Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism

Nat Genet. 2015 Feb;47(2):158-63. doi: 10.1038/ng.3178. Epub 2015 Jan 12.

Abstract

Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis. By conducting whole-genome sequencing and high-throughput viral integration detection, we identified 3,667 HPV integration breakpoints in 26 cervical intraepithelial neoplasias, 104 cervical carcinomas and five cell lines. Beyond recalculating frequencies for the previously reported frequent integration sites POU5F1B (9.7%), FHIT (8.7%), KLF12 (7.8%), KLF5 (6.8%), LRP1B (5.8%) and LEPREL1 (4.9%), we discovered new hot spots HMGA2 (7.8%), DLG2 (4.9%) and SEMA3D (4.9%). Protein expression from FHIT and LRP1B was downregulated when HPV integrated in their introns. Protein expression from MYC and HMGA2 was elevated when HPV integrated into flanking regions. Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways. Our data provide insights into HPV integration-driven cervical carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alphapapillomavirus / genetics
  • Alphapapillomavirus / isolation & purification
  • Alphapapillomavirus / physiology*
  • Base Sequence
  • Cell Line, Tumor
  • Cervical Intraepithelial Neoplasia / genetics*
  • Cervical Intraepithelial Neoplasia / virology
  • DNA, Viral / genetics
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human / genetics
  • Genome, Viral / genetics
  • Genome-Wide Association Study
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / virology
  • Sequence Analysis, DNA
  • Up-Regulation
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / virology
  • Virus Integration*

Substances

  • DNA, Viral

Associated data

  • SRA/SRA180295
  • SRA/SRA189003
  • SRA/SRA189004