THE JEREMIAH METZGER LECTURE: ENVIRONMENTAL INFLUENCES ON COLORECTAL CANCER

Abstract

Gene-environmental interactions create risk profiles for sporadic cancer development in patients with colorectal cancer (CRC). For instance, a person's socioeconomic status over their lifetime can affect their level of physical activity and type of diet, and their exposure to tobacco and alcohol may affect their gut microbiome and ultimate risk for developing CRC. Metabolic disease can independently or further change the gut microbiome and alter the typical timing of CRC development, such as is observed and linked with early-onset disease. Patients with microsatellite unstable tumors where DNA mismatch repair is defective have altered immune environments as a result of tumor hypermutability and neoantigen generation, allowing for immune checkpoint inhibitor susceptibility; in such cases, the genetics of the tumor changed the environment. The environment can also change the genetics, where interleukin-6-generated inflammation can inactivate MSH3 protein function that is associated with CRCs which are more metastatic, and patients show poor outcomes. Some specific aspects of the local microbial environment that may be influenced by diet and metabolism are associated with CRC risk, such as Fusobacterium nucleatum infection, and may affect the initiation, perpetuation, and spread of CRC. Overall, both the macro- and microenvironments associated with a person play a major role in CRC formation, progression, and metastases.

Fig. 1.

Examples of Gene-Environmental Interactions for Cancer Development in Humans. Each human has a different level of genetic susceptibility based on their genetic makeup and, therefore, has a variable risk for developing a cancer if exposed to a pro-carcinogenic environmental agent.

Fig. 2.

Risk Factors for Colorectal Cancer. Ultimate lifetime risk for colorectal cancer is determined by non-modifiable factors such as age and genetic susceptibility, plus modifiable factors exposed over one’s lifetime. Colorectal cancer screening can mitigate risk if utilized effectively.

Fig. 3.

Progression of DNA Mismatch (MMR) Repair Deficient Colorectal Cancers and Outcome Consequences. (Top) Inactivation of MSH2, PMS2, MSH6, and MLH1 either through germline or through somatic mechanisms leads to tumor microsatellite instability-high (MSI-H) and hypermutated DNA. Because of a limited number of coding (mostly mononucleotide) microsatellites, MSI-H tumors generate novel peptides that are immunogenic, and along with their hypermutability provide responsiveness to immune checkpoint inhibitor drug susceptibility. MSI-H tumors are relatively drug resistant to 5-fluorouracil therapy, but patients with MSI-H tumors have improved survival compared to patients without MSI-H tumors. (Bottom) Interleukin-6-driven inflammation can somatically inactivate MSH3 by moving it from the nucleus to the cytosol. This causes a unique form of microsatellite instability called EMAST (elevated microsatellite alterations at selected tetranucleotide repeats) that does not involve mononucleotide instability. MSH3 is also involved in homologous recombination events that in its absence can lead to DNA double strand breaks. These tumors are not hypermutable and, thus, are less likely susceptible to immune checkpoint therapy. They remain sensitive to 5-fluorouracil, but patients show poor survival with advanced disease and higher levels of metastases. EMAST was found more frequently in colorectal cancers in patients of African descent in the United States.

Fig. 4.

Schematic of Microbiome Interaction During the Pathogenesis of Colorectal Cancer. The gut microbiome, shaped by diet and metabolism as well as potential genetic changes in the gut, can modify by promoting, accelerating, or potentially decelerating colorectal cancer at any and all stages of progression including metastasis.