Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer

Sara J. Felts, Virginia P. Van Keulen, Michael J. Hansen, Michael P. Bell, Kathleen Allen, Alem A. Belachew, Richard Geoffrey Vile, Julie M Cunningham, Tanya L. Hoskin, V. Shane Pankratz, Larry R Pease

Research output: Contribution to journalArticle

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Abstract

Breast tumors in (FVB × BALB-NeuT) F1 mice have characteristic loss of chromosome 4 and sporadic loss or gain of other chromosomes. We employed the Illumina GoldenGate genotyping platform to quantitate loss of heterozygosity (LOH) across the genome of primary tumors, revealing strong biases favoring chromosome 4 alleles from the FVB parent. While allelic bias was not observed on other chromosomes, many tumors showed concerted LOH (C-LOH) of all alleles of one or the other parent on sporadic chromosomes, a pattern consistent with cytogenetic observations. Surprisingly, comparison of LOH in tumor samples relative to normal unaffected tissues from these animals revealed significant variegated (stochastic) deviations from heterozygosity (V-LOH) in every tumor genome. Sequence analysis showed expected changes in the allelic frequency of single nucleotide polymorphisms (SNPs) in cases of C-LOH. However, no evidence of LOH due to mutations, small deletions, or gene conversion at the affected SNPs or surrounding DNA was found at loci with V-LOH. Postulating an epigenetic mechanism contributing to V-LOH, we tested whether methylation of template DNA impacts allele detection efficiency using synthetic oligonucleotide templates in an assay mimicking the GoldenGate genotyping format. Methylated templates were systematically over-scored, suggesting that the observed patterns of V-LOH may represent extensive epigenetic DNA modifications across the tumor genomes. As most of the SNPs queried do not contain standard (CpG) methylation targets, we propose that widespread, non-canonical DNA modifications occur during Her2/neuT-driven tumorigenesis.

Original languageEnglish (US)
Pages (from-to)348-357
Number of pages10
JournalNeoplasia
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2015

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Loss of Heterozygosity
Epigenomics
Breast Neoplasms
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 4
Chromosomes
Alleles
Genome
Neoplasms
DNA
Gene Conversion
Sequence Deletion
DNA Methylation
Oligonucleotides
Cytogenetics
Methylation
Sequence Analysis
Carcinogenesis

ASJC Scopus subject areas

  • Cancer Research

Cite this

Felts, S. J., Van Keulen, V. P., Hansen, M. J., Bell, M. P., Allen, K., Belachew, A. A., ... Pease, L. R. (2015). Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer. Neoplasia, 17(4), 348-357. https://doi.org/10.1016/j.neo.2015.02.006

Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer. / Felts, Sara J.; Van Keulen, Virginia P.; Hansen, Michael J.; Bell, Michael P.; Allen, Kathleen; Belachew, Alem A.; Vile, Richard Geoffrey; Cunningham, Julie M; Hoskin, Tanya L.; Pankratz, V. Shane; Pease, Larry R.

In: Neoplasia, Vol. 17, No. 4, 01.04.2015, p. 348-357.

Research output: Contribution to journalArticle

Felts, SJ, Van Keulen, VP, Hansen, MJ, Bell, MP, Allen, K, Belachew, AA, Vile, RG, Cunningham, JM, Hoskin, TL, Pankratz, VS & Pease, LR 2015, 'Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer', Neoplasia, vol. 17, no. 4, pp. 348-357. https://doi.org/10.1016/j.neo.2015.02.006
Felts SJ, Van Keulen VP, Hansen MJ, Bell MP, Allen K, Belachew AA et al. Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer. Neoplasia. 2015 Apr 1;17(4):348-357. https://doi.org/10.1016/j.neo.2015.02.006
Felts, Sara J. ; Van Keulen, Virginia P. ; Hansen, Michael J. ; Bell, Michael P. ; Allen, Kathleen ; Belachew, Alem A. ; Vile, Richard Geoffrey ; Cunningham, Julie M ; Hoskin, Tanya L. ; Pankratz, V. Shane ; Pease, Larry R. / Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer. In: Neoplasia. 2015 ; Vol. 17, No. 4. pp. 348-357.
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