Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression

Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression with treatment cessation, opportunistic infection, or death as a consequence. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We mapped the transcriptome and promoter-interaction landscape using targeted chromosome conformation capture (HiCap) of three blood cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in vivo using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Finally, we overlapped our results with a whole-genome sequencing dataset from 96 individuals with differing myelosuppression levels to isolate candidate enhancer mutations that could explain the observed toxicity.