Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status

Cancer Lett. 2017 Oct 1:405:22-28. doi: 10.1016/j.canlet.2017.07.013. Epub 2017 Jul 19.

Abstract

Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor. Somatic mutation profiles of cancer-related genes were also determined for the same 24 samples by next-generation sequencing. The CC number was estimated successfully for 23 of the 24 cancer samples. The mean ± SD value for the CC number was 1.7 ± 1.1 (range of 0-4). A somatic mutation in at least one gene was identified in 22 of the 24 ovarian cancer samples, with the mutations including those in the oncogenes KRAS (29.2%), PIK3CA (12.5%), BRAF (8.3%), FGFR2 (4.2%), and JAK2 (4.2%) as well as those in the tumor suppressor genes TP53 (54.2%), FBXW7 (8.3%), PTEN (4.2%), and RB1 (4.2%). Tumors with one or more oncogenic mutations had a significantly lower CC number than did those without such a mutation (1.0 ± 0.8 versus 2.3 ± 0.9, P = 0.0027), suggesting that cancers with driver oncogene mutations are less heterogeneous than those with other mutations. Our results thus reveal a reciprocal relation between oncogenic mutation status and clonal composition in ovarian cancer using the established method for the estimation of the CC number.

Keywords: Clonal composition; Heterogeneity; Oncogenic mutation; Ovarian cancer.

MeSH terms

  • Cell Proliferation
  • Clone Cells / pathology
  • DNA Mutational Analysis / methods*
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Dosage*
  • Genome
  • Humans
  • Mutation*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Proto-Oncogene Proteins / genetics*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins