Common cancer stem cell gene variants predict colon cancer recurrence

Armin Gerger, Wu Zhang, Dongyun Yang, Pierre Bohanes, Yan Ning, Thomas Winder, Melissa J LaBonte, Peter M Wilson, Leonor Benhaim, David Paez, Rita El-Khoueiry, Anthony El-Khoueiry, Michael Kahn, Heinz-Josef Lenz, Melissa LaBonte Wilson

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)

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 = 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.

Original languageEnglish
Pages (from-to)6934-43
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number21
DOIs
Publication statusPublished - 01 Nov 2011

Bibliographical note

©2011 AACR

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Antineoplastic Combined Chemotherapy Protocols
  • Colonic Neoplasms
  • Female
  • Fluorouracil
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Neoplastic Stem Cells
  • Polymorphism, Genetic
  • Young Adult

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