An integrative approach to assess X-chromosome inactivation using allele-specific expression with applications to epithelial ovarian cancer

Nicholas Larson, Zachary C. Fogarty, Melissa C. Larson, Kimberly R. Kalli, Kate Lawrenson, Simon Gayther, Brooke L. Fridley, Ellen L Goode, Stacey J Winham

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

X-chromosome inactivation (XCI) epigenetically silences transcription of an X chromosome in females; patterns of XCI are thought to be aberrant in women's cancers, but are understudied due to statistical challenges. We develop a two-stage statistical framework to assess skewed XCI and evaluate gene-level patterns of XCI for an individual sample by integration of RNA sequence, copy number alteration, and genotype data. Our method relies on allele-specific expression (ASE) to directly measure XCI and does not rely on male samples or paired normal tissue for comparison. We model ASE using a two-component mixture of beta distributions, allowing estimation for a given sample of the degree of skewness (based on a composite likelihood ratio test) and the posterior probability that a given gene escapes XCI (using a Bayesian beta-binomial mixture model). To illustrate the utility of our approach, we applied these methods to data from tumors of ovarian cancer patients. Among 99 patients, 45 tumors were informative for analysis and showed evidence of XCI skewed toward a particular parental chromosome. For 397 X-linked genes, we observed tumor XCI patterns largely consistent with previously identified consensus states based on multiple normal tissue types. However, 37 genes differed in XCI state between ovarian tumors and the consensus state; 17 genes aberrantly escaped XCI in ovarian tumors (including many oncogenes), whereas 20 genes were unexpectedly inactivated in ovarian tumors (including many tumor suppressor genes). These results provide evidence of the importance of XCI in ovarian cancer and demonstrate the utility of our two-stage analysis.

Original languageEnglish (US)
JournalGenetic Epidemiology
DOIs
StateAccepted/In press - 2017

Fingerprint

X Chromosome Inactivation
Alleles
Neoplasms
Genes
Ovarian Neoplasms
Ovarian epithelial cancer
X-Linked Genes
X Chromosome
Statistical Models
Tumor Suppressor Genes
Oncogenes
Chromosomes
Genotype

Keywords

  • Bayesian
  • Mixture model
  • Ovarian cancer
  • RNA-Seq

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

Cite this

An integrative approach to assess X-chromosome inactivation using allele-specific expression with applications to epithelial ovarian cancer. / Larson, Nicholas; Fogarty, Zachary C.; Larson, Melissa C.; Kalli, Kimberly R.; Lawrenson, Kate; Gayther, Simon; Fridley, Brooke L.; Goode, Ellen L; Winham, Stacey J.

In: Genetic Epidemiology, 2017.

Research output: Contribution to journalArticle

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