancer, including colorectal cancer (CRC), states that neoplastic development requires a sequence of mutations and epigenetic changes in driver genes. We have previously proposed that obesity increases CRC risk by supporting neoplastic development through adipokine-induced signaling, and this proliferative signaling substitutes for specific driver gene mutations. In support of this hypothesis, analyses of The Cancer Genome Atlas (TCGA) mutation data have revealed that obese patients with microsatellite stable CRC exhibit fewer driver gene mutations than CRC patients with normal body mass index. The lower number of driver gene mutations required for cancer development may shorten the neoplastic process and lead to an early onset of CRC. Therefore, obesity could be one factor explaining the rise of CRC incidence among younger individuals (< 50 years of age); furthermore, early onset CRC has been associated with the increasing incidence of metabolic syndrome and obesity in this age group. However, CRC incidence among older individuals (> 50 years of age) is stable or declining, despite the high rates of metabolic syndrome and obesity in this age group. In search for explanations of this phenomenon, we discuss several factors that may contribute to the divergent CRC incidence trends in populations under, and above, the age of 50, despite the rising levels of metabolic syndrome and obesity across all ages. First, older individuals with metabolic dysregulation are more frequently on maintenance medications, such as aspirin, β-blockers, lipid-lowering drugs, ACE inhibitors, metformin, etc., compared to younger individuals. Such treatments may suppress specific adipokine-induced proliferative signaling pathways, and therefore counteract and slow down neoplastic development in medicated overweight/obese individuals. Second, in the past decades, the incidence of infectious diseases accompanied by febrile episodes has been decreasing and the use of antipyretics increasing. Compared to normal cells, neoplastic cells are more sensitive to high body temperature; therefore, the decreased number of febrile episodes in childhood and adolescence may contribute to increased cancer incidence before the age of 50. Third, obesity at younger age may expand the stem cell compartment. An increased number of intestinal stem cells and stem cell divisions translates into a higher probability of sporadic mutations in the stem cells, and therefore, a greater chance of neoplasia. In conclusion, we hypothesize that early onset CRC has multifactorial causation and the proposed associations could be examined through analyses of existing data.