Big genes are big mutagen targets: A connection to cancerous, spherical cells?

Abstract

We determined the most commonly mutated genes in five cancer genome atlas (TCGA) datasets. Many of these genes were extraordinarily large, as are many cancer fusion gene partners. And many of these genes had cytoskeletal related functions. We further determined that these genes were distributed into high and low frequency mutation groups largely according to overall rate of gene-occurrence in the high and low mutation frequency groups, as was also the case with common metastasis and tumor suppressor genes. Oncoproteins were selectively mutated in the low mutation frequency groups in colon and lung datasets. Thus, genes that have very large coding regions and may impact the cytoskeleton are more commonly mutated than are common metastasis and tumor suppressor genes in both high and low frequency mutation groups. These analyses raise questions related to cell shape: (i) Are cancer cells often spherical because cytoskeletal-related proteins are large mutagen targets? (ii) Is drug-resistance facilitated by relatively common mutant proteins that lead to round cells, with altered cell physiology or reduced surface to volume ratios that could reduce intra-cellular drug concentrations?