Mutational processes underlying tumor development in United States Veterans

Philadelphia Va Medical Center, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Precision oncology aims to identify specific characteristics of a tumor, for example pathological or genomic features, that allow selection of a treatment most likely to achieve success in a patient. While a large number of single genomic alterations have been identified by large scale exome sequencing efforts, the National Cancer Institute MATCH trial has revealed that targeting single pathologic exonic alterations achieve clinical benefit in a minority of cancer patients. For example, lung cancer has the most molecularly directed targets; however, work from multiple studies, including those conducted by the VA National Precision Oncology Program (NPOP) has shown that therapeutic targets are identified in <30% of cases. Furthermore, therapeutic target rates are lower in Veteran lung cancer compared to public data repositories like The Cancer Genome Atlas (TCGA). Therefore, there is a critically urgent need to develop new tumor biomarkers for precision oncology. One reason for the limited success of current precision oncology approaches is current clinical sequencing tests focus mostly on point alterations (ie. BRAF, EGFR, BRCA1/2), which do not reflect the phenotypic consequences of the mutational processes that initially caused the tumor. Mutational processes that underlie human cancer leave mutational signatures in the genome that can be identified by whole genome sequencing (WGS). Seminal work by the Sanger Institute has identified mutational patterns indicative of defects in DNA replication and repair, mutagen exposures, and enzymatic modification of DNA. Currently, 79 single base substitution, 11 doublet base substitution, and 18 insertion/deletion signatures have been identified that reflect these mutational processes. In addition, patterns of copy number variants can identify tumor genomes that have undergone doubling events, chromothripsis, kategsis, loss of heterozygosity, and homologous recombination based DNA repair deficiency. The major published catalogs of tumor mutational signatures include cancers predominantly from individuals of English descent from efforts in the United Kingdom. Whether the same mutational signatures are at work in tumors from Veterans, and those from diverse genetic ancestries, is currently unknown. We hypothesize that mutational signatures will identify carcinogenic mechanisms resulting from Veterans’ service-related environmental exposures, provide clinical utility in defining treatment for Veteran cancer, and will inform further preventative measures to limit cancer-causing exposures. In order to test this hypothesis, we propose two independent Specific Aims. In Specific Aim 1, we will perform whole genome sequencing (WGS) on Veteran tumors and extract known and novel mutational signatures, comparing the Veteran signatures to public data. In Specific Aim 2, we will determine the clinical utility of mutational signatures. Our enterprise-wide team will leverage the resources of the National Precision Oncology Program (Kelley), the Million Veterans Program (Pyarajan) and VA cancer genomics expertise (Maxwell/Kratz/Neff/Pritchard) to perform and analyze WGS from existing tumor DNA specimens housed within NPOP. We will determine whether mutational signatures are superior biomarkers in predicting response to therapy (Fojo) by coupling with disease-specific experts in genitourinary (Garraway/Montgomery/Rettig), gastrointestinal (Kratz) and lung (Herman/Kelley/Klein) cancers. At a fundamental level, whether the mutational signatures identified in civilian tumors are found in tumors from Veterans and whether novel signatures might develop due to war-time exposures is unknown. Identification of novel mutational signatures may therefore inform preventative measures. Leveraging the diverse Veteran population, our findings will also greatly expand the knowledge of mutational processes in non-White individuals. Finally, we will define pathways for novel target development to treat Veterans with cancer and determine whether mutational signatures should be included in the Precision Oncology care of Veterans.