It is now generally accepted that cancer is a genetic disease, mediated in large part by somatic mutations in specific genes. However, many of the key tumor suppressor genes and oncogenes responsible for cancer initiation and progression remain to be identified. Although technical hurdles have limited our ability to identify such genes in a comprehensive fashion, the delineation of the sequence of the human genome, coupled with recent advances DMAanalysis technologies, have created an unprecedented opportunity for progress in this area. Over the past several years we have developed high throughput technologies for sequencing and mutational analyses to rapidly analyze gene families in human cancer. We have specifically focused on gene families involved in signal transduction, as these have been implicated in tumorigenesis and may be amenable to therapeutic intervention. These approaches have recently permitted the mutational analysis of all members of the PI-3 kinase, tyrosine kinase, tyrosine phosphatase, and serine/threonine kinase gene families. These genetic analyses have identified a high frequency of somatic mutations in PIK3CA as well as mutations in several kinases and phosphatases not previously implicated in human cancers. The purpose of this proposal is to use our cancer sequencing technologies to perform large-scale genetic analyses of gene families involved in signal transduction in human cancer. These families will include the serine/threonine protein phosphatase family, the lipid phosphatase gene family, the G protein-coupled receptor gene family, the heterotrimeric G protein gene family, the GTPase gene superfamily, and the G protein modulator gene family. Initially, the genes comprising these families will be analyzed for somatic alterations in colorectal cancers. Subsequently, selected genes will be further analyzed in lung, breast, gastric, brain, pancreatic and ovarian cancers to determine whether mutations in these genes provide common mechanisms of tumorigenesis shared by different cancer types. Finally, we will examine the mutation spectrum observed in the different tumors in order to determine if the mutated genes may have equivalent tumorigenic effects and are involved in specific signaling pathways. We envision that analyses of these gene families will allow us to identify genes not previously implicated in human cancer and provide insights into signaling pathways involved in tumor progression. The studies described in this application should lead to a greater understanding of cancer etiology, improved tools for cancer detection and diagnosis, new targets for therapeutic and preventative intervention, and opportunities for individualized treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121113-05
Application #
7777364
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Li, Jerry
Project Start
2006-05-01
Project End
2012-07-31
Budget Start
2010-04-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$282,659
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cottrell, T R; Thompson, E D; Forde, P M et al. (2018) Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol 29:1853-1860
Boudadi, Karim; Suzman, Daniel L; Anagnostou, Valsamo et al. (2018) Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget 9:28561-28571
Forde, Patrick M; Chaft, Jamie E; Smith, Kellie N et al. (2018) Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 378:1976-1986
Danilova, Ludmila; Anagnostou, Valsamo; Caushi, Justina X et al. (2018) The Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) Assay: A Sensitive Platform for Monitoring Antitumor Immunity. Cancer Immunol Res 6:888-899
Vaz, Michelle; Hwang, Stephen Y; Kagiampakis, Ioannis et al. (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell 32:360-376.e6
Spira, Avrum; Yurgelun, Matthew B; Alexandrov, Ludmil et al. (2017) Precancer Atlas to Drive Precision Prevention Trials. Cancer Res 77:1510-1541
Liu, Joyce F; Palakurthi, Sangeetha; Zeng, Qing et al. (2017) Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics. Clin Cancer Res 23:1263-1273
Husain, Hatim; Velculescu, Victor E (2017) Cancer DNA in the Circulation: The Liquid Biopsy. JAMA 318:1272-1274
Anagnostou, Valsamo; Smith, Kellie N; Forde, Patrick M et al. (2017) Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Discov 7:264-276
AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831

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