Researchers found how human genetics and intratumoral microbiota influence colorectal cancer

A recent study conducted by the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences (CAS), in collaboration with Sun Yat-sen University and the University of Hong Kong, investigated the association between host genetics and intratumoral microbiota and their interplay in the progression of colorectal cancer (CRC). This study demonstrates that patients who carry the single-nucleotide polymorphism (SNP) rs2355016 can regulate the adhesion of intratumoral microbiota, subsequently promoting CRC progression. The findings were published in Cell Host & Microbe.

CRC is among the most prevalent cancers worldwide. It is believed that microbiota play a significant role in both the occurrence and progression of CRC. Thus far, most explored cancer-microbe relationships have concentrated on fecalmicrobiota. However, new evidence indicates the presence of intratumoral microbiota, which are crucial in cancer progression. While research has predominantly examined the link between human genetics and gut microbiota, the effect of human genetics on intratumoral microbiota in CRC patients remains largely unstudied.

To clarify how human genetics influences intratumoral microbiota, this team enrolled 748 CRC patients and conducted a thorough evaluation to explore the connection between host genetics and intratumoral microbiota in CRC patients. Host genetics were analyzed using the Asian Screening Array, while the intratumoral microbiota was identified through 16S rRNA sequencing. Genome-wide association study analyses assessed the relationships between SNPs and intratumoral microbiota.

The results indicated that SNP rs2355016, positioned within the intronic region of the KCNJ11 gene (ATP-sensitive inward rectifier potassium channel 11), was significantly correlated with the levels of F. nucleatum in CRC tissues. Additionally, expression Quantitative Trait Locus (eQTL) and protein Quantitative Trait Locus (pQTL) analyses demonstrated that the A allele of SNP rs2355016 downregulates the expression of KCNJ11 in CRC cells, which may subsequently increase the presence of Gal-GalNAc on the surface of tumor cells. This increased Gal-GalNAc interacts with Fap2, thereby enhancing the adhesion and invasion of F. nucleatum, ultimately aiding in CRC growth.

These findings enhance our understanding of CRC growth and can inform the development of effective treatments to curb tumor progression driven by intratumoral microbiota. Additionally, this research expands our comprehension of the intricate dynamics of host-microbiota interactions and sheds light on the involvement of intratumoral microbiota in other types of cancer.

This study was supported by the National Natural Science Foundation of China, the Shenzhen-Hong Kong-Macao Science and Technology Project (Category C project), the Guangdong Science and Technology Department Foundation, the Guangdong Cheung Kong Philanthropy Foundation, and the National Key R&D Program of China, among others.

 Fig. GWAS analyses show that a rs2355015 SNP in the KCNJ11 gene intron downregulates KCNJ11 expression, enhancing Gal-GalNAc on tumor cell surfaces, promoting adhesion and invasion of F. nuceatum through its Fap2 protein. (Image by Prof. Wu’s team)

Contacts:

WU Baixing, Ph.D., Principal Investigator;

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530.

Email: wu_baixing@gibh.ac.cn