Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer

  1. Sohrab P. Shah1,3,6,7
  1. 1Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
  2. 2Bioinformatics Training Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
  3. 3Department of Computer Science, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
  4. 4Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
  5. 5Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom;
  6. 6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

    Abstract

    Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors.

    Footnotes

    • 7 Corresponding author

      E-mail sshah{at}bccrc.ca

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.137570.112.

      Freely available online through the Genome Research Open Access option.

    • Received January 11, 2012.
    • Accepted May 22, 2012.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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