Full Text CA-94-021 CLONING AND SEQUENCING THE BRCA1 GENE NIH GUIDE, Volume 23, Number 14, April 8, 1994 RFA: CA-94-021 P.T. Keywords: National Cancer Institute Application Receipt Date: June 14, 1994 PURPOSE The Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute (NCI) invites research project grant applications to clone and sequence the BRCA1 gene. Although the region of DNA that contains BRCA1 has been identified by physical and genetic mapping, the gene or genes of interest have not been cloned and sequenced. The aim of this Request for Applications (RFA) is to foster and stimulate collaborations among investigators who can expedite the process of cloning and sequencing the BRCA1 gene. Such collaborations may involve scientists from academia and industry. It is expected that the achievement of this goal will lead to new research opportunities for prevention, screening, early detection, and treatment of breast and ovarian cancer, and perhaps other malignancies. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Cloning and Sequencing the BRCA1 Gene, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign nonprofit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Applications can be from single or several institutions (collaborating institutions, consortia). Foreign institutions may also participate in Laboratory or Clinical Programs through subcontract or consortium arrangements. Applications from minority and women investigators are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) as its funding mechanism. Applicants will be responsible for the planning, direction and execution of the proposed projects. The total proposed project period for each application submitted in response to this RFA may not exceed two years. Recognizing the complexity of this initiative, it is appropriate to include multiple specific aims within a single research project application. The total proposed direct costs for the first year may not exceed $1,400,000. This does not include indirect costs on a subcontract that appears as a direct cost by the applicant organization. The anticipated award date is August 15, 1994. The award and level of support depends on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, the award of grants pursuant to this RFA is contingent upon the continuing availability of funds for this purpose. This RFA is a one-time solicitation. At this time, the NCI has not determined whether or how this solicitation will be continued. FUNDS AVAILABLE Approximately $2,000,000 in total costs per year will be committed to specifically fund applications submitted in response to this RFA. It is anticipated that one or more awards will be made. RESEARCH OBJECTIVES Background Despite important progress in the early diagnosis and treatment of breast cancer, mortality and morbidity due to this disease remain high. A detailed picture of the specific genetic changes and somatic mutation underlying the development of breast cancer is emerging, primarily from molecular genetic analysis of tumors. An important genetic component is indicated by demonstration of linkage in several families with high frequencies of early-onset breast cancer and ovarian cancer to a genetic marker, BRCA1, at chromosome 17q21. Mutational change at the BRCA1 locus may be a critical step in the pathway ultimately leading to breast cancer in at least some patients because there is an increased incidence of breast cancer in individuals who inherit mutations at that locus. The same reasoning applies to ovarian cancer. Isolation or identification of a gene or genes at chromosome 17q21 could, therefore, be an outcome of profound importance to understanding the etiology of certain cancers in women, with clear ramifications in prevention, diagnosis, and treatment. Objective and Scope In those families with very high frequencies of breast cancer (and ovarian cancer), the epidemiologic pattern is compatible with the transmission of a dominant allele of a gene that predisposes women to breast cancer. Characterization of DNA from familial breast cancers indicates that allelic loss occurs at the locus called BRCA1 on chromosome 17q21, consistent with the interpretation that this locus contains the functional equivalent of a tumor suppressor gene, the loss of which may lead to the development and maintenance of a neoplastic state. The goals of mapping the regions of 17q21 likely to contain the BRCA1 gene and the reconciliation of the large-scale genetic and physical maps have to a great extent been achieved. There may now be several ways to find and isolate the BRCA1 gene. For example, one unexplored method would be to determine the complete sequence of the 400-500 kilobase genomic region thought to contain BRCA1, using DNA from persons thought to inherit wild-type or mutant genes, and DNA from breast tumors. The secondary benefit from this approach would be the first sequencing of a large segment of the human genome containing many uncharacterized genes to allow comparison with the recently determined genomes of yeast and C. elegans. This approach could be in conjunction with the process of isolating, screening, and sequencing candidate cDNA clones that might be synthesized from RNAs transcribed from the BRCA1 locus. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in the earlier publication, and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for this RFA. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267; and from the NCI program staff listed under INQUIRIES. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA number and title must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute Executive Plaza North, Room 636 6130 Executive Boulevard Rockville, MD 20852 Applications must be received by June 14, 1994. If an application is received after that date, it will be returned. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the DRG for completeness and for responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NCI staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications may be triaged by an NCI peer review group on the basis of relative competitiveness. The NCI will withdraw from further competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated, using the review criteria stated below, for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be provided by the National Cancer Advisory Board. The review group will assess the scientific merit of the studies according to the following criteria: 1. Scientific, technical, or medical significance and originality of proposed research; 2. Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; 3. Qualifications and research experience of the Principal Investigator, staff, and collaborators, particularly in the areas of DNA sequencing and cloning; 4. Likelihood that the proposed research plan will achieve its stated goals within the available project period and budget; 5. Availability of the resources, such as relevant clones and appropriate mapping and sequencing power, necessary to perform the research; 6. Appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA Applications considered by the National Cancer Advisory Board will be considered for award based upon (a) scientific and technical merit; (b) availability of funds; and (c) programmatic priorities. Applications considered for award must include a significant DNA sequencing element. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are strongly encouraged. Direct inquiries regarding programmatic issues to: Dr. Cheryl Marks Division of Cancer Biology, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 505 Bethesda, MD 20892 Telephone: (301) 496-7028 FAX: (301) 402-1037 Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800 Ext. 266 FAX: (301) 496-8601 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.396, Cancer Biology Research. Awards are made under the authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, 42 U.S.C. 241, as amended; Public Law 100-607, 42 U.S.C. 285 and 285a) and administered under HHS grants policies. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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