Potentially Functional SNPs (pfSNPs) as Novel Genomic Predictors of 5-FU Response in Metastatic Colorectal Cancer Patients

Abstract

5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

Single nucleotide polymorphisms in the non-coding region of STIM1 gene are associated with Parkinson disease risk in Chinese Han population

“…In the present study, we selected 5 SNPs in the non-coding region of STIM1 gene, in which rs7934581 and rs3794050 are located in the intron region, rs1561876, rs3750994, and rs3750996 are located in the 3’UTR region of the STIM1 gene. The rs7934581, rs3794050, rs1561876, rs3750996 SNPs influence the binding site of transcription factors, [ 22 ] while the G-C haplotype formed by rs3750996 / rs3750994 was significantly associated with higher levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). [ 23 ] Furthermore, these SNPs are prevalent in the Han Chinese of southern China (Table 1 ).…”

“…It has been shown that these four SNPs alter the binding site of the transcription factors, thereby, affect the efficiency of transcription and translation of the STIM1 gene. [ 22 ] Since the 3’UTR region of STIM1 gene is common binding sites of microRNA (miRNA), it is still unclear whether rs1561876 or rs3750996 SNP affects the regulation of STIM1 gene expression by miRNA, and further studies are needed to verify this.…”

Immune-related genes STIM1, ITPKC and PELI1 polymorphisms are associated with risk of colorectal cancer

“…(2020) found that rs3794050 and rs3750996 polymorphisms in STIM1 might influence the plasma STIM1 level and were associated with the risk of Parkinson’s disease. Moreover, rs3794050 and rs3750996 variants might change the transcription factor binding site of STIM1 (Wang et al ., 2014). In our study, we found that the minor alleles of rs3794050 and rs3750996 exhibited an increased risk of CRC, suggesting that rs3794050 and rs3750996 variants may change the expression level of STIM1 and further disrupt the immune system of CRC patients by breaking the Ca 2+ homeostasis.…”

“…Three SNPs rs3794050, rs7934581 and rs3750996 in STIM1 were identified as potentially functional SNPs that were associated with 5-FU response in advanced CRC patients (Wang et al ., 2014). The rs28493229 in ITPKC was correlated with cervical cancer risk in Taiwanese women (Yang et al ., 2012).…”

MicroRNA-340 inhibits the proliferation and promotes the apoptosis of colon cancer cells by modulating REV3L

“…The involvement of REV3L in drug resistance to several chemotherapeutic agents have been reported in different cancer types [ 18 , 27 ]. In the present study, miR-340 based co-treatment with 5-Flurouracil enhanced treatment cytotoxic efficiency against colon cancer cells, that is, co-treatment with miR-340 and 5-FU increased cell death significantlyversus miR-340 or 5-FU treated cancer cells, which suggest combinations of miR-340 with chemotherapeutics might enhance therapeutic efficacy.…”