Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence

Abstract

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 DNAsequencing.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 ¼ 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P ¼ 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P ¼ 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. Clin Cancer Res; 17(21); 6934-43. Ó2011 AACR.

Cluster of Differentiation 44 (CD44) Gene Variants: A Putative Cancer Stem Cell Marker in Risk Prediction of Bladder Cancer in North Indian Population

“…In our study, CD44 rs4755392 revealed a significant reduced risk in BC as compared to the study of Gerger et al [23] where they demonstrated colon cancer risk. Germline variant of CD44 rs4755392 revealed no significant statistical association in patients with localized gastric adenocarcinoma [15] and in patients with gastrointestinal (non-colorectal) cancer [24].…”

DNA Damage Repair Pathways in Cancer Stem Cells

“…For instance, an "invasiveness gene signature" composed of 186 differentially expressed genes in breast CSCs compared with normal breast epithelium has been associated with overall and metastasis-free survival of patients with breast cancer (29). More recently, germ line polymorphisms in colon CSC-related genes have been linked to the time to tumor recurrence in high-risk patients with stage II and stage III colon cancer treated with standard adjuvant chemotherapy (30). However, the relative small cohort of patients examined in these studies and their retrospective nature impose further investigations to assess the prognostic/predictive value of CSC-related parameters in the clinical setting.…”

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

“…CSCs can fuel tumor growth, confer resistance to standard chemotherapy and radiation, and are likely to contribute to recurrent disease (21). Correspondingly, high LGR5 expression in gastrointestinal tumors of different tissue types correlates with higher incidence of metastasis, drug resistance, and poor patient survival (16,(22)(23)(24). Thus, LGR5 may serve as an effective therapeutic target for the treatment of gastrointestinal cancers and CSC-based therapy.…”