Arginine Depletion in Human Cancers.

Area of Science:

• Genetics
• Cancer Biology
• Molecular Evolution

Background:

• Arginine is encoded by six codons, and mutations can lead to various amino acid substitutions or stop codons.
• A significant bias exists in arginine substitutions, with four amino acids (histidine, cysteine, glutamine, tryptophan) accounting for over 75% of changes.
• This mutational bias is linked to C > T and G > A transitions in arginine codons, a pattern observed across diverse cancer types.

Purpose of the Study:

• To review literature and reanalyze data on arginine substitution bias in cancer.
• To identify genes exhibiting this bias, including known and novel cancer drivers.
• To propose a model where base pair substitution bias and amino acid physiology contribute to purifying selection.

Main Methods:

• Literature review.
• Reanalysis of publicly available cancer mutation data from the Catalogue of Somatic Mutations in Cancer (COSMIC).
• Identification and analysis of genes with significant arginine substitution bias.

Main Results:

• The study confirms a universal C > T and G > A transition bias in four of the six arginine codons, independent of cancer origin or histology.
• Several genes were identified with arginine substitution bias, including IDH1, FGFR3, PPP6C, MAX, and GNAQ.
• The findings highlight specific genes, including four cancer driver genes, affected by this mutational bias.

Conclusions:

• A mutational bias, driven by specific base pair transitions, influences arginine substitutions in cancer.
• Both base pair substitution patterns and amino acid physiology likely contribute to purifying selection.
• The proposed model helps explain the observed arginine substitution bias in various cancers.