The two best described familial predispositions to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC). Recent advances make genetic diagnosis of these predispositions a reality. FAP is due to germline mutations in the APC tumor suppressor gene whereas HNPCC is caused by mutations in any one of at least four human DNA mismatch repair (MMR) genes. While these findings have paved the way for genetic diagnosis of FAP and HNPCC, many critical issues must be addressed before this work can be optimally translated to a clinical setting. The studies proposed in this application have three aims. The first is improving the sensitivity of testing for FAP and HNPCC. We have previously developed assays that can identify the genetic defect in about 80% of FAP and 50% of HNPCC patients. Recently, we have developed a sensitive and novel strategy for mutational testing (MAMA) which can detect mutations missed by conventional assays. In an effort to improve, screening sensitivity, we will use MAMA to test FAP and HNPCC patients who have tested negative with conventional analyses. Second, we will determine which patient populations warrant screening for APC and MMR gene alterations. Our previous studies have largely focused on patients who meet the classic criteria for FAP and HNPCC. However, we have identified APC and MMR mutations in several patients who do not meet these criteria. We will extend these studies to other similar patient populations who may have a predisposition to colorectal cancer. Third, we will attempt to improve the accuracy of testing by using functional tests to evaluate the disease- causing potential of selected mutations. A subset of the variants identified in the APC and MMR genes result in relatively subtle changes in the encoded protein. Determining whether these changes represent disease- causing mutations or harmless variations requires functional analysis. Together, these studies should provide information necessary for the translation of genetic testing for hereditary colorectal cancer syndromes to the clinic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Kuboki, Yuko; Fischer, Catherine G; Beleva Guthrie, Violeta et al. (2018) Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. J Pathol :
Zhang, Jiajia; Quadri, Shafat; Wolfgang, Christopher L et al. (2018) New Development of Biomarkers for Gastrointestinal Cancers: From Neoplastic Cells to Tumor Microenvironment. Biomedicines 6:
Hata, Tatsuo; Suenaga, Masaya; Marchionni, Luigi et al. (2018) Genome-Wide Somatic Copy Number Alterations and Mutations in High-Grade Pancreatic Intraepithelial Neoplasia. Am J Pathol 188:1723-1733
Noë, Michaël; Rezaee, Neda; Asrani, Kaushal et al. (2018) Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology. Am J Pathol 188:1530-1535
Schunke, Kathryn J; Rosati, Lauren M; Zahurak, Marianna et al. (2018) Long-term analysis of 2 prospective studies that incorporate mitomycin C into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers. Adv Radiat Oncol 3:42-51
Zhang, Jiajia; Wolfgang, Christopher L; Zheng, Lei (2018) Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer. Cancers (Basel) 10:
Dejea, Christine M; Fathi, Payam; Craig, John M et al. (2018) Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359:592-597
Staedtke, Verena; Bai, Ren-Yuan; Kim, Kibem et al. (2018) Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 564:273-277
Deng, Yang; Tu, Huakang; Pierzynski, Jeanne A et al. (2018) Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma. Eur J Cancer 92:20-32
Tamura, Koji; Yu, Jun; Hata, Tatsuo et al. (2018) Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A 115:4767-4772

Showing the most recent 10 out of 883 publications