Pancancer analysis identifies prognostic high-APOBEC1 expression level implicated in cancer in-frame insertions and deletions.

Genome insertions and deletions (indels) show tremendous functional impacts despite they are much less common than single nucleotide variants, which are at the center of studies assessing cancer mutational signatures. We studied 8891 tumor samples of 32 types from The Cancer Genome Atlas in order to explore those genes which are potentially implicated in cancer indels. Survival analysis identified in-frame indels as the most important variants predicting adverse outcome. Transcriptome-wide association study identified 16 genes overexpressed in both tumor samples and tumor types with high number of in-frame indels, of whom four (APOBEC1, BCL2L15, FOXL1 and PDX1) were identified with gene products distributed within the nucleus. APOBEC1 emerged as the mere consistently hypomethylated gene in tumor samples with high number of in-frame indels. The correlation of APOBEC1 expression levels with cancer indels was independent of age and defects in DNA homologous recombination (HR) and/or mismatch repair. Unlike frame-shift indels, triplet repeat motifs were found to occur frequently at in-frame indel sites. The splicing variant 3, making a shorter isoform b, showed essentially all the same indel correlations as of APOBEC1. Expression levels of both APOBEC1 and variant 3 were found to be predicting adverse prognosis independent of DNA HR and mismatch repair. Not less importantly, high level of variant 3 in paired normal tissues was also proved to predict cancer outcome. Our findings propose APOBEC1 and isoform b as the potential endogenous mutators implicated in cancer in-frame indels and pave the way for their use as novel prognostic tumor markers.