Molecular subtypes in stage II-III colon cancer defined by genomic instability: early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A

PLoS One. 2015 Apr 16;10(4):e0122391. doi: 10.1371/journal.pone.0122391. eCollection 2015.

Abstract

Objective: We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer.

Methods: We sought to investigate various molecular subtypes defined by instability at microsatellites (MSI), changes in methylation patterns (CpG island methylator phenotype, CIMP) or copy number variation (CNV) in 8 genes. Stage II-III colon cancers (n = 64) were investigated by methylation-specific multiplex ligated probe amplification (MS-MLPA). Correlation of CNV, CIMP and MSI, with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni- and multivariate regression.

Results: The CIMP phenotype occurred in 34% (22/64) and MSI in 27% (16/60) of the tumors, with noted CIMP/MSI overlap. Among the molecular subtypes, a high CNV phenotype had an associated odds ratio (OR) for recurrence of 3.2 (95% CI 1.1-9.3; P = 0.026). Losses of CACNA1G (OR of 2.9, 95% CI 1.4-6.0; P = 0.001), IGF2 (OR of 4.3, 95% CI 1.1-15.8; P = 0.007), CDKN2A (p16) (OR of 2.0, 95% CI 1.1-3.6; P = 0.024), and RUNX3 (OR of 3.4, 95% CI 1.3-8.7; P = 0.002) were associated with early recurrence, while MSI, CIMP, KRAS or BRAF V600E mutations were not. The CNV was significantly higher in deceased patients (CNV in 6 of 8) compared to survivors (CNV in 3 of 8). Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk-model for early recurrence.

Conclusions: A high copy number variation phenotype is a strong predictor of early recurrence and death, and may indicate a dose-dependent relationship between genetic instability and outcome. Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Colonic Neoplasms / genetics*
  • Core Binding Factor Alpha 3 Subunit / genetics*
  • DNA Copy Number Variations*
  • Female
  • Genes, p16*
  • Genomic Instability*
  • Humans
  • Male
  • Middle Aged
  • Recurrence
  • Survival Analysis

Substances

  • Core Binding Factor Alpha 3 Subunit
  • Runx3 protein, human

Grants and funding

This study was funded in part by grants from the Folke Hermansens Cancer Foundation (grant #424508 to KS for MB as a post-doctoral fellow, http://www.folke-fondet.org/Folke_Hermansen.html) and the Mjaaland Cancer Research Fund (grant #424506 to KS).