Genetic variants linked to type 2 diabetes in CDKN1B and TCF7L2 influence survival outcomes in metastatic colorectal cancer

Abstract

Evidence suggests that metastatic colorectal cancer patients with type 2 diabetes (T2D) experience a poorer prognosis in contrast to their non-diabetic counterparts. Considering the multifactorial genetic nature of colon cancer development, we examined whether gene polymorphisms associated with T2D could affect the clinical outcome of metastatic colon cancer. Using in silico analysis, we evaluated gene variants linked to both T2D and colon cancer utilizing data from The Cancer Genome Atlas (TCGA). Subsequently, we assessed the prognostic relevance of polymorphisms in CCND2, CDKN1B, CDKN2A, CDKN2B, EML4, HNF1A, ID3, IGF1, IGF1R, IGF2, INHBA, INSR, IRS1, IRS2, and TCF7L2 in a cohort of 99 consecutive metastatic non-diabetic colon cancer patients with favorable clinical conditions. Primary colon cancer DNA was sequenced using the TruSight Oncology 500 kit, followed by sequencing on an Illumina NovaSeq 6000 platform. Notably, patients carrying the CDKN1B p.V109G and TCF7L2 p.P370R polymorphisms exhibited significantly shorter median survivals compared to wild-type counterparts, with adjusted hazard ratios (covariates: age, gender, metastatic extent, RAS/BRAF mutations, and response to therapy) of 2.28 (95% CI: 1.18-4.41) and 4.45 (95% CI: 1.26-15.70), respectively. Our findings provide scientific evidence of T2D genetic polymorphisms' involvement in determining the aggressiveness of metastatic colon cancer, identifying CDKN1B p.V109G and TCF7L2 p.P370R as novel unfavorable prognostic markers.

Keywords: CKN1B; TCF7L2; gene polymorphisms; metastatic colon cancer; prognosis; type 2 diabetes.

FIGURE 1

Phenolyzer systematically examines key gene‐disease databases (see Section 2) to prioritize genes by considering current scientific knowledge such as shared biological pathways, gene families, gene–gene transcriptional regulation, and protein–protein interactions. The outcomes are presented through a network visualization image (A), and a score system visible at the end of each bar in the graph (B), offering readers an intuitive overview of the weighted interactions of the involved genes.

FIGURE 2

Kaplan–Meier survival curves, stratified by gene polymorphisms significantly associated with overall survival in the analyzed cohorts, are shown. The corresponding hazard ratios and p‐values are reported in Table 3. (A) Overall survival in patients with the CDKN1B wild‐type allele compared to those carrying the p.V109G variant. (B) Prognostic trends in patients with the TCF7L2 wild‐type allele versus those harboring the p.P370R variant. (C) Survival outcomes in patients carrying more than three polymorphisms versus those with three or fewer.