DNA DAMAGE, GENOMIC INSTABILITY AND BREAST CANCER NIH GUIDE, Volume 22, Number 26, July 15, 1994 PA NUMBER: PA-94-079 P.T. 34 Keywords: 0715036 Etiology Nucleic Acids Genetics National Cancer Institute PURPOSE The Division of Cancer Etiology of the National Cancer Institute (NCI) invites grant applications from interested investigators through a Program Announcement (PA) to establish whether or not there is greater genomic instability is associated with individuals in families with hereditary breast cancer than in individuals that do not have a family history of cancer. This initiative is in response to Congressional language that NCI emphasize studies on the etiology of female breast cancer as one of its top priorities. 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 PA, DNA Damage, Genomic Instability and Breast Cancer, 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; 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 for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Applications from minority and women investigators are encouraged. MECHANISM OF SUPPORT This PA will be supported through the National Institutes of Health (NIH) traditional research project grant (R01). The applicant will have the sole responsibility for planning, directing and executing the proposed research. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will vary also. RESEARCH OBJECTIVES Background The generally accepted mutation model of cancer requires a small number of select mutations, all in a single cell, for the development of cancer. An increase in mutation rate would significantly decrease the time of onset. Such a mutation rate increase could result from a mutation in any of the multiple genes that affect genomic stability. Because there are multiple sites on each gene for impairing or inactivating normal function, there is a high probability for the formation of genetically unstable clones or mosaics during normal human development (for a pertinent review see: K.C. Cheng and L.A. Loeb, Adv. Cancer Res. 60:121-156, 1993). The association of karyotypic abnormalities with cancer cells and with normal cells from individuals with various syndromes predisposing to cancer suggests that karyotypic instability as a phenotype can be transmitted through the germline and underlies a substantial fraction of the changes required for cancer expression. It is conservatively estimated that one hundred genes are involved in maintaining genomic fidelity. A functional decline in any one of them would be expected to increase the mutation rate. This suggests that genomic instability phenotypes other than karyotypic instability also may exist. The possibility that genomic instability, originating from the germline and/or somatically acquired, is a significant element in the initiation or progression of a cell to cancer is important to establish. This possibility would provide for additional segregation ratios, less than the dominant ratio of 0.5, which are frequently suggested by investigations of cancer families, and it would strongly suggest that hereditary cancer is associated with a significantly greater fraction of the overall incidence than is presently believed. Objectives The goal of this PA is to encourage research on human breast cancer using molecular, biochemical and cytogenetic techniques to determine whether or not a genomic instability in non-tumorigenic cells is associated with familial breast cancer family members both with and without cancer. Normal individuals with no family history of cancer could serve as controls. Suitable cells for this approach might include circulating lymphocytes, normal breast epithelial cells, normal fibroblasts or other appropriate cell types. The term "genomic instability" is taken broadly to mean a significant difference, presumably a decrease from an established normal base line, in any of various parameters expected to decrease the integrity of the cellular genome or its expression. Study of parameters toward this end could include, but need not be limited to: (1) Determination of the relative capacity of suitable cells from members of breast cancer families to repair DNA damaged by either radiation or chemical carcinogens. Analogous cells from individuals who do not have a family history of cancer would serve as normal controls. (2) Determination of the relative abilities of suitable cells from breast cancer family members to deactivate genotoxic chemicals compared with those from normal (as defined above) controls. (3) Determination of the relative capacity of suitable cells from breast cancer family members to repair chromosome or chromatid damage from radiation or chemicals compared to those from normal (as defined above) controls. (4) Comparison of the sensitivity of appropriate cells from breast cancer family members and those from normal (as defined above) controls to the initial damage of DNA by radiation or chemicals. (5) Comparison of the relative capacities of suitable cells from breast cancer family members and those from normal (as defined above) controls to maintain the primary sequence of DNA, i.e., replication fidelity, proof reading capacity, prevention of DNA damage and recombination fidelity. Because these investigations can involve several disciplines, both interdisciplinary studies and more focused investigations are appropriate. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principle investigator could be included with the application. 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 staff listed below. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications must be submitted on form PHS 398 (rev. 9/91), available at most institutional offices of sponsored research and may be obtained 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. The format and instructions applicable to regular research grant applications must be followed in preparing an application in response to this PA. The number and title of the PA must be typed on line 2a of the face page of the application and the YES box must be checked. A signed, typewritten original grant application, including the checklist, and five signed, exact photocopies, must be mailed, in one package, to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the Division of Research Grants for completeness. Incomplete applications will be returned to the applicant without further consideration. Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. AWARD CRITERIA Scientific merit, contribution to overall programmatic balance, and availability of funds will be major criteria for making award decisions. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Raymond Gantt, Ph.D. Division of Cancer Etiology National Cancer Institute Executive Plaza North, Suite 530 Bethesda, MD 20892 Telephone: (301) 496-9326 FAX: (301) 496-1224 Inquiries regarding fiscal matters may be directed to: Mr. Earl Bowman Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800 ext. 217 FAX: (301) 496-8601 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.393, Cancer Cause and Prevention Research. Awards are made under authorization of Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grant policies and Federal regulations 42 CFR 52 and 45 CFR Part 74. This program in not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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