PURPOSE: 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.
EXPERIMENTAL DESIGN: 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.
RESULTS: 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).
CONCLUSION: 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.