Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells
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% ofmore »
- Authors:
-
- Univ. of Arizona, Tucson, AZ (United States)
- Univ. of Arizona Cancer Center, Tucson, AZ (United States)
- Univ. of Arizona Cancer Center, Tucson, AZ (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Univ. of Arizona, Tucson, AZ (United States); Univ. of Arizona Cancer Center, Tucson, AZ (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1257834
- Alternate Identifier(s):
- OSTI ID: 1556359
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Mutation Research/Genetic Toxicology and Environmental Mutagenesis
- Additional Journal Information:
- Journal Volume: 775-776; Journal Issue: C; Journal ID: ISSN 1383-5718
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Benzo[a]pyrene; Carcinogenesis; HMEC; p16; human mammary epithelial cells
Citation Formats
Severson, Paul L., Vrba, Lukas, Stampfer, Martha R., and Futscher, Bernard W. Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. United States: N. p., 2014.
Web. doi:10.1016/j.mrgentox.2014.10.011.
Severson, Paul L., Vrba, Lukas, Stampfer, Martha R., & Futscher, Bernard W. Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. United States. https://doi.org/10.1016/j.mrgentox.2014.10.011
Severson, Paul L., Vrba, Lukas, Stampfer, Martha R., and Futscher, Bernard W. Tue .
"Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells". United States. https://doi.org/10.1016/j.mrgentox.2014.10.011. https://www.osti.gov/servlets/purl/1257834.
@article{osti_1257834,
title = {Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells},
author = {Severson, Paul L. and Vrba, Lukas and Stampfer, Martha R. and Futscher, Bernard W.},
abstractNote = {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. In conclusion, 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.},
doi = {10.1016/j.mrgentox.2014.10.011},
journal = {Mutation Research/Genetic Toxicology and Environmental Mutagenesis},
number = C,
volume = 775-776,
place = {United States},
year = {Tue Nov 04 00:00:00 EST 2014},
month = {Tue Nov 04 00:00:00 EST 2014}
}
Web of Science
Works referenced in this record:
The Consensus Coding Sequences of Human Breast and Colorectal Cancers
journal, October 2006
- Sjoblom, T.; Jones, S.; Wood, L. D.
- Science, Vol. 314, Issue 5797
The Mutational Landscape of Head and Neck Squamous Cell Carcinoma
journal, July 2011
- Stransky, N.; Egloff, A. M.; Tward, A. D.
- Science, Vol. 333, Issue 6046
Cancer Genome Landscapes
journal, March 2013
- Vogelstein, B.; Papadopoulos, N.; Velculescu, V. E.
- Science, Vol. 339, Issue 6127
Signatures of mutational processes in human cancer
journal, August 2013
- Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.
- Nature, Vol. 500, Issue 7463
Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53
journal, October 1996
- Denissenko, M. F.; Pao, A.; Tang, M. -s.
- Science, Vol. 274, Issue 5286
Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers
journal, October 2002
- Pfeifer, Gerd P.; Denissenko, Mikhail F.; Olivier, Magali
- Oncogene, Vol. 21, Issue 48
Metabolism of benzo[a]pyrene by human mammary epithelial cells: toxicity and DNA adduct formation.
journal, October 1981
- Stampfer, M. R.; Bartholomew, J. C.; Smith, H. S.
- Proceedings of the National Academy of Sciences, Vol. 78, Issue 10
Metabolism of Benzo(a)pyrene by Human Epithelial and Fibroblastic Cells: Metabolite Patterns and DNA Adduct Formation
journal, January 1982
- Bartley, Jack; Bartholomew, James C.; Stampfer, Martha R.
- Journal of Cellular Biochemistry, Vol. 18, Issue 2
Factors influencing benzo[a]pyrene metabolism in human mammary epithelial cells in culture
journal, January 1985
- Bartley, Jack C.; Stampfer, Martha R.
- Carcinogenesis, Vol. 6, Issue 7
A small-cell lung cancer genome with complex signatures of tobacco exposure
journal, December 2009
- Pleasance, Erin D.; Stephens, Philip J.; O’Meara, Sarah
- Nature, Vol. 463, Issue 7278
Inactivation of p53 Function in Cultured Human Mammary Epithelial Cells Turns the Telomere-Length Dependent Senescence Barrier from Agonescence into Crisis
journal, August 2007
- Garbe, James C.; Holst, Charles R.; Bassett, Ekaterina
- Cell Cycle, Vol. 6, Issue 15
Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo[a]pyrene.
journal, April 1985
- Stampfer, M. R.; Bartley, J. C.
- Proceedings of the National Academy of Sciences, Vol. 82, Issue 8
Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation
journal, July 1998
- Brenner, Andrew J.; Stampfer, Martha R.; Aldaz, C. Marcelo
- Oncogene, Vol. 17, Issue 2
Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes
journal, February 2001
- Romanov, Serguei R.; Kozakiewicz, B. Krystyna; Holst, Charles R.
- Nature, Vol. 409, Issue 6820
In situ analyses of genome instability in breast cancer
journal, August 2004
- Chin, Koei; de Solorzano, Carlos Ortiz; Knowles, David
- Nature Genetics, Vol. 36, Issue 9
Molecular Distinctions between Stasis and Telomere Attrition Senescence Barriers Shown by Long-term Culture of Normal Human Mammary Epithelial Cells
journal, September 2009
- Garbe, J. C.; Bhattacharya, S.; Merchant, B.
- Cancer Research, Vol. 69, Issue 19
Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion
journal, September 2002
- Olsen, Catherine L.; Gardie, Betty; Yaswen, Paul
- Oncogene, Vol. 21, Issue 41
TGF- signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells
journal, May 2011
- Cipriano, R.; Kan, C. E.; Graham, J.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 21
Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells: Oncogenes induce atypical senescence phenotype
journal, September 2011
- Sherman, Michael Y.; Meng, Le; Stampfer, Martha
- Aging Cell, Vol. 10, Issue 6
IntOGen-mutations identifies cancer drivers across tumor types
journal, September 2013
- Gonzalez-Perez, Abel; Perez-Llamas, Christian; Deu-Pons, Jordi
- Nature Methods, Vol. 10, Issue 11
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
journal, December 2008
- Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A.
- Nature Protocols, Vol. 4, Issue 1
Accumulation of Multipotent Progenitors with a Basal Differentiation Bias during Aging of Human Mammary Epithelia
journal, May 2012
- Garbe, J. C.; Pepin, F.; Pelissier, F. A.
- Cancer Research, Vol. 72, Issue 14
A framework for variation discovery and genotyping using next-generation DNA sequencing data
journal, April 2011
- DePristo, Mark A.; Banks, Eric; Poplin, Ryan
- Nature Genetics, Vol. 43, Issue 5
Somatic mutations affect key pathways in lung adenocarcinoma
journal, October 2008
- Ding, Li; Getz, Gad; Wheeler, David A.
- Nature, Vol. 455, Issue 7216
The mutation spectrum revealed by paired genome sequences from a lung cancer patient
journal, May 2010
- Lee, William; Jiang, Zhaoshi; Liu, Jinfeng
- Nature, Vol. 465, Issue 7297
Transcription past DNA adducts derived from polycyclic aromatic hydrocarbons
journal, September 2005
- Scicchitano, David A.
- Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 577, Issue 1-2
Chromosome analyses of human mammary epithelial cells at stages of chemical-induced transformation progression to immortality
journal, February 1989
- Walen, Kirsten H.; Stampfer, Martha R.
- Cancer Genetics and Cytogenetics, Vol. 37, Issue 2
Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines
journal, August 2003
- Stampfer, Martha R.; Garbe, James; Nijjar, Tarlochan
- Oncogene, Vol. 22, Issue 34
Quantification of benzo[a]pyrene and other PAHs in the serum and follicular fluid of smokers versus non-smokers
journal, January 2008
- Neal, Michael S.; Zhu, Jiping; Foster, Warren G.
- Reproductive Toxicology, Vol. 25, Issue 1
Changing Incidence of Breast Cancer in Japanese-American Women2
journal, November 1973
- Buell, Philip
- JNCI: Journal of the National Cancer Institute, Vol. 51, Issue 5
Migration Patterns and Breast Cancer Risk in Asian-American Women
journal, November 1993
- Ziegler, R. G.; Hoover, R. N.; Pike, M. C.
- JNCI Journal of the National Cancer Institute, Vol. 85, Issue 22
Rapidly rising breast cancer incidence rates among Asian-American women
journal, May 2002
- Deapen, Dennis; Liu, Lihua; Perkins, Carin
- International Journal of Cancer, Vol. 99, Issue 5
Rating the Risk Factors for Breast Cancer
journal, January 2003
- Singletary, S. Eva
- Annals of Surgery, Vol. 237, Issue 4
Modelling mutational landscapes of human cancers in vitro
journal, March 2014
- Olivier, Magali; Weninger, Annette; Ardin, Maude
- Scientific Reports, Vol. 4, Issue 1
Developmental and tissue-specific regulation of mouse telomerase and telomere length.
journal, May 1995
- Prowse, K. R.; Greider, C. W.
- Proceedings of the National Academy of Sciences, Vol. 92, Issue 11
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
journal, September 2006
- Gil, Jesús; Peters, Gordon
- Nature Reviews Molecular Cell Biology, Vol. 7, Issue 9
Epigenetic regulation of normal human mammary cell type-specific miRNAs
journal, August 2011
- Vrba, L.; Garbe, J. C.; Stampfer, M. R.
- Genome Research, Vol. 21, Issue 12
Works referencing / citing this record:
TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
journal, July 2019
- Gudmundsson, Sanna; Wilbe, Maria; Filipek-Górniok, Beata
- Scientific Reports, Vol. 9, Issue 1
A comprehensive survey of the mutagenic impact of common cancer cytotoxics
journal, May 2016
- Szikriszt, Bernadett; Póti, Ádám; Pipek, Orsolya
- Genome Biology, Vol. 17, Issue 1
Experimental identification of cancer driver alterations in the era of pan‐cancer genomics
journal, October 2019
- Korenjak, Michael; Zavadil, Jiri
- Cancer Science, Vol. 110, Issue 12
MutSpec: a Galaxy toolbox for streamlined analyses of somatic mutation spectra in human and mouse cancer genomes
journal, April 2016
- Ardin, Maude; Cahais, Vincent; Castells, Xavier
- BMC Bioinformatics, Vol. 17, Issue 1
Exome Sequencing of Fresh-frozen or Formalin-fixed Paraffin-embedded B6C3F1/N Mouse Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Chemical Exposure
journal, July 2018
- Auerbach, Scott S.; Xu, Miaofei; Merrick, B. Alex
- Toxicologic Pathology, Vol. 46, Issue 6
Base changes in tumour DNA have the power to reveal the causes and evolution of cancer
journal, June 2016
- Hollstein, M.; Alexandrov, L. B.; Wild, C. P.
- Oncogene, Vol. 36, Issue 2
Modeling cancer driver events in vitro using barrier bypass-clonal expansion assays and massively parallel sequencing
journal, July 2017
- Huskova, H.; Ardin, M.; Weninger, A.
- Oncogene, Vol. 36, Issue 43
MutSpec: a Galaxy toolbox for streamlined analyses of somatic mutation spectra in human and mouse cancer genomes
journal, April 2016
- Ardin, Maude; Cahais, Vincent; Castells, Xavier
- BMC Bioinformatics, Vol. 17, Issue 1
A comprehensive survey of the mutagenic impact of common cancer cytotoxics
journal, May 2016
- Szikriszt, Bernadett; Póti, Ádám; Pipek, Orsolya
- Genome Biology, Vol. 17, Issue 1
Genome-wide DNA methylome and whole-transcriptome landscapes of spontaneous intraductal papilloma in tree shrews
journal, April 2021
- Liu, Chengxiu; Han, Yuanyuan; Tong, Pinfen
- Annals of Translational Medicine, Vol. 9, Issue 8