Impact of Human Genetics and Intratumoral Microbiota on Colorectal Cancer Progression

Colorectal cancer (CRC) remains one of the most common cancers worldwide, driven by a complex interplay of genetic, environmental, and microbial factors. Recent scientific research highlights the significant role of the microbiome residing within tumors—referred to as intratumoral microbiota—in influencing CRC progression.

While prior studies established the involvement of gut microbiota in CRC development and progression, emerging evidence points to the impact of bacteria that specifically inhabit tumor tissues. However, the influence of host genetics on these intratumoral microbiota has been less understood.

A groundbreaking study conducted by researchers from the Guangzhou Institutes of Biomedicine and Health of the Chinese Academy of Sciences, along with collaborators from Sun Yat-sen University and the University of Hong Kong, has shed light on this relationship. The study focused on how specific genetic variations — single-nucleotide polymorphisms (SNPs) — can affect microbiota's behavior within tumors and consequently influence cancer progression.

The researchers identified that the SNP rs2355016, located within an intronic region of the KCNJ11 gene (which encodes an ATP-sensitive potassium channel), plays a crucial role. This genetic variation modulates the adhesion of intratumoral bacteria such as Fusobacterium nucleatum, an anaerobic bacterium commonly found in the human mouth and gut, which is known to be associated with CRC.

Their findings indicated that the A allele of rs2355016 reduces the expression of the KCNJ11 gene in CRC cells. This downregulation results in increased presence of Gal-GalNAc on tumor cell surfaces. The Gal-GalNAc molecule interacts with bacterial proteins like Fap2, promoting bacterial adherence, invasion, and tumor growth. This interaction ultimately facilitates the progression of colorectal cancer.

Understanding these mechanisms illuminates how genetic factors can influence tumor-associated microbiota and affect cancer progression. Such insights may pave the way for novel therapeutic strategies targeting microbiota-host interactions, offering hope for more personalized and effective treatments for CRC. Moreover, this research expands our comprehension of how microbiota-host genetic interactions could be relevant in other cancer types as well.

This study underscores the importance of considering genetic background and microbiota composition in cancer research and treatment development, highlighting the intricate balance between host genetics and microbial communities within the tumor microenvironment.