Epidemiology, molecular biology, and genetics of sporadic young onset colorectal cancer

Abstract

The incidence of colorectal cancer (CRC) in individuals under 50 years of age—termed young-onset colorectal cancer (YOCRC)—has been increasing despite declining rates of CRC overall. YOCRC now comprises up to 15 % of new CRC diagnoses. Most cases of YOCRC are sporadic, occurring without identifiable hereditary syndromes or family history. It exhibits distinct epidemiological and molecular characteristics, including a predilection for rectal and left-sided tumors, aggressive histology, and more advanced stage at diagnosis. Suspected risk factors contributing to this rising incidence are multifactorial and include lifestyle and environmental exposures, such as westernized diets, obesity, sedentary behavior, increased antibiotic exposure, and chronic inflammation. These factors interact with the gut microbiome to induce dysbiosis, pro-inflammatory states, and DNA damage. At the molecular level, YOCRC is most associated with chromosomal instability (CIN), while a minority exhibit microsatellite instability (MSI) or CpG island methylator phenotype (CIMP). Compared to late-onset CRC, YOCRC displays lower rates of KRAS, BRAF, and APC mutations, but increased TP53 and PTEN alterations. Emerging research also highlights differences in the tumor microenvironment, including immune cell infiltration and complement expression, which may influence therapeutic response. Understanding the unique biology of sporadic YOCRC is essential for developing risk stratification models, refining screening strategies, and advancing targeted treatment approaches. Continued investigation into genetic susceptibility, environmental triggers, and tumor immunobiology will be crucial in addressing this evolving public health challenge.