Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer

Nat Genet. 2016 Jul;48(7):758-67. doi: 10.1038/ng.3573. Epub 2016 May 16.

Abstract

We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Clone Cells / metabolism
  • Clone Cells / pathology*
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology*
  • Disease Progression
  • Fallopian Tube Neoplasms / genetics
  • Fallopian Tube Neoplasms / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation / genetics*
  • Genome, Human
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / pathology*
  • Phylogeny
  • Single-Cell Analysis / methods
  • Survival Rate
  • Tumor Microenvironment / genetics*

Substances

  • Biomarkers, Tumor