Cancer stem cell gene variants associated with colon cancer recurrence.

Abstract

3612 Background: Recent evidence suggests that cancer stem cells (CSCs) are responsible for colon cancer (CC) progression and tumor recurrence. Despite the potentially high clinical relevance of CSCs, little is known about the prognostic value of CSC markers in CC. There is substantial germline genetic variability in the genes of CSC markers, including single nucleotide polymorphisms (SNPs). SNPs may alter transcription, translation or splicing, thereby causing inter-individual differences. We hypothesized that SNPs analyzed in a comprehensive panel of CSC marker genes predict tumor recurrence in patients with CC. SNPs were selected based on previous literature, functional data and frequency. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs [range 22–87 yrs]) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. Twenty-six SNPs in genes of CSC markers (CD44, CD133, CD26, EpCAM, CD166, Msi-1, CD29, CD24, Lgr5 and ALDH1) were determined by PCR-RFLP or direct DNA-sequencing. Primary endpoint of the study was time to tumor recurrence (TTR). This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK). Results: The minor alleles of CD44 rs8193 C/T, CD166 rs1157 G/A and Lgr5 rs17109926 T/C showed significantly longer median TTR (5.7 vs 9.4 yrs, HR 0.66, p=0.024; 5.7 vs 11.3 yrs, HR 0.56, p=0.024; 6.6 vs 10.7 yrs, HR 0.33, p=0.023) in univariate analysis. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy and stratification by race these results remained significant (HR 0.71, p=0.034; HR 0.55, p=0.027; HR 0.34, p=0.035). No significant association was found between TTR and the remaining tested gene variants. Conclusions: To the best of our knowledge, this is the first study identifying common gene variants in CSC marker genes as independent prognostic marker in stage II and III CC. Larger prospective trials are warranted to confirm these findings.