The ‘two hit’ model for malignancy has been the dominant paradigm for tumorigenesis for nearly 40 years, after first being formulated by Alfred Knudson. The hypothesis states that both copies of a tumor suppressor gene need to be inactivated for cancer to be initiated. If one copy of the gene is already mutated, cancer is inevitable if the healthy copy is lost. This loss could occur if the region of the genome containing the healthy copy of the gene is deleted from the genome, an event called loss of heterozygosity. Alternatively, transcription of the healthy copy could be turned off, leaving only expression of the mutant copy, an event called allele specific expression.
Zhao and colleagues have used exome and transcriptome sequencing to compare a breast cancer cell line and normal cell line from the same patient in order to identify loss of heterozygosity and allele specific expression events that may have contributed to tumorigenesis. 403 genes showed loss of heterozygosity in the breast cancer cells, many of which had functions associated with cancer and tumorigenesis. 86 genes showed allele specific expression in the tumour cells.
This proof of principle study demonstrates that combining exome sequencing with transcript analysis may better define drivers of the tumorigenesis process and the significance of allele specific expression in cancer.