Abstract
Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing. The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001). This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients.
Highlights
Adjuvant treatment is recommended for patients with stage III and high-risk stage II colon cancer
The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and leucine-rich repeat containing G proteincoupled receptor-5 (LGR5) rs17109924 T>C were significantly associated with increased to tumor recurrence (TTR) (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35–0.93; P 1⁄4 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33–0.94; P 1⁄4 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12–0.90; P 1⁄4 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity
A specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and aldehyde dehydrogenase-1 family member A1 (ALDH1A1) rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71–16.63, P < 0.001)
Summary
Adjuvant treatment is recommended for patients with stage III and high-risk stage II colon cancer. The risk of tumor recurrence can be significantly reduced by treating these patients with 5-fluorouracil (5-FU)–based chemotherapy. The addition of oxaliplatin to 5-FU–based chemotherapy is a standard adjuvant treatment for colon cancer, with a higher 5-year disease-free survival (DFS) rate, compared with 5-FU–based treatment alone A considerable number of patients will relapse despite adjuvant treatment [2]. Tumor recurrence after curative surgery remains a major obstacle for improving overall cancer survival, which may be in part due to the existence of cancer stem cells (CSC). Cancer cells with the properties of stem cells possess the ability to self-renew, to undergo multilineage differentiation, and to survive an adverse tissue microenvironment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
