Genetic Polymorphisms in MHC Classes I and II Predict Outcomes in Metastatic Colorectal Cancer

Abstract

The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of the antigen presentation pathway. Therefore, the present study aimed to explore the effect of genetic variants in genes involved in MHC class I and II pathways in patients treated with first-line chemotherapy in combination with targeted antibodies in metastatic colorectal cancer (mCRC) patients. Genomic DNA from the blood samples of 775 patients enrolled in three independent, randomized, first-line trials, namely TRIBE (FOLFIRI-bevacizumab, N = 215), FIRE-3 (FOLFIRI-bevacizumab, N = 107; FOLFIRI-cetuximab, N = 129), and MAVERICC (FOLFIRI-bevacizumab, N = 163; FOLFOX6-bevacizumab, N = 161), was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on the outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways was analyzed. We identified several SNPs in multiple genes associated with targeted treatment benefits across different treatment arms in our study population (p < 0.05). Treatment-SNP interaction analyses confirmed a significant treatment interaction with the targeted agents (bevacizumab vs. cetuximab) and the chemotherapy backbone (FOLFIRI vs. FOLFOX) in certain selected SNPs. Our results highlight a potential role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on the biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.

Keywords: MHC; antigen presentation; biomarkers; colorectal cancer; survival.

Figure 1

Schematic representation of the antigen processing and presentation pathway (MHC classes I and II).

Figure 2

Consort diagram and workflow of the study. * Patients without sufficient peripheral whole blood samples, SNP data, and/or any oth-er relevant data for analyses were excluded from the study.

Figure 3

Association between TAP2 rs241447 expression and patient outcomes in the FIRE-3 and MAVERICC trials. Kaplan–Meier curves show OS stratified by TAP2 rs241447 alleles any T and C/C tumor expression according to different treatments of the FIRE-3 and MAVERICC trials. (A) FIRE-3 bev/FOLFIRI OS, (B) FIRE-3 cet/FOLFIRI OS, (C) MAVERICC bev/FOLFIRI OS, (D) MAVERICC bev/FOLFOX6 OS. Bev, bevacizumab; cet, cetuximab; OS, overall survival.

Figure 4

Association between ERAP1 rs2287987 expression and patient outcomes in the FIRE-3 and TRIBE trials. Kaplan–Meier curves show PFS stratified by ERAP1 rs2287987 alleles any T and C/C tumor expression according to different treatments of the FIRE-3 and TRIBE trials. (A) FIRE-3 bev/FOLFIRI PFS, (B) FIRE-3 cet/FOLFIRI PFS, (C) TRIBE bev/FOLFIRI PFS, (D) TRIBE bev/FOLFOXIRI PFS. Bev, bevacizumab; cet, cetuximab; PFS, progression-free survival.

Figure 5

Association between CIITA rs4774 expression and patient outcomes in the FIRE-3 and MAVERICC trials. Kaplan–Meier curves show PFS stratified by CIITA rs4774 alleles G/G and any C tumor expression according to different treatments of the FIRE-3 and MAVERICC trials. (A) FIRE-3 bev/FOLFIRI PFS, (B) FIRE-3 cet/FOLFIRI PFS, (C) MAVERICC bev/FOLFIRI PFS, (D) MAVERICC bev/FOLFOX6 PFS. Bev, bevacizumab; cet, cetuximab; PFS, progression-free survival.

Figure 6

Amino acid substitution of threonine (Thr) to alanine (Ala) at residue number 665 by TAP2 variant rs241447. TAP2 protein structure downloaded from Protein Data Bank (PDB code: 8T46) and visualized in PyMol. Color representation for Thr665 is pink and for Ala665 is orange.