Carcinogenicity Health Effects Innovation Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

A summary of the projects in support of the major objectives described above are included below. A. Studies to understand the environmental contributions leading to early onset colorectal cancer: The studies on early onset colorectal cancer (EO-CRC) include several projects that are aligned with the Division of Translational Toxicology (DTTs) Translational Toxicology Pipeline. This includes examining and mining existing scientific literature to obtain actionable information and employ in silico, in vitro, and short-term in vivo methods to generate research data that provide insights into the environmental contributions related to EO-CRC. The data mining project involves bioinformatic analysis of whole genome/whole exome sequencing data from human colorectal cancers deposited in various national and international genomic data repositories, such as the TCGA, ICGC, Hartwig, and Genomics England. In addition to partnering with the Drs. Jian-liang Li and Ashley Brooks from the NIEHS bioinformatics core, we have also established national and international collaborations with research teams that are focusing on the same objective. These collaborators include Dr. Scott Kopetz from MD Anderson Cancer Center, Dr. Ian Tomlinson from University of Edinburgh, UK, and Dr. Claire Palles from the University of Birmingham, UK. The data analyses are in progress. We have optimized air-liquid interface (ALI) 3D colonoids established from human (ES, iPSC, PDX) and rat (primary) cells. We aim to mutate key cancer driver genes in these ALI colonoids using CRISPR technology and test potential exposures implicated in the etiology of EO-CRC. We plan to compare the underlying molecular alterations in these complex in vitro cultures to the genomic alterations observed in corresponding human tumors. Some of this work is being done in collaboration with Dr. Jatin Roper at Duke University.a We have designed a short-term in vivo animal model using the APC-mutated rat model (Polyposis in rat colon (PIRC)) that will serve to test various environmental exposures that potentially contribute to EO-CRC. In addition to the above studies, we are optimizing multi-omics bioinformatic pipelines to examine genomic and epigenomic alterations in rat tissues and human colonoids derived from these studies. By leveraging the translational toxicology pipeline to study EO-CRC, we aim to obtain mechanistic knowledge that is actionable and translationally relevant for public health. B. Investigate the etiologic role of environment in human cancers using multi-omics technologies: While the NTP is mainly known for generating high quality in vitro and in vivo mechanistic toxicity and carcinogenicity data using rodents and in vitro systems, no major efforts were directed to study tissues/fluids derived directly from human cancers to understand the influence of the environment on human cancers. As a part of this objective, Carci-HEI has three projects aimed at generating multi-omics data from human cancers. Project #1: DODSR proteomics/miRNA project to understand the mechanisms and identify predictive biomarkers related to breast cancer and potential exposures related to deployment in military personnel. This work is being done in collaboration with Dr. Craig Shriver from the Murtha Cancer Center and Dr. Kangmin Zhu from the Uniformed Services University of the Health Sciences. Project #2: Whole exome sequencing of human tumors from the Agent Orange tumor registry to decipher exposure specific mutation signatures. This work is a collaboration between the DTT and the Joint Pathology Center (Drs. Joel Moncur and Michael Lewin-Smith). A Material Transfer Agreement has been signed to allow a pilot project to determine the quality of the tumors for next generation sequencing studies. Project #3: Whole exome sequencing of renal cell carcinomas and other tumors from Camp Lejune/Camp Pendleton to identify exposure specific mutation signatures: Tumors from Camp Lejune are suspected to result from ground water contamination while tumors from Camp Pendleton have no known environmental exposures. This project is a collaboration with the Veterans Administration (Drs. Michale Kelley, Elizabeth Boswell, and Karen Block) and CDC/ATSDR (Dr. Frank Bove). C. Evaluation of the genomic and epigenomic alterations in chemical carcinogenesis studies using invitro and in vivo models: We recently completed a multi-omics study on mouse hepatocellular carcinomas (HCCs) resulting from chronic exposure to various genotoxic and non-genotoxic carcinogens. The manuscripts summarizing these data are currently under preparation by Dr. Miaofei Xu, a postdoc in the Molecular Pathology Laboratory. We have generated similar data from rodent tumors from recent NTP bioassays, examples include tris(Chloropropyl)phosphate (mouse HCCs), and alpha-pinene (mouse HCCs and alveolar/bronchiolar carcinomas and rat mammary fibroadenomas and mammary adenocarcinomas). These data will contribute to the mechanistic understanding of chemical carcinogenesis and will be included in the appendix of the respective NTP technical reports. In addition to these studies, several omics studies are in progress in collaboration with various national and international partners. The DTT has a long-standing collaboration with Dr. Daniele Mandrioli, Ramazzini Institute, Italy as well as Dr. David Adams, Sanger Institute, UK. In addition, DTT has established recent collaborations with Prof. Dr. Bettina Grasl-Kraupp, Medical University of Vienna, Austria and Dr. Jesse Salk from TwinStrand Biosciences, Seattle. One goal of these collaborations is to understand the mutation signatures of rodent tumors resulting from chronic exposures to known and probable human carcinogens. Another important goal of these whole exome/whole genome studies is to better understand the mutation signatures and cancer driver genes related to non-genotoxic mode of carcinogenesis. These rodent cancer -omics data will be compared to the -omics data from the corresponding chemical exposures implicated in human cancers, such as vinyl chloride, benzene, trichloroethylene, etc., to establish the translational relevance of these exposures in human cancers. In addition, the rodent specific cancer driver gene information will be used to generate targeted duplex sequencing panel to screen non-tumor tissues from short term animal studies to predict a potential carcinogenic response.