A Genetic Variant in CD274 Is Associated With Prognosis in Metastatic Colorectal Cancer Patients Treated With Bevacizumab-Based Chemotherapy

Abstract

Bevacizumab plus chemotherapy is a well-established first-line treatment for metastatic colorectal cancer (mCRC). We investigated whether polymorphisms of genes involved in immune regulation signaling are related to the clinical outcome of mCRC patients treated with bevacizumab-based chemotherapy. In this study, we genotyped 14 single-nucleotide polymorphisms (SNP) in IFN-γ/IFNGRs/JAKs/STATs/PD-L1 pathway by using DNA from blood samples of 141 mCRC patients treated with first-line bevacizumab-based chemotherapy. In the univariate and multivariate analysis, patients with AA genotype of CD274:rs2297136 had a significantly better PFS and OS than patients with AG or GG genotype (10.8 versus 9.8, log-rank P=0.0031; 31.4 versus 20.9, log-rank P=0.0233). Patients with AG/GG genotype of IFNGR1:rs2234711, CT/TT genotype of IFNGR1:rs9376267 also showed longer OS than patients with AA or CC genotype, however, the statistic did not reach significant after adjusted by clinical factors in the multivariate analysis. A nomogram based on the genetic variants and clinic characteristics was developed with a good accuracy to predict patients’ survival. Our result indicates that CD274:rs2297136 is one of the most important predictors for the prognosis of mCRC patients treated with bevacizumab-based chemotherapy, if further validated in larger population.

Pharmacogenetics Role of Genetic Variants in Immune-Related Factors: A Systematic Review Focusing on mCRC

“…Variants in the INFG receptor gene (INFGR1) have been investigated for their predictive role in 141 Chinese mCRC treated patients with bevacizumab-based regimens. In particular, patients with the IFNGR1-rs2234711-G allele and IFNGR1-rs9376267-T allele showed longer OS only in univariate analysis (p = 0.041; p = 0.0312) [58].…”

“…The CD274-rs2297137-A allele was also associated with prolonged OS in multivariate analysis in the additional control cohort 2 (FOLFIRI plus bevacizumab) (HR:0.65 p = 0.021) [57]. Moreover, in 141 mCRC Chinese patients treated with first-line bevacizumab-based regimens, the CD274-rs2297136-AA genotype was associated with better PFS (HR:1.68, p = 0.018) and OS (HR:1.88, p = 0.012) in the whole population and also in the KRAS mutant subgroup [58]. The binding of CD24, present on tumor cells, to Siglec-10, expressed on immune cells, causes inhibition of the immune response mediated by the tyrosine phosphatases SHP-1 and SHP-2.…”

“…The regulation of the killing function of NK and T cells is mediated by a family of type I transmembrane glycoproteins called killer-cell immunoglobulin-like receptors (KIRs) that interact with MHC class I. NK cells are able to discriminate MHC class I in transformed and virus-infected cells, ignoring potential targets, expressing normal levels of autologous MHC class I, and leading to inhibition of antiviral and cytotoxic activities [141]. Genetic variants in the KIRs and their ligands, HLA class I (HLA-A, -B, -C), were investigated in 224 mCRC patients receiving FOLFIRI [58]. KIR3DL1/HLA-Bw4-I80 combination emerged as a positive predictive marker of survival (HR for T80:2.8, p < 0.001 and HR for no functional KIR/HLA interaction:1.8, p = 0.007) and the presence of the KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 combination was associated with an increased rate of complete response (ORs ranging from 2.1 to 4.3) [58].…”

“…Genetic variants in the KIRs and their ligands, HLA class I (HLA-A, -B, -C), were investigated in 224 mCRC patients receiving FOLFIRI [58]. KIR3DL1/HLA-Bw4-I80 combination emerged as a positive predictive marker of survival (HR for T80:2.8, p < 0.001 and HR for no functional KIR/HLA interaction:1.8, p = 0.007) and the presence of the KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 combination was associated with an increased rate of complete response (ORs ranging from 2.1 to 4.3) [58]. Most KIRs have an inhibitory effect on immune cells, while some, such as KIR2DS4, can activate immune cells.…”

Deregulation of interferon-gamma receptor 1 expression and its implications for lung adenocarcinoma progression

“…Moreover, the risk of developing colon and rectal cancer is associated with polymorphisms in IFN-γ and its receptors, the influence of other genes related to inflammation, the use of nonsteroidal anti-inflammatory drugs, and smoking[ 50 ]. Nevertheless, a longer overall survival has been observed in patients with variations in the IFNGR1 promoter region (rs2234711, rs9376267) diagnosed with metastatic colorectal cancer under treatment with bevacizumab-based chemotherapy[ 52 ].…”