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.
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.
|Hoang, Margaret L; Kinde, Isaac; Tomasetti, Cristian et al. (2016) Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc Natl Acad Sci U S A 113:9846-51|
|Robles, Ana I; Traverso, Giovanni; Zhang, Ming et al. (2016) Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology 150:931-43|
|Roberts, Nicholas J; Norris, Alexis L; Petersen, Gloria M et al. (2016) Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 6:166-75|
|Ewing, Adam D; Gacita, Anthony; Wood, Laura D et al. (2015) Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res 25:1536-45|
|Li, Ryan; Faden, Daniel L; Fakhry, Carole et al. (2015) Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke. Head Neck 37:1642-9|
|Wang, Yuxuan; Springer, Simeon; Mulvey, Carolyn L et al. (2015) Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med 7:293ra104|
|Jiao, Yuchen; Lumpkins, Kimberly; Terhune, Julia et al. (2015) Intraductal papillary mucinous neoplasm in a neonate with congenital hyperinsulinism and a de novo germline SKIL gene mutation. Pancreatology 15:194-6|
|Tie, J; Kinde, I; Wang, Y et al. (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715-22|
|Le, Dung T; Uram, Jennifer N; Wang, Hao et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372:2509-20|
|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|
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