Arginine Depletion in Human Cancers

Abstract

Arginine is encoded by six different codons. Base pair changes in any of these codons can have a broad spectrum of effects including substitutions to twelve different amino acids, eighteen synonymous changes, and two stop codons. Four amino acids (histidine, cysteine, glutamine, and tryptophan) account for over 75% of amino acid substitutions of arginine. This suggests that a mutational bias, or “purifying selection”, mechanism is at work. This bias appears to be driven by C > T and G > A transitions in four of the six arginine codons, a signature that is universal and independent of cancer tissue of origin or histology. Here, we provide a review of the available literature and reanalyze publicly available data from the Catalogue of Somatic Mutations in Cancer (COSMIC). Our analysis identifies several genes with an arginine substitution bias. These include known factors such as IDH1, as well as previously unreported genes, including four cancer driver genes (FGFR3, PPP6C, MAX, GNAQ). We propose that base pair substitution bias and amino acid physiology both play a role in purifying selection. This model may explain the documented arginine substitution bias in cancers.

Computational investigation of missense somatic mutations in cancer and potential links to pH-dependence and proteostasis

“…Arginine depletion [14] overall is related to underlying mutational signatures in DNA, but the balance of AA mutations varies for higher instances compared with lower instances (Fig 1B).…”

“…Using these data, enrichments for mutation from arginine and (to a lesser degree) for mutation from glutamic acid to lysine, have been seen [11][12][13]. This observation has been termed arginine depletion in human cancers, and related to C > T transitions in nucleotide mutational signatures, with subsequent selection for function at the amino acid (AA) level suggested for some sites [14]. Proposed functional significance of arginine mutation includes a potential role for cysteine in neutralising reactive oxygen species [13], and pH-sensing for the introduction of histidine [15], with variation of AA mutation frequencies between cancer types noted [11,14].…”

“…This observation has been termed arginine depletion in human cancers, and related to C > T transitions in nucleotide mutational signatures, with subsequent selection for function at the amino acid (AA) level suggested for some sites [14]. Proposed functional significance of arginine mutation includes a potential role for cysteine in neutralising reactive oxygen species [13], and pH-sensing for the introduction of histidine [15], with variation of AA mutation frequencies between cancer types noted [11,14]. Arginine to histidine mutations that mediate altered pH-dependence of activity, and could be related to fitness advantage in cancer cells include EGFR-R776H and p53-R273H [15], and IDH1-R132H where production of the oncometabolite D-2-hydroxyglutarate is rendered pH-dependent if mutant and wild type IDH1 form a heterodimer [16].…”