TY - JOUR
T1 - Stochastic changes in gene expression promote chaotic dysregulation of homeostasis in clonal breast tumors
AU - Felts, Sara J.
AU - Tang, Xiaojia
AU - Willett, Benjamin
AU - Van Keulen, Virginia P.
AU - Hansen, Michael J.
AU - Kalari, Krishna R.
AU - Pease, Larry R.
N1 - Funding Information:
The authors acknowledge the technical contributions and expertise provided by Darlene Knutson and Dr. Patricia T. Greipp of the Mayo Cytogenetics Core for karyotype analyses, Gene Expression Core (Bruce Eckloff and Dr. Jin Jen) for performing RNAseq. Support for this work came from the Breast SPORE DRP Award (NCI/NIH P50CA116201) and a Mayo Clinic Center for Biomedical Discovery Pilot Award to L.R. P., K.R.K., and X.T. are supported by the Mayo Clinic Center for Individualized Medicine and Breast Cancer SPORE award (NCI/NIH P50CA116201). Additional thanks go to A. Johnson, K. Ayasoufi, and E. Wieben for helpful comments on the manuscript.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Cells within tumors vary in phenotype as a result of changes in gene expression caused by a variety of mechanisms, permitting cancers to evolve under selective pressures from immune and other homeostatic processes. Earlier, we traced apparent losses in heterozygosity (LOH) of spontaneous breast tumors from first generation (F1) intercrossed mice to atypical epigenetic modifications in the structure of DNA across the tumor genomes. Here, we describe a parallel pattern of LOH in gene expression, revealed through quantitation of parental alleles across a population of clonal tumors. We found variegated patterns of LOH, based on allelic ratio outliers in hundreds of genes, enriched in regulatory pathways typically co-opted by tumors. The frequency of outliers was correlated with transcriptional repression of a large set of homozygous genes. These findings suggest stochastic losses in gene expression across the genome of tumors generate phenotypic variation among cells, allowing clonal selection during tumor development.
AB - Cells within tumors vary in phenotype as a result of changes in gene expression caused by a variety of mechanisms, permitting cancers to evolve under selective pressures from immune and other homeostatic processes. Earlier, we traced apparent losses in heterozygosity (LOH) of spontaneous breast tumors from first generation (F1) intercrossed mice to atypical epigenetic modifications in the structure of DNA across the tumor genomes. Here, we describe a parallel pattern of LOH in gene expression, revealed through quantitation of parental alleles across a population of clonal tumors. We found variegated patterns of LOH, based on allelic ratio outliers in hundreds of genes, enriched in regulatory pathways typically co-opted by tumors. The frequency of outliers was correlated with transcriptional repression of a large set of homozygous genes. These findings suggest stochastic losses in gene expression across the genome of tumors generate phenotypic variation among cells, allowing clonal selection during tumor development.
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U2 - 10.1038/s42003-019-0460-0
DO - 10.1038/s42003-019-0460-0
M3 - Article
C2 - 31925044
AN - SCOPUS:85071196051
SN - 2399-3642
VL - 2
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 206
ER -