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Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence

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Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence Published OnlineFirst September 14, 2011; DOI: 10.1158/1078-0432.CCR-11-1180 Clinical Cancer Predictive Biomarkers and Personalized Medicine Research Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence Armin Gerger1, Wu Zhang1, Dongyun Yang2, Pierre Bohanes1, Yan Ning1, Thomas Winder1, Melissa J. LaBonte1, Peter M. Wilson1, Leonor Benhaim1, David Paez1, Rita El-Khoueiry1, Anthony El-Khoueiry1, Michael Kahn3, and Heinz-Josef Lenz1,3 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 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 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. Introduction 67.4%; ref. 1). However, a considerable number of patients will relapse despite adjuvant treatment (2). Adjuvant treatment is recommended for patients with Tumor recurrence after curative surgery remains a major stage III and high-risk stage II colon cancer. The risk of obstacle for improving overall cancer survival, which may tumor recurrence can be significantly reduced by treating be in part due to the existence of cancer stem cells (CSC). these patients with 5-fluorouracil (5-FU)–based chemo- Growing evidence suggests that human cancers are stem cell therapy. The addition of oxaliplatin to 5-FU–based chemo- diseases and only a small subpopulation of cancer cells, therapy is now a standard adjuvant treatment for colon endowed with stem cell-like features, might be responsible cancer, with a higher 5-year disease-free survival (DFS) rate, for tumor initiation, progression and chemoresistance (3). compared with 5-FU–based treatment alone (73.3% vs. Cancer cells with the properties of stem cells possess the ability to self-renew, to undergo multilineage differentia- tion, and to survive an adverse tissue microenvironment. Putative CSC populations have been identified in colon Authors' Affiliations: 1Division of Medical Oncology; 2Department of Preventive Medicine; Norris Comprehensive Cancer Center, 3USC Center cancer on the basis of the expression of specific markers and for Molecular Pathways and Drug Discovery, Keck School of Medicine, their functional properties; however, phenotypic character- University of Southern California, Los Angeles, California ization of colon CSCs is still a matter of debate and ongoing Corresponding Author: Heinz-Josef Lenz, Sharon A. Carpenter Labora- research studies (4). Ideally, definitive markers should be tory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA gene products that are coupled to the function of the stem 90033. Phone: 1-323-865-3967; Fax: 1-323-865-0061; E-mail: cell. CSC markers in colon cancer include CD133, CD44, [email protected] and CD166 (5). More recently, EpCAM, CD26, Msi-1, doi: 10.1158/1078-0432.CCR-11-1180 CD29, CD24, LGR5, and ALDH1A1 have been added to Ó2011 American Association for Cancer Research. the list of putative stem cell markers for colon cancer (6, 7). 6934 Clin Cancer Res; 17(21) November 1, 2011 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst September 14, 2011; DOI: 10.1158/1078-0432.CCR-11-1180 Cancer Stem Cell Gene Variants and Colon Cancer Recurrence vated leukocyte cell adhesion molecule (ALCAM/CD166), Translational Relevance musashi homolog-1 (MSI-1), integrin beta-1 (ITGB1/ CD29), CD24, leucine-rich repeat containing G protein- Germline variants in cancer stem cell (CSC) genes coupled receptor-5 (LGR5), and aldehyde dehydrogenase-1 have recently been linked to cancer outcome and che- family member A1 (ALDH1A1). To the best of our knowl- moresistance. Here, we investigated germline poly- edge, this is the first study investigating common germline morphisms in a comprehensive panel of genes that have genetic variants in a comprehensive panel of colon CSC been previously associated with colon CSC to predict genes to predict tumor recurrence. This study was conducted time to tumor recurrence (TTR) in patients with stage III adhering to the reporting recommendations for tumor and high-risk stage II colon cancer treated with 5-fluo- marker prognostic studies (11–13). rouracil–based adjuvant chemotherapy. We hypothe- sized that these gene variants may alter the gene’s func- Patients and Methods tion and/or activity, thereby causing interindividual differences in a patient’s tumor recurrence capacity and Eligible patients chemoresistance. Our findings suggest that TTR varies A total of 234 patients with stage III and high-risk stage II according to CD44, ALCAM, LGR5, and ALDH1A1 gen- colon cancer were included in this study. High-risk stage II otypes, thus representing valuable biomarkers to sepa- colon cancer patients were defined if they presented with at rate high-risk from low-risk colon cancer patients. least one of the following features: lymph node sampling less than 12; poorly differentiated tumor; vascular, lym- phatic or perineural invasion; tumor presentation with obstruction or perforation and pT4. All patients were treated These colon CSC markers are representative of a range of with 5-FU–based adjuvant chemotherapy at the Norris pathways including the Wnt-target genes, cell adhesion Comprehensive Cancer Center/University of Southern Cali- molecules, RNA-binding proteins, and detoxifying fornia (NCCC/USC) or the Los Angeles County/USC-Med- enzymes, and play distinct roles in a variety of processes ical Center (LAC/USCMC) from 1987 to 2007. All patients including cell differentiation, proliferation, migration, apo- were included in the colon cancer surveillance program of ptosis, adhesion, lymphocyte homing, angiogenesis, and NCCC/USC or LAC/USCMC, providing history and phys- cellular response to chemotherapy (8). Current therapies ical examination and CEA determination every 3 months target populations of rapidly growing and differentiated for 3 years and every 6 months at years 4 and 5 after surgery, tumor cells, but have been shown to lack activity against colonoscopy at year 1 and thereafter every 3 to 5 years and CSCs (4). CSCs therefore may have an important role in CT scans of chest and abdomen every 6 months for the first 3 tumor recurrence despite adjuvant chemotherapy. Thus far, years. Patient data were collected retrospectively through preclinical studies in colon cancer have identified that CSCs chart review. Whole blood was collected at the time of are capable of initiating tumor development, however, little diagnosis and stored at À80C. Blood samples from 216 is known about the role of CSCs in colon cancer tumor patients were available for current genetic analyses. The recurrence. study was approved by the Institutional Review Boards at There is substantial germline genetic variability within USC and all study participants signed informed consent for the genes used as markers to identify CSCs, including the analysis of molecular correlates. multiple single nucleotide polymorphisms (SNP). These common DNA-sequence variations may alter the gene Candidate polymorphisms function and/or activity including transcription, translation Common and putatively functional polymorphisms or splicing, thereby causing interindividual differences in within genes that have been previously associated with relation to tumor recurrence capacity and chemoresistance colon CSC were selected using public literature resources (9). We recently tested the impact of common gene variants and databases including: NCBI-PubMed, dbSNP, Ensembl, in the cell surface glycoprotein, CD44, a gastric and colon GeneCards, and the Pharmacogenomics-Knowledge-Base. CSC marker, on clinical outcome of patients with localized Stringent and predefined selection criteria used were: (a) gastric adenocarcinoma and found that the minor allele of minor allele frequency 10% or more in Caucasians; (b) CD44 rs187116 was significantly associated with decreased polymorphism that could alter the function of the gene in a time to tumor recurrence (TTR) and overall survival (OS), biologically relevant manner [either published data or pre- identifying a "high-risk" patient population based on a dicted function using Functional-Single-Nucleotide-Poly- germline genetic variant (10). morphism (F-SNP) database, http://compbio.cs.queensu. In this study, we investigated 25 germline polymorph- ca/F-SNP (14, 15)]; and (c) published clinical associations isms in a comprehensive panel of genes that have been (e.g., cancer risk/outcome or chemoresistance; Table 1). previously associated with colon CSC to predict tumor recurrence in patients with stage III and high-risk stage II Genotyping colon cancer.
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