Gene switches, not just mutations, drive severe chemo side effects
Scientists discovered that mutations in gene regulators—not just protein-coding genes—determine how severely cancer patients suffer bone marrow damage from chemotherapy. The finding could eventually guide which patients receive standard chemo versus alternative treatments, reducing hospitalizations and improving outcomes for lung cancer patients.
Originaltitel: Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression
<p>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. 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 produced transcriptome and promoter-interaction maps (using HiCap) of three blood stemlike cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations. © 2024 Zhigulev et al.</p>