The care of patients with inflammatory bowel disease (IBD) is complex. One crucial clinical dilemma is the management of the increased risk for colon cancer. Unfortunately, current knowledge does not allow for accurate determination of neoplastic risk and the best tailored management. This challenge is due, in part, to the lack of genetic information regarding somatic mutations occurring in colon cancer arising in IBD patients. Furthermore, the order of mutations and the significance of sequential mutations in regards to the course of neoplastic transformation are currently unexplored. We hypothesize that a comprehensive genetic survey of human IBD-associated neoplasia (IBDN), with detailed mathematical mapping and testing at discrete developmental/temporal stages, can be used to identify genetic alterations that drive neoplastic progression in IBD. We further hypothesize that by performing longitudinal analyses of genetic alterations in our IBDN porcine model, we will identify characteristic genetic oncogenic trajectories that drive cancer progression. Iterative biopsy specimens from neoplasia, as it develops and evolves within each animal, will be obtained via serial colonoscopic sampling, and genetic analyses will be performed. By integrating these human and animal datasets, we will learn which molecular events drive and/or predict the progression of early lesions to more advanced malignant disease in IBD. Throughout this grant, we will characterize small-scale exome alterations (point mutations, indels) and copy number alterations, using both whole-exome sequencing (WES) and SNP arrays. We will investigate these hypotheses by pursuing the following Specific Aims:
Aim 1 - To identify and order genetic alterations in human IBD-associated neoplastic progression. A) Perform exome sequencing and SNP-array assays on a cross-sectional cohort of 100 IBD-Ca. B) Using a combination of algorithms, identify the most likely driver alterations and infer oncogenic trajectories. C) Test oncogenic trajectories by Sanger-sequencing and SNP-arraying 30 LGD, 30 HGD, & 30 IBD-Ca.
Aim 2 - To characterize the temporal order and functional impact of genetic alterations in colon cancer arising in a porcine IBDN model. A) To determine the phenotypic impact of oncogenic trajectories determined in Aim 1. B) To identify temporal profiles of genetic alterations in longitudinal biopsies and compare to ordering of alterations in human IBDN. In toto, this novel integrated strategy is likely to provide insight into early and predictiv molecular events, since we will be able to temporally map these events in exquisite detail, as well as to catch them in the act as soon as they occur. Ultimately, the successful completion of this project will translate in better tailoring of curative and preventative treatments for IBD patients.

Public Health Relevance

We hypothesize that a comprehensive genetic survey of human inflammatory bowel disease (IBD)-associated neoplasia (IBDN), with detailed mathematical mapping and testing at discrete developmental stages, can be used to identify genetic alterations that drive neoplastic progression in IBD (Aim 1). To better characterize the order of these alterations and their causal impact on colon cancer arising in IBD patients, we will generate a porcine model. We further hypothesize that by performing longitudinal analyses of genetic alterations in this porcine model, we will identify characteristic genetic 'trajectories' tat drive cancer progression (Aim 2). By integrating these human and animal datasets, we will learn which molecular events drive and/or predict the progression of early lesions to more advanced malignant disease in IBD.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA190040-02
Application #
8934074
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Li, Jerry
Project Start
2014-09-25
Project End
2018-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Wang, Fang; Li, Ling; Piontek, Klaus et al. (2018) Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology 67:940-954
Wang, Zhe; Ma, Ke; Pitts, Steffie et al. (2018) Novel circular RNA NF1 acts as a molecular sponge, promoting gastric cancer by absorbing miR-16. Endocr Relat Cancer :
Kumbhari, Vivek; Li, Ling; Piontek, Klaus et al. (2018) Successful liver-directed gene delivery by ERCP-guided hydrodynamic injection (with videos). Gastrointest Endosc 88:755-763.e5
Xiong, Ji-Xian; Wang, Yan-Song; Sheng, Jingyi et al. (2018) Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer. Int J Biol Sci 14:1658-1668
Liu, Xi; Abraham, John M; Cheng, Yulan et al. (2018) Synthetic Circular RNA Functions as a miR-21 Sponge to Suppress Gastric Carcinoma Cell Proliferation. Mol Ther Nucleic Acids 13:312-321
Liu, Xi; Cheng, Yulan; Abraham, John M et al. (2018) Modeling Wnt signaling by CRISPR-Cas9 genome editing recapitulates neoplasia in human Barrett epithelial organoids. Cancer Lett 436:109-118
Liu, Xi; Meltzer, Stephen J (2017) Gastric Cancer in the Era of Precision Medicine. Cell Mol Gastroenterol Hepatol 3:348-358
Wang, Zhixiong; Cheng, Yulan; Abraham, John M et al. (2017) RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement. Cancer 123:3916-3924
Abraham, John M; Meltzer, Stephen J (2017) Long Noncoding RNAs in the Pathogenesis of Barrett's Esophagus and Esophageal Carcinoma. Gastroenterology 153:27-34
Ke, Xiquan; Yan, Rong; Sun, Zhenguo et al. (2017) Esophageal Adenocarcinoma-Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids. Neoplasia 19:941-949

Showing the most recent 10 out of 17 publications