Integrative analysis of genome-wide loss of heterozygosity and mono-allelic expression at nucleotide resolution reveals disrupted pathways in triple negative breast cancer
- Gavin Ha1,
- Andrew Roth1,
- Daniel Lai1,
- Ali Bashashati1,
- Jiarui Ding1,
- Rodrigo Goya2,
- Ryan Giuliany1,
- Jamie Rosner1,
- Arusha Oloumi1,
- Karey Shumansky1,
- Suet-Feung Chin3,
- Gulisa Turashvili1,
- Martin Hirst2,
- Carlos Caldas3,
- Marco A Marra2,
- Samuel Aparicio1 and
- Sohrab P Shah1,4
- ↵* Corresponding author; email: sshah{at}bccrc.ca
Abstract
Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumours. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumour suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumour 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 mono-allelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumour/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 tumours using RNA-seq derived measurements of allele-specific expression. We show that the majority of mono-allelic expression in the transcriptomes of triple negative breast cancer can be explained by genomic regions of LOH, and establish a upper bound for mono-allelic expression that may be explained by other tumour-specific modifications such as epigenetics or mutations. Mono-allelically expressed genes associated with LOH reveals 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 tumours. Together, this contribution provides robust methodology and data to support the inclusion of LOH in the comprehensive characterization and interpretation of cancer genomes from sequencing data.
- Received January 11, 2012.
- Accepted May 22, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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