title: Common cancer stem cell gene variants predict colon cancer recurrence.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohanes
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.forename: Thomas
authors.initials: T
authors.lastname: Winder
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: LaBonte
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wilson
authors.forename: Leonor
authors.initials: L
authors.lastname: Benhaim
authors.forename: David
authors.initials: D
authors.lastname: Paez
authors.forename: Rita
authors.initials: R
authors.lastname: El-Khoueiry
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology*; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D005472:Fluorouracil