Association Study of the let-7 miRNA-complementary Site Variant in the 3' Untranslated Region of the KRAS Gene in Stage III Colon Cancer (NCCTG N0147 Clinical Trial)

Clin Cancer Res. 2014 Jun 15;20(12):3319-27. doi: 10.1158/1078-0432.CCR-14-0069. Epub 2014 Apr 11.

Abstract

Purpose: A let-7 microRNA-complementary site (LCS6) polymorphism in the 3' untranslated region of the KRAS gene has been shown to disrupt let-7 binding and upregulate KRAS expression. We evaluated the LCS6 genotype and its association with KRAS mutation status, clinicopathologic features, and disease-free survival (DFS) in patients with stage III colon cancer who enrolled in a phase III clinical trial (NCCTG N0147).

Experimental design: The LCS6 genotype was assayed by real-time PCR in DNA extracted from whole blood (n = 2,834) and compared with paired tumor tissue (n = 977). χ(2) and two-sample t tests were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed associations between LCS6 status and DFS, respectively.

Results: We identified 432 (15.2%) blood samples and 143 (14.6%) tumor samples heterozygous or homozygous for the LCS6 G-allele, and 2,402 of 2,834 (84.8%) blood samples and 834 of 977 (85.4%) tumor samples homozygous for the LCS6 T-allele. Genotype results were highly concordant (99.8%) in cases with paired blood and tumor tissue (n = 977). G-allele carriers were significantly more frequent in Caucasians versus other races (χ(2) test, P < 0.0001). The LCS6 genotype was not associated with KRAS mutation status, clinicopathologic features (all P > 0.2), or DFS (log-rank P = 0.49; HR, 0.929; 95% confidence interval, 0.76-1.14), even after combining LCS6 genotype with KRAS mutation status.

Conclusions: In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Binding Sites
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Grading
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Survival Rate
  • Young Adult
  • ras Proteins / genetics*

Substances

  • 3' Untranslated Regions
  • KRAS protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • mirnlet7 microRNA, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins