Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells

Paul L. Severson, Lukas Vrba, Martha R. Stampfer, Bernard W Futscher

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutations were C:G. >. A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. The results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.

Original languageEnglish (US)
Pages (from-to)48-54
Number of pages7
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume775-776
DOIs
StatePublished - Dec 1 2014

Fingerprint

Exome
Benzo(a)pyrene
Breast
Epithelial Cells
Mutation
Neoplasms
Environmental Carcinogens
Biological Phenomena
Neoplasm Genes
Point Mutation
DNA Repair
Chromatin
Exons
Cell Cycle

Keywords

  • Benzo[a]pyrene
  • Carcinogenesis
  • HMEC
  • P16

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Genetics

Cite this

Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. / Severson, Paul L.; Vrba, Lukas; Stampfer, Martha R.; Futscher, Bernard W.

In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 775-776, 01.12.2014, p. 48-54.

Research output: Contribution to journalArticle

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