In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors

• DOI: 10.1101/gr.230219.117
• Publication Date: 2018-04-09T14:40:16Z
• Authors: Arnoud Boot; Mi Ni Huang; Alvin W.T. Ng; Szu-Chi Ho; Jing Quan Lim; Yoshiiku Kawakami; Kazuaki Chayama; Bin Tean Teh; Hidewaki Nakagawa; Steven G. Rozen
• Keywords: 0301 basic medicine; 0303 health sciences; Carcinoma, Hepatocellular; Esophageal Neoplasms; Genome, Human; Research; DNA Mutational Analysis; Liver Neoplasms; Antineoplastic Agents; Hep G2 Cells; Adenocarcinoma; Cell Line; 3. Good health; 03 medical and health sciences; Mutagenesis; Mutation; Exome Sequencing; Humans; Cisplatin

Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called mutational signature. Despite widespread use cisplatin in cancer treatment its role contributing to secondary malignancies, signature has not been delineated. We hypothesize that cisplatin's can serve as biomarker identify mutagenesis suspected malignancies. Knowledge which tissues are at risk developing cisplatin-induced malignancies could lead guidelines for noninvasive monitoring after chemotherapy. performed whole genome sequencing 10 independent clones cisplatin-exposed MCF-10A HepG2 cells delineated the patterns single dinucleotide mutations terms flanking sequence, transcription strand bias, other characteristics. used mSigAct presence test nonnegative matrix factorization search hepatocellular carcinomas esophageal adenocarcinomas. All showed highly consistent substitutions. The proportion substitutions was high: 8.1% nucleotide were part substitutions, presumably due propensity form intra- interstrand crosslinks between purine bases DNA. identified exposure nine three clinical data available all cancers indeed had histories treatment. experimentally cisplatin. This enabled us detect previous human adenocarcinomas high confidence.