Algorithms for deciphering cancer genomes: from differential mutation to differential allele specific expression

Abstract

Large-scale cancer genome sequencing consortia have provided a huge influx of somatic mutation data across large cohorts of patients. Understanding how these observed genetic alterations give rise to specific cancer phenotypes represents a major aim of cancer genomics. In this dissertation, I present two methods for utilizing natural variation as a background for interpreting cancer genomes.

In Chapter 2, I introduce differential mutation analysis, a framework for uncovering cancer genes that compares the mutational profiles of genes across cancer genomes with natural germline variation across healthy individuals. I hypothesize that if a gene is less constrained with respect to variation across the healthy population, it may also be able to tolerate a greater amount of somatic mutation without experiencing a drastic detrimental functional change. I develop a fast and simple approach that uncovers genes that are differentially mutated between cancer genomes and the genomes of healthy individuals. I demonstrate that my differential mutation approach outperforms considerably more sophisticated approaches for discovering cancer genes.

In Chapter 3, I propose the concept of differential allele-specific expression to identify genes within an individual’s cancer whose allele-specific expression (ASE) differs from what is found in matched normal tissue, with the overall goal of uncovering genes whose regulation is altered via functional noncoding somatic mutations. I reason that since specific noncoding mutations usually occur on only one chromosome, they are expected to affect only the expression of the allele derived from that chromosome. Thus, ASE is a potential avenue towards detecting cis mutations that lead to regulatory changes. I present three methods to identify differential ASE in paired tumor-normal samples, and apply them to breast cancer tumor samples. I demon- strate that differential ASE can detect dysregulation caused by nonsense mediated decay and copy number variation, that known cancer-related genes are enriched for differential ASE, and that genes with cis noncoding mutations are enriched for diffferential ASE. Finally, I show that noncoding mutations in cis with genes exhibiting differential ASE often disrupt known regulatory mechanisms. I thus conclude that differential ASE is a powerful means for characterizing gene dysregulation due to cis noncoding mutations.