The microbiome and rise of early-onset cancers: knowledge gaps and research opportunities

Abstract

Accumulating evidence indicates an alarming increase in the incidence of early-onset cancers, which are diagnosed among adults under 50 years of age, in the colorectum, esophagus, extrahepatic bile duct, gallbladder, liver, stomach, pancreas, as well as the bone marrow (multiple myeloma), breast, head and neck, kidney, prostate, thyroid, and uterine corpus (endometrium). While the early-onset cancer studies have encompassed research on the wide variety of organs, this article focuses on research on digestive system cancers. While a minority of early-onset cancers in the digestive system are associated with cancer-predisposing high penetrance germline genetic variants, the majority of those cancers are sporadic and multifactorial. Although potential etiological roles of diets, lifestyle, environment, and the microbiome from early life to adulthood (i.e. in one's life course) have been hypothesized, exact contribution of each of these factors remains uncertain. Diets, lifestyle patterns, and environmental exposures have been shown to alter the oral and intestinal microbiome. To address the rising trend of early-onset cancers, transdisciplinary research approaches including lifecourse epidemiology and molecular pathological epidemiology frameworks, nutritional and environmental sciences, multi-omics technologies, etc. are needed. We review current evidence and discuss emerging research opportunities, which can improve our understanding of their etiologies and help us design better strategies for prevention and treatment to reduce the cancer burden in populations.

Keywords: Big data; bioinformatics; exposome; inflammation; omics; population health science.

Figure 1.

Life course perspective on factors related to early-onset cancers. Early-onset digestive system cancers develop through the accumulation of somatic mutations and epigenetic alterations in tumor cells under interactive influences of germline genetic variations and various exposures, i.e., gene-by-environmental interactions. An interplay between epithelial, microbial, immune, other cells, and extracellular matrices plays a pivotal role in the tumorigenic (and/or anti-tumorigenic) processes. Theoretically, these processes may start from the prenatal period and remain variably operative throughout one’s life course.

Figure 2.

Potential interactions of the gut microbiome with host genetics, metabolism, and immunity during the development of early-onset colorectal cancer. The gut microbiota-derived gallic acid can inhibit the tumor-suppressive function of mutant TP53, which is found more frequently in early-onset colorectal cancer than in later-onset colorectal cancer. pks⁺ Escherichia coli and enterotoxigenic Bacteroides fragilis can increase DNA damage in colonic epithelium and induce IL17A and colonic inflammation. Flavonifractor plautii can degrade flavonoids, which have been shown to possess a wide variety of anti-cancer effects by modulating reactive oxygen species-scavenging enzyme activities, arresting the cell cycle, inducing apoptosis and autophagy, and suppressing cancer cell proliferation and invasiveness.

Figure 3.

Simplified schemes illustrating factors related to the rising incidence of early-onset cancers.