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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