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) 435-0714; 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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