Notice Number: NOT-CA-05-010
Release Date: January 25, 2005
NIH is seeking input from the community on a project with an ultimate goal of large-scale identification of somatic mutations in cancer through the comparison of sequences of multiple tumor samples to reference sequence from normal tissue from the same individuals. The hypothesis is that the identification of somatic mutations will accelerate the development and application of diagnostic and therapeutic approaches for the prevention, diagnosis, and treatment of cancer.
This Request for Information (RFI) is for analysis and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Government. The Government does not intend to award a cooperative agreement, contract, or grant on the basis of responses to this RFI or otherwise pay for the preparation of any information submitted or for the Government's use of such information.
Cancer, with some exceptions, is a complex genetic disease in which mutations cause its initiation and progression. Research has already identified a large number of the mutations implicated in tumorigenesis. In-depth studies of the genes and their pathways have led to an understanding of many of the details underlying tumor development. The successes of some newly introduced cancer drugs that act on known mutated proteins demonstrate that products of somatic genetic alterations are legitimate targets for therapy. Low resolution, genome-wide studies are cataloging additional changes, such as deletions, amplifications, and/or translocations. Directed studies of individual genes implicated in tumor biology are steadily increasing our awareness of the range and variety of mutations that may contribute to the etiology of cancer. These data indicate that only a modest fraction of the molecular targets involved in tumorigenesis have been identified and that cancer is a very heterogeneous disease with both genetics and environment playing important roles. The development of targeted interventions will require that we identify as many of these events as possible.
NCI's Cancer Genome Anatomy Project (CGAP) was established to develop databases populated by information generated on a large scale by the research community. Many groups were involved in generating the data that provided the first large-scale molecular taxonomy of cancer. To make the information easily accessible, and to enhance the data mining, new analytical tools were developed and made available. All components of the project were sequence-based to allow easier integration of the results. The data is uniform, easily accessible, and downloadable for analyses by all users through the web sites located at cgap.nci.nih.gov .
The recently obtained reference human genome sequence, and the ongoing development of advanced sequencing technologies provide a good starting point to consider large-scale, comprehensive sequencing of tumor samples and the corresponding constitutional tissue. A report of a meeting organized by NCI and the National Human Genome Research Institute (NHGRI) to examine these issues can be found at http://cgap.nci.nih.gov/Info/genomic_comparison.
A comprehensive identification of tumor molecular taxonomy is an ambitious endeavor. A project of this scope requires delineation of the complexities, especially technical and design challenges. Therefore, the NCI intends to initially conduct a pilot cancer genome sequencing project to inform decisions on optimal approaches and strategies in areas such as sequencing technologies, selection of tumor subtypes, and clinical translation to establish a basis for a large scale project. For example, what is the study design for the pilot program could best assess the feasibility of the project? How could such an effort be piloted? A feasibility or pilot study would be expected to determine whether this approach would result in detection of genomic changes that might be candidate regions or markers implicated in the initiation and progression of cancer. This request is to identify novel approaches, not to reexamine already existing concepts.
We ask that you send us your input for the design of the feasibility study by providing recommendations on the following:
1. Which three tumor subtype(s) should receive initial focus? How should they be prioritized (e.g., morbidity, mortality, prevalence, stage, tractability)? What are the important issues to be considered in sample collection? How many samples and how does molecular and tissue heterogeneity impact the selection?
2. How much sequence information would be desirable from each sample (e.g., whole genome shotgun or a directed region; coding regions or conserved regions)? If sequencing is to be done by directed methods, how the region would be chosen (e.g., by looking for regions of amplification, deletion, etc.) or how would the gene list be derived? What is the rationale and data for each approach and the cost/benefit ratio?
3. When should the normal control be sequenced? What would be the benefit vs. the cost? What is the most appropriate normal matching sample (e.g., lymphocytes, neighboring normal tissue)?
4. Which sequencing technologies would provide the most reliable data? What new technologies would be applicable and how mature are they? Please provide the strengths and weaknesses of the proposed technology. Will single cell sequencing be feasible, in what time frame and what will be the data quality?
5. What computational tools are needed to analyze the sequence data? How mature are they or what is the timeline for their development? For example, it will become critical to isolate mutations implicated in cancer from the large number of irrelevant mutations.
6. What complementary transcription and proteomic data should be collected in addition to the genomic sequence (e.g., SAGE or cDNA chip; modification, mass spectrometric analysis)? What are the new technologies being developed?
7. What legal and ethical issues will need to be resolved before the results can be posted on a public web site? How will it influence the data accessibility?
These complexities suggest that organization, strategic planning, and rigor in implementation will be critical to the success of this ambitious cancer genome sequencing pilot project.
The document should not be longer than 5 pages double-spaced; therefore, brevity and clarity is key. Respondents need not provide their thoughts on every question; rather prorate the length of the text accordingly. The response time is 4 weeks from the publication of this announcement; therefore the closing date is February 25, 2005. Please send your comments to us either via mail or e-mail to the address below:
Daniela S. Gerhard, Ph.D.
Office of Cancer Genomics
National Cancer Institute
31 Center Drive, Rm 31A07
Bethesda, MD 20892
Administrative Program Assistant
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
Office of Extramural
National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
Department of Health
and Human Services (HHS)
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