The NFGC selected the “Molecular Analysis of Human Tissue” project by Dr. Tim Yeatman to support, and provided funds for microarray chips to push his research project closer to validation of a molecular signature for colon cancer diagnosis and prognosis.
In the project, Dr. Yeatman endeavors to prove that by using microarray analysis of RNA isolated from portions of human surgical specimens (which would otherwise be discarded) derived from cancer patients, molecular profiles or fingerprints can be developed that can:
Dr. Yeatman began collecting tumor samples for this project in 2000. By amassing a significant number of cancerous specimens from each stage of various diseases and by comparing the results of gene expression analyses of these tissues with that of their "normal" adjacent tissue counterparts, he seeks to address a number of specific aims:
To develop an RNA and protein expression library of the genes associated with cancerous and normal adjacent tissues from numerous organ sites, histologies, and clinical and pathological stages.
To compare the results of microarray and proteomic analyses with clinical data including demographic data such as sex and age, cancer staging data, routine pathological parameters including p53 analysis of tumors, and follow-up data (survival and recurrence) in attempts to identify new markers for: 2.1 Identification of cancer cell origin 2.2 Identification of new prognostic markers 2.3 Identification of new staging parameters 2.4 Identification of new molecular targets for drug discovery
Identification of new markers predicting response to chemotherapy, biological therapy or radiotherapy.
With preliminary data, Dr. Yeatman identified a 43 gene classifier of colon cancer prognosis, published in the Journal of Clinical Oncology (15:3526-35, 2005) and filed for patent protection (Timothy Yeatman, MD, FACS, “Methods and Systems for Predicting Continuation Cancer Outcomes”). This patent application was later abandoned, but patent protection was continued with: Timothy Yeatman, MD, FACS; "Methods and systems for predicting continuation cancer outcomes;" status - US Continuation and European applications filed. This was licensed to Xceed Molecular on May 29, 2008. The licensed invention is directed to the development of a genetic signature into a gene chip used to protect disease stage and to select among therapy options in cancer patients.
The second publication to emerge was: Kwong KY, Bloom GC, Yang I, Boulware D, Coppola D, Haseman J, Chen E, McGrath A, Makusky AJ, Taylor J, Steiner S, Zhou J, Yeatman TJ, Quackenbush J. Synchronous global assessment of gene and protein expression in colorectal cancer progression. Genomics. 2005 Aug; 86(2):142-58. PMID: 15951154.
In 2007, Dr. Yeatman et al. published a tumor classifier discovered using 2-dimensional gel analysis of protein samples that can detect the site of origin of a metastatic tumor and can also distinguish between six common types in an unknown primary diagnosis setting (Bloom GC, Eschrich S, Zhou JX, Coppola D, Yeatman TJ. Elucidation of a protein signature discriminating six common types of adenocarcinoma. Int J Cancer. 2007 Feb 15;120(4):769-75. PMID: 17131332)
In 2008, data from this project resulted in the publication of, "A predictive risk probability approach for microarray data with survival as an endpoint." Please click here for this PubMed Central open access article.
In late 2008, Dr. Yeatman et al. published the results from expression array data analyzed from tissue samples collected from Australian collaborators at the Ludwig Institute for Cancer Research and the Royal Melbourne Hospital in Parkville, Victoria, Australia. From this data they found significant differences in the overall signal as well as a loss of signal from low abundant transcripts. The Australian colleagues later applied a different approach to the expression analysis by first ranking the expression on the different probe sets and then analyzing expression differences. With this approach Dr. Yeatman’s group has shown the Australian data correlates with multiple colon sample expression data sets, including Moffitt’s. Details can be found in this publication: Jorissen RN, Lipton L, Gibbs P, Chapman M, Desai J, Jones IT, Yeatman TJ, East P, Tomlinson IP, Verspaget HW, Aaltonen LA, Kruhøffer M, Orntoft TF, Andersen CL, Sieber OM. DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers. Clin Cancer Res. 2008 Dec 15;14(24):8061-9. PMID: 19088021
There is currently an additional patent pending on this project: Timothy Yeatman, MD, FACS; Determining the mitotic capacity of tumor samples from gene expression data; status - PCT Application pending.
Page updated 9/16/09