Haploinsufficiency and mutation are two sides of the cancer coin as cause and therapeutics target

Unprecedented intensity in the investigation of cancer genomes over the past 20 years has firmly established genome instability as a central hallmark of cancer. Publications from international consortia, particularly The Cancer Genome Atlas (TCGA), have painstakingly cataloged the genomic alterations that are frequently observed in all major cancer types (1-5). There are two primary categories of genome alterations: mutations at the nucleotide level and alterations at the level of chromosomal copy number (deletion and amplification). In some cancer types, such as colorectal cancer (CRC), genomic instability can be broadly classified as having chromosome instability (CIN) or microsatellite instability (MSI) (6,7). Whereas a majority of research investigation and drug development has been targeted on missense mutations (8,9), CIN has clearly been shown to play a key role in cancer development and progression and is associated with poor prognosis and drug resistance (10,11). Therefore, copy number alterations represent a wellspring for both research and therapeutics that have been underexplored. In this regard, nucleotide mutations and copy number alterations are really two sides of the same genomics instability coin for tumorigenesis. With the recent realization of the “randomness” in gene mutations due to replication errors in cancer (12), perhaps copy number alterations provide less randomness in therapeutic design.