Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study

Abstract

Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.

Keywords: biomarkers; colorectal cancer; pharmacogenomics.

Figure 1

Flowchart of disposition of patients within this study.

Figure 2

Kaplan–Meier curve of colorectal cancer patients according to liver metastasis status (without liver metastases = blue line and a median survival of 103.7 months, with liver metastases = red line and a median survival of 31.5 months).

Figure 3

Kaplan–Meier curve of colorectal cancer patients according to High-Risk (DPYD rs1801265 T/C + C/C genotypes, ABCB1 rs1045642 C/C genotype, and MTHFR rs180113 C/C genotype) (Low risk = blue line (median survival of 68.5 months), High-risk = red line (median survival of 28.2 months)).

Figure 4

Kaplan–Meier curves of colorectal cancer patients according to: (a) High-Risk profile and BRAF mutational status (Low risk and BRAF V600E wild-type = blue line (median survival of 50.3 months), Low risk and BRAF V600E mutated = red line (median survival of 71.9 months), High-risk and BRAF V600E wild-type = green line (median survival of 26.2 months), High-risk and BRAF V600E mutated = sky blue line (median survival not reached). (b) High-Risk profile and KRAS mutational status: (Low risk and KRAS wild-type = blue line (median survival of 68.5 months), Low risk and KRAS mutated = red line (median survival of 58.8 months), High-risk and KRAS wild-type = green line (median survival of 23.0 months), High-risk and KRAS mutated = sky blue line (median survival of 35.0 months). (c) High-Risk profile and PI3KCA mutational status: (Low risk and PI3KCA wild-type = blue line (median survival of 47.9 months), Low risk and PI3KCA mutated = red line (median survival of 111.7 months), High-risk and PI3KCA wild-type = green line (median survival of 26.9 months), High-risk and PI3KCA mutated = sky blue line (median survival not reached). Risk genotype profile includes DPYD rs1801265 T/C + C/C genotypes, ABCB1 rs1045642 C/C genotype, and MTHFR rs180113 C/C genotype).

Figure 4

Kaplan–Meier curves of colorectal cancer patients according to: (a) High-Risk profile and BRAF mutational status (Low risk and BRAF V600E wild-type = blue line (median survival of 50.3 months), Low risk and BRAF V600E mutated = red line (median survival of 71.9 months), High-risk and BRAF V600E wild-type = green line (median survival of 26.2 months), High-risk and BRAF V600E mutated = sky blue line (median survival not reached). (b) High-Risk profile and KRAS mutational status: (Low risk and KRAS wild-type = blue line (median survival of 68.5 months), Low risk and KRAS mutated = red line (median survival of 58.8 months), High-risk and KRAS wild-type = green line (median survival of 23.0 months), High-risk and KRAS mutated = sky blue line (median survival of 35.0 months). (c) High-Risk profile and PI3KCA mutational status: (Low risk and PI3KCA wild-type = blue line (median survival of 47.9 months), Low risk and PI3KCA mutated = red line (median survival of 111.7 months), High-risk and PI3KCA wild-type = green line (median survival of 26.9 months), High-risk and PI3KCA mutated = sky blue line (median survival not reached). Risk genotype profile includes DPYD rs1801265 T/C + C/C genotypes, ABCB1 rs1045642 C/C genotype, and MTHFR rs180113 C/C genotype).

Figure 5

Kaplan–Meier curve of colorectal cancer patients comparing High-Risk profiles and BRAFV600E wild-type patients (red line, median survival of 26.2 months) versus all the other patients (blue line, median survival of 69.7 months). Patients with a High-Risk genotype profile (any of the following polymorphisms: DPYD rs1801265 T/C + C/C genotypes, ABCB1 rs1045642 C/C genotype, and MTHFR rs180113 C/C genotype) must have the BRAF wild-type.

Figure 6

Kaplan–Meier curve of stage III colon cancer patients according to DPYD expression in the TCGA cohort (DPD low = blue line, DPD normal = red line).

Figure 7

Kaplan–Meier curve of TCGA colon cancer patients according to TYMS, TK1, TYMP, and FOXM1 expression in the TCGA cohort by clinical stage.

Figure 8

Drug sensitivity analysis of COREAD (Colon and rectum adenocarcinoma) cell lines to 5-fluorouracil (GDSC2 dataset, Sanger Screening Site, n = 968). Each circle represents one cell line. The data were obtained from “Genomics of Drug Sensitivity” (https://www.cancerrxgene.org/; accessed on 30 October 2023) [48].

Figure 8

Drug sensitivity analysis of COREAD (Colon and rectum adenocarcinoma) cell lines to 5-fluorouracil (GDSC2 dataset, Sanger Screening Site, n = 968). Each circle represents one cell line. The data were obtained from “Genomics of Drug Sensitivity” (https://www.cancerrxgene.org/; accessed on 30 October 2023) [48].