Aberrant Alternative Splicing Is Another Hallmark of Cancer

The vast majority of human genes are alternatively spliced. Not surprisingly, aberrant alternative splicing is increasingly linked to cancer. Splice isoforms often encode proteins that have distinct and even antagonistic properties. The abnormal expression of splice factors and splice factor kinases in cancer changes the alternative splicing of critically important pre-mRNAs. Aberrant alternative splicing should be added to the growing list of cancer hallmarks. 1. The Growing List of Cancer Hallmarks In the year 2000, Doug Hanahan and Bob Weinberg published a paper in which they suggested that all cancers share six common features, or hallmarks [1]. They were self-sufficiency in relation to growth signals; insensitivity to growth inhibitory signals; limitless replicative potential; the ability to evade apoptosis; the ability to sustain angiogenesis; and lastly, the ability to invade tissues and metastasize. These hallmarks provided a useful framework with which to conceptualise cancer. The paper has been cited several thousands of times as a result. Despite the benefit of the six hallmarks concept, it became clear that other processes in cancer are also consistently altered. This led Hanahan and Weinberg to publish a follow-up review in 2011 in which they extended the cancer hallmarks to a list of ten. The four new hallmarks were the ability to evade the immune system, the presence of inflammation, the tendency towards genomic instability, and dysregulated metabolism [2]. The latter hallmark resonates with an observation made in the early 20th century by Otto Warburg, namely, that cancer cells are characterised by abnormal respiration and unusually high anaerobic metabolism [3]. This was called the “Warburg effect” and is generally thought to be linked to the fact that tumour cells need to adapt to hypoxic environments [4–6]. It is undoubtedly useful to think of common processes that apply to all cancers. The ten hallmarks suggest theoretical frameworks for research and therapy. However, several additional hallmarks could be added to the list, and there is also a significant amount of intersection between the ten hallmarks. Specific cancer-associated genes can also be involved in more than one hallmark. There is therefore a tension between the need to think systematically about cancer and the reality that cancer is a remarkably complex and heterogenous disease. 2. Dysregulated Alternative Splicing Is Another Key Feature of Cancer In cancer, genetic lesions arise in several forms including chromosomal rearrangements, point mutations, and gene