Systematic detection of putative tumor suppressor genes through the combined use of exome and transcriptome sequencing

By comparing exome sequences from the two cell lines, we identified loss of heterozygosity events at 403 genes in HCC1954 and at one gene in HCC1954BL. The combination of exome and transcriptome sequence data also revealed 86 and 50 genes with allele specific expression events in HCC1954 and HCC1954BL, which comprise 5.4% and 2.6% of genes surveyed, respectively. Many of these genes identified by loss of heterozygosity and allele-specific expression are known or putative tumor suppressor genes, such as BRCA1, MSH3 and SETX, which participate in DNA repair pathways.Our results demonstrate that the combined application of high throughput sequencing to exome and allele-specific transcriptome analysis can reveal genes with known tumor suppressor characteristics, and a shortlist of novel candidates for the study of tumor suppressor activities.Cancer arises from the accumulation of genetic and epigenetic changes that disrupt the normal regulatory controls in cells. Recently, next generation sequencing technology has been employed to identify variations in protein-coding sequences and genome structure for several types of cancers [1-9]. These studies have revealed the effectiveness of high throughput sequence analysis to identify somatic genomic alterations, such as point mutations, and structural variations, including gain and loss of chromosome regions. An important finding is that integrated analysis of the various somatic alterations is key for identifying genes that may drive cancer development and progression through oncogenic or tumor suppressor functions. Here, we combine the detection of two types of molecular events, loss of heterozygosity (LOH) and allele-specific expression (ASE), to identify genes with known and potential tumor suppressor characteristics.The common feature of LOH and ASE is loss of expression from one allele, which has frequently been observed for tumor suppressor genes. In ASE, a dominant gene product is expressed from the selected allele. Fo