Correlation of single nucleotide polymorphisms (SNPs) of hypoxia-related genes with pathologic complete response (pCR) following neoadjuvant chemoradiation (chemoXRT) for locally advanced rectal cancer.

Abstract

Background: Neoadjuvant chemoXRT for locally advanced rectal cancer improves locoregional control and rates of sphincter preservation. There are currently no established genetic markers predictive of tumor response to chemoXRT. The purpose of this study was to evaluate the role of genes associated with tumor hypoxia and its downstream pathways of angiogenesis and apoptosis on chemoradiosensitivity. Methods: We prospectively enrolled 54 patients (pts) with clinical AJCC stage II or III cancer who received 5-FU based neoadjuvant chemoXRT. Pretreatment biopsies of tumors were obtained in all pts for DNA extraction. A retrospective analysis was completed using the TaqMan SNP Genotyping Assays. We examined 11 SNPs of 7 genes; HIF1 (hypoxia-inducible factor 1), VHL (von Hippel-Lindau), CBP (CREB-binding protein), VEGF (vascular endothelial growth factor), leptin, THBS1 (Thrombospondin 1), and BIRC5 (baculoviral IAP repeat-containing 5). The association of pCR on surgical specimens with genotypes or clinical features was analyzed by chi-square test and logistic regression. Results: Median age was 56.5 yrs old (range: 27-79). Fourteen pts achieved pCR (26%). Sex, age, pretreatment T, and N stage were not associated with pCR. At a median follow-up of 31.7 months, no pt with pCR had recurrence, but 8 (20%) pts without pCR developed distant metastasis but not local recurrence. The genotype of CBP A214G (rs130021) was associated with pCR; 12 (35.3%) of the CBP 214 GG/AG carriers compared with 2 (10.0%) of the AA carriers had pCR (p = 0.041). The genotype of HIF1(alpha) C85T (rs11549465) had a weak association with pCR (p = 0.111). A combined genotype effect of CBP A214G and HIF1(alpha) C85T was observed; pts carrying 1 and/or 2 at-risk alleles had a significantly lower pCR rate than pts carrying no at-risk alleles (OR = 4.96, 95% CI = 1.20-20.6, p = 0.027). Conclusions: Our analysis indicates the significance of gene polymorphisms of the tumor hypoxia pathway in chemoradiation sensitivity. The CBP A214G genotype alone or with HIF1(alpha) C85T may potentially predict pCR following chemoXRT for rectal cancer; further analysis is ongoing.