Abstract
Accumulation of DNA mutations alters amino acid sequence in the key domains of oncoproteins, leading to cellular malignant transformation. Due to redundancy of the genetic code, the same amino acid alteration can be achieved by multiple distinct genetic mutations, which are considered functionally identical and not actively distinguished in the current cancer genome research. For the first time, we analyzed the distribution of codon level transitions acquired by somatic mutations in human cancers. By analyzing the ~2.5 million nonsynonymous somatic single nucleotide variations (SNVs) found in the COSMIC database, we found 41 recurrent amino acid alterations whose DNA changes are significantly biased toward a specific codon transition. Additional analyses partially identified functional discrepancies between the favored and avoided codon transitions in terms of mutational process, codon usage, alternative splicing, and mRNA stability.
Highlights
Cancer is a genetic disease caused by a single or a few catastrophic somatic mutations that are responsible for cellular transformation, with accompanying many passenger mutations[1]
Numerical representation of this deviation, such as relative synonymous codon usage (RSCU)[11] enables researchers to infer whether there has been a codon level selection. Even without identifying the exact molecular process, it is known that the synonym codon usage bias (CUB) is common in many species[12]
Just as the model organisms and systems for CUB analysis, the tumor environment can be seen as a microcosm of an ecosystem under rapid natural selection[13,14] because it satisfies the essential prerequisites of evolution: First, genetic variation occurs with an increased frequency due to the uncontrolled proliferation and the compromised DNA integrity
Summary
Cancer is a genetic disease caused by a single or a few catastrophic somatic mutations that are responsible for cellular transformation, with accompanying many passenger mutations[1]. The mutant protein, in turn, may initiate the cascades of downstream signaling (e.g., cell proliferation and inhibition of apoptosis) and eventually transforms the cellular phenotype from normal to malignant In this context, the semantic basis of the entire event is the change of amino acids, not nucleotides, because different nonsynonymous SNVs are translated to the identical protein level alteration, thereby leading to the same functional impact. The redundancy of the genetic code causes the amino acid changes and, along with its observational frequency, codon usage can have other functional effects beyond altering translation efficiency[2]. Cancer cells are usually under harsh environmental pressure such as hypoxia[16], glucose starvation[17], or even physical forces[18] to expedite the evolutionary process This analogy leads us to an intriguing question regarding the CUB in cancer cells: is there a favored codon used in cancer mutations? Multiple computational analyses were conducted to find a possible relation of the bias to post-transcriptional efficiency (e.g., RNA secondary structure, translation speed) of the genes with the mutant codons
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