Mutational signatures are markers of drug sensitivity of cancer cells

Abstract

Genomic analyses have revealed mutational signatures that are associated with DNA maintenance gone awry, a common occurrence in tumors. Because cancer therapeutics often target synthesis of DNA building blocks, DNA replication or DNA repair, we hypothesized that mutational signatures would make useful markers of drug sensitivity. We rigorously tested this hypothesis by a global analysis of various drug screening and genetic screening data sets, derived from cancer cell line panels. We introduce a novel computational method that detects mutational signatures in cell lines by stringently adjusting for the confounding germline mutational processes, which are difficult to remove when healthy samples from the same individuals are not available. This revealed many associations between diverse mutational signatures and drug activity in cancer cell lines, which are comparably or more numerous than associations with classical genetic features such as cancer driver mutations or copy number alterations. Validation across independent drug screening data and across genetic screens involving drug target genes revealed hundreds of robustly supported associations, which are provided as a resource for drug repurposing guided by mutational signature markers. We suggest that cancer cells bearing genomic signatures of deficiencies in certain DNA repair pathways may be vulnerable to particular types of therapeutics, such as epigenetic drugs.

Therapeutic and prognostic insights from the analysis of cancer mutational signatures

“…In all, over 500 significant mutational signature-drug sensitivity correlations were observed, including signature 26 (MMR deficiency) associated with camptothecin sensitivity in colorectal cancer cell lines; signature 20 (POLD1 mutation and MMR deficiency) associated with topotecan sensitivity in skin cancer and histone deacetylase (HDAC) inhibitor sensitivity in multiple cancers; and signature 36 (ROS-induced) associated with sensitivity to the kinase inhibitor cabozantinib in several cancers. This study thus reveals a plethora of mutational signature biomarkers that might be used to inform precision cancer therapy [62].…”

“…Levatić and colleagues recently performed a systematic correlation between SNV mutational signatures in cell lines (under basal culture conditions) and drug response using molecular data from the Genomics of Drug Sensitivity in Cancer database [62,63]. Mutational signature analysis generally requires matched germline tissue, in addition to tumor tissue, so that somatic mutations can be identified; however, germline tissue is usually not available for cancer cell lines.…”

The impact of rare germline variants on human somatic mutation processes

“…For the somatic features which were based on SNVs, DNVs, and indels, the somatic calls from the MC3 Project 109 were used. For the somatic features based on CNVs, TCGA exome data was downloaded from the GDC Data Portal 110 and processed as described in ref 111 . Copy numbers were identified with the tool FACETS 112 .…”

“…Extraction of Rare Germline Variants in the Discovery Cohort TCGA bam files were downloaded as described here 111 . Strelka 119 2.9.7 was run on TCGA WES normal and tumor samples to extract germline variants.…”

A framework for mutational signature analysis based on DNA shape parameters

“…Tumor evolution is characterized by distinctive somatic mutational processes resulting from mutagen exposures (environmental or endogenous) or defects in DNA repair mechanisms that result in genome instability [ 8 – 10 ]. Identification of these mutational processes can add to our knowledge of DNA damage and repair mechanisms that operate in human cells [ 11 , 12 ]; it can contribute to understanding the etiology of various tumor types, with implications for predicting cancer risk [ 13 , 14 ]; it can improve statistical methodologies for detecting cancer driver genes by refining baseline estimates of mutation rates [ 15 , 16 ]; and finally, it has the potential to identify mutational biomarkers that can aid diagnostics [ 17 , 18 ] and personalized treatment of tumors [ 19 – 21 ].…”