Epidemiology and biology of early onset colorectal cancer

Abstract

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.

Keywords: cancer genetics; cancer prevention; cancer risk factors; cancer screening; cancer treatment; colon cancer; colonoscopy; diabetes mellitus; early onset; genetic testing; inflammation; obesity; rectal cancer; tumor microenvironment; young onset.

Table 1. Definitions and key terms for early onset colorectal cancer

Table 2. Key association factors with early onset colorectal cancer

Figure 1. Possible epidemiological scenarios accounting for the observed increased incidence of early onset colorectal cancer. (A) An environmental exposure occurs in the total population, but an increase in colorectal cancer is not seen in patients that are screened, with an apparent increase in patients solely because that group is not screened. This scenario might imply genetic and epigenetic factors and pathways are like those observed in later onset colorectal cancer. (B) An environmental exposure occurs, but the exposure selectively affects younger populations over older populations (through accelerated pathogenesis), providing a true increase in colorectal cancer in that population without affecting older populations. This pathway might imply genetic and epigenetic factors and pathways that are distinct from those observed in later onset colorectal cancer. This scenario also implies that tumor initiation and possibly tumor progression are accelerated over the typical progression timeframes observed for later onset colorectal cancer.

Figure 2. Hypothesized sporadic normal-to-adenoma-to-carcinoma progression in the colon for early onset colorectal cancer. A presumed environmental trigger in the microenvironment milieu helps create the conditions that trigger early existing and/or initiating genetic and epigenetic alterations that begin to propel a normal colonocyte or colon stem cell towards excessive proliferation. After neoplastic initiation, the local microenvironment intermittently or constantly continues to provide the conditions to propel further genetic and epigenetic alterations that are manifested by histologic changes, ultimately accumulating sufficient genomic changes to define it as a cancer and acquiring the capability of metastatic spread. The local microenvironment is highly influenced by diet and diet supplements, tobacco and alcohol use, aspirin and NSAID use, and metabolic pathways important in obesity regulation. Within the local microenvironment are multiple factors that may indirectly or directly influence epithelial behavior, including the makeup of the gut microbiome and its metabolites and toxins, levels and types of inflammatory cells, presence of oxygen and free radicals, and other potential carcinogens.