Prominent features of the amino acid mutation landscape in cancer

Abstract

Cancer can be viewed as a set of different diseases with distinctions based on tissue origin, driver mutations, and genetic signatures. Accordingly, each of these distinctions have been used to classify cancer subtypes and to reveal common features. Here, we present a different analysis of cancer based on amino acid mutation signatures. Non-negative Matrix Factorization and principal component analysis of 29 cancers revealed six amino acid mutation signatures, including four signatures that were dominated by either arginine to histidine (Arg>His) or glutamate to lysine (Glu>Lys) mutations. Sample-level analyses reveal that while some cancers are heterogeneous, others are largely dominated by one type of mutation. Using a non-overlapping set of samples from the COSMIC somatic mutation database, we validate five of six mutation signatures, including signatures with prominent arginine to histidine (Arg>His) or glutamate to lysine (Glu>Lys) mutations. This suggests that our classification of cancers based on amino acid mutation patterns may provide avenues of inquiry pertaining to specific protein mutations that may generate novel insights into cancer biology.

Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins

“…Despite published work reporting a higher than expected frequency of Arg>His mutations in cancer (9–11), functional effects or physiological relevance of recurring Arg>His substitutions has not been reported. Our data show that Arg>His mutations can confer a gain in pH sensing to mutant proteins and suggest that Arg>His substitutions may provide a fitness advantage to the increased pHi of cancer cells.…”

“…Our data show that Arg>His mutations can confer a gain in pH sensing to mutant proteins and suggest that Arg>His substitutions may provide a fitness advantage to the increased pHi of cancer cells. This work provides the first analysis of potential physiological relevance of the higher than expected frequency of Arg>His mutations observed in cancer (9–11). Furthermore, our functional assays in cells suggest that the tumorigenic effects of some somatic Arg>His cancer mutations become penetrant only at high pHi and suggest that lowering pHi in cancer cells may reduce the deleterious effects of some Arg>His mutations.…”

“…Determining how distinct amino acid mutational signatures contribute to the physiological changes seen in cancer evolution is an understudied but important area of research. Recent work has analyzed cancers by amino acid substitution signatures (9–11) and found that arginine-to-histidine (Arg>His) mutations are dominant in a subset of cancers. Anoosha and colleagues (10) also showed that Arg>His mutations are enriched in driver mutations compared with passenger mutations.…”

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

“…Stepwise increases of oxygen in the biosphere over time (see Section 6 for more details) could have given the impulse for the late incorporation into the genetic code of amino acids that can act as "ROS scavengers" (including Trp, Tyr, Met, Cys, and His), and thereby protect biopolymers from oxidative damages [80]. Interestingly, the most frequent mutations in ROS-producing cancer cells affect Arg codons (and in particular, the CGN codons), with mutations producing codons for Cys (TGY), Trp (TGG), stop codons (TGA), and His (CAR) [81][82][83][84][85]. It has been proposed that these mutations (i) are induced by ROS-mediated deamination of (methyl) cytosine, leading to C > T mutations, or incorporation of oxidized guanine during replication, leading to G > A mutations and (ii) protect cancer cells from the high levels of ROS by increasing the global antioxidant capacity of the cancer proteome [81][82][83][84][85].…”

What is pH regulation, and why do cancer cells need it?

“…The first involves a re-modeling of pH sensitivity, which could be achieved through genetic mutations involving titratable residues, such as histidines [4,[24][25][26]. The protonation state of histidine changes dramatically over the expanded physiological range, bestowing proteins with exquisite pH-dependence [27][28][29].…”