Genetic heterogeneity of colorectal cancer and the microbiome

Table 2 The main pathways for the development of sporadic CRC and their relationship to gut dysbiosis

Pathway	Clinical features	Genetic and epigenetic disorders
The chromosomal instability (CIN) – 38%-85%[157,158]	- Associated with traditional adenomas[158]; - Associated with Fusobacterium, Escherichia/Shigella и Leptotrichia[63]; - CIN-H tumors are more frequently located on the left colon (87%), are associated with lymphocytic infiltration (82%), are more common in older patients (73%) and are associated with worse prognosis[157]	- Alteration in chromosome number or structure, loss of heterozygosity and aneuploidy[158]; - Mutations in the APC gene, a negative regulator of β-catenin-dependent Wnt signaling pathway (in 70%-80% of cases)[158]; - Mutations in TP53, KRAS, and PIK3CA genes and tumor suppressor genes SMAD2, SMAD4, and DCC[157,158]; - 20%-60% of tumors are CIN-H[158]
The CpG island methylator phenotype (CIMP) – 15%-30%Three groups based on the degree of gene methylation: High CIMP (CIMP -H); low CIMP (CIMP -L) and negative (CIMP-)[157,158]	- Associated with sessile serrated polyps[158,161,218]; - Associated with F. nucleatum[161,208], and E. faecalis[219]; - Data on the clinical features of CIMP-H tumors are controversial:- CIMP-H tumors are more frequently located in the left colon (67%) and are more common in men (68%) and in older patients (73%)[157,158]; - CIMP-H tumors are more common in females (68%) and in older patients (73%) and are associated with smoking, alcohol consumption, overweight, Western diet, right colon cancer, tumor lymphocytic infiltration, and poor differentiation[159,220,221]; - CIMP-H tumors are associated with worse prognosis[157,158,198,221,222];- CIMP-H tumors with MSI-H and BRAF mutations are more common in the proximal colon, whereas CIMP-L tumors with KRAS mutations are more common in the distal colon[158,159]	- Data on the presence of mutations in BRAF, PIK3CA, KRAS and TP53 genes are contradictory:- KRAS mutation in 27% tumors, PI3KCA mutation in 27%, and BRAF mutation in 7% tumors[157]; - Mutations in BRAF and PIK3CA genes and absence of mutations in KRAS and TP53 genes[154,159,161]; - Methylation of the MINT1, MINT2, MINT31, p14, p16 and MLH1 genes[154,159,161]; - 25% to 60% of tumors are MSI-H[157-159]
The microsatellite instability (MSI) – 15%-20%Three groups based on the number of microsatellites associated: High MSI (MSI-H); low MSI (MSI-L), and microsatellite stable (MSS)[158]	- 20% of cases are hereditary[158]; - Associated with F. nucleatum[124,161,208], E. faecalis[219] and P. micra[124]; - MSI-H are more frequently located on the right colon (86,7%), are more common in older patients(80%), and have a good prognosis at an early stage[157,158]	- High frequency of replication errors in MLH1 and MSH3 mismatch repair (MMR) genes[158]; - Hereditary CRC is associated with germline mutations in MMR genes: MLH1, MSH2, MSH6, and PMS2[158]; - 20%- 70% of tumors are CIMP-H[157,158]; - Often BRAF mutation (40%)[158]; - Mutations in the ACVR2A, TGFBR, MSH3, and MSH6 genes, as well as in the RNF43, RNF213, and ZNRF3 Wnt regulatory pathways[158]; - APC, TP53 and KRAS mutations are rare[158]

APC: Adenomatous polyposis coli; CIMP: CpG island methylator phenotype; CIN: Chromosomal instability; KRAS: Kirsten ras; MMR: Mismatch repair; MSI: Microsatellite instability; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SMAD4: Small mothers against decapentaplegic 4; TP53: Tumor protein 53.