Colorectal cancer represents a major public health issue but also provides exceptional opportunities for investigating human tumorigenesis. We have recently developed experimental approaches that allow us to analyze human cancers in unprecedented detail and address questions that were difficult or impossible to answer in the past. We intend to use these approaches to fill gaps in our understanding of the early events in colorectal tumor development.
Aim #1 is directed at identifying the genetic basis of two polyposis syndromes, Serrated Polyposis Syndrome (SPS) and Atypical Adenomatous OligoPolyposis (AAOP). To determine the genetic basis for both these syndromes, we will perform whole genome sequence analysis of normal and tumor tissues from representative patients.
Aim #2 is directed at identifying the clonal relationship and timing of genetic alteratios during colorectal tumorigenesis in the canonical Adenoma-Carcinoma and the Serrated Colorectal Cancer Pathways. We will perform genome-wide analyses of clonal somatic mutations in a unique collection of lesions including hyperplastic polyps, serrated adenomas, sessile serrated adenomas, small adenomatous polyps and, most importantly, invasive and adjacent non-invasive components (adenomatous and hyperplastic) from the same lesions. We will thereby be able to determine the clonal relationships among different components of the same tumor and evaluate the time periods required for tumor progression.
Aim #3 is directed at characterizing non-clonal somatic mutations in normal and neoplastic colorectal tissues. The number and type of non-clonal somatic mutations can provide a window into past endogenous and exogenous mutagen exposures. We have recently developed a technique (SafeSeqS) that can reliably identify non-clonal somatic mutations in clinical samples. SafeSeqS will be used to assess such mutations in benign and malignant tumors as well as in normal colorectal tissues.
Aim #4 is directed at identifying the full compendium of early events in colorectal tumorigenesis. Several lines of evidence support the idea that APC or CTNNB1 mutations are the initiating events in colorectal tumorigenesis. Is tumor development simply gated by inactivation of the APC pathway or are additional early changes required? Using technologies developed during the past funding period, we will pursue an integrated (i.e., genetic, epigenetic and transcriptomic) analysis of multiple synchronous adenomas removed from the same patients to look for recurring genetic and epigenetic changes that may act as early events in tumor development. Relevance:
Our specific aims are directed at identification of the early events in colorectal tumorigenesis. It can be argued that understanding these early changes is essential for the development of more effective strategies for colorectal tumor prevention and treatment.

Public Health Relevance

Colorectal cancer is the second leading cause of cancer deaths in the United States with 141,000 cases and 49,000 deaths expected in 2011. Understanding the earliest changes in colorectal tumorigenesis will be key to developing the most effective preventions and treatments for colorectal cancer. The goals of the studies proposed in this application are to characterize early events in various types of colorectal tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA057345-23
Application #
8677696
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
1992-09-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
23
Fiscal Year
2014
Total Cost
$495,472
Indirect Cost
$189,625
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J et al. (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24
Joseph, Christine G; Hwang, Heejung; Jiao, Yuchen et al. (2014) Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer 53:15-24
Joseph, Christine G; Darrah, Erika; Shah, Ami A et al. (2014) Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343:152-7
Sausen, Mark; Leary, Rebecca J; Jones, Sian et al. (2013) Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45:12-7
Hoang, Margaret L; Chen, Chung-Hsin; Sidorenko, Viktoriya S et al. (2013) Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med 5:197ra102
Bettegowda, Chetan; Agrawal, Nishant; Jiao, Yuchen et al. (2013) Exomic sequencing of four rare central nervous system tumor types. Oncotarget 4:572-83
Agrawal, Nishant; Jiao, Yuchen; Sausen, Mark et al. (2013) Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 98:E364-9
Killela, Patrick J; Reitman, Zachary J; Jiao, Yuchen et al. (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 110:6021-6
Jones, Sian; Li, Meng; Parsons, D Williams et al. (2012) Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 33:100-3
Kinde, Isaac; Wu, Jian; Papadopoulos, Nick et al. (2011) Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 108:9530-5

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