A RESOURCE OF ARRAYED BAC CLONES FOR FISH MAPPING OF THE HUMAN
GENOME

Release Date:  January 16, 1998

RFA:  CA-98-005

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 27, 1998

PURPOSE

This Request for Applications (RFA) is to solicit applications to
generate a resource that will facilitate the identification of
chromosome aberrations in cancer and to provide reference points
for the development of a "cancer chromosome aberrations" database.

The Tumor Genetics Program, Cancer Genetics Branch, Division of
Cancer Biology (DCB), National Cancer Institute (NCI) invites
applications for research projects to generate a resource of mapped
human large-insert Bacterial Artificial Chromosomes (BAC) clones
that can be used for fluorescence in situ hybridization (FISH)
mapping studies, with a resolution of approximately 1 megabasepair, 
which is equivalent to 3,000-5,000 BAC clones for the whole human
genome.

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, A Resource of Arrayed BAC Clones for Fish Mapping
of the Human Genome, is related to several priority areas. 
Potential applicants may obtain a copy of "Healthy People 2000"
(Full Report:  Stock No. 017-001-00474-0 or Summary Report: Stock
No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications  may be submitted by domestic and foreign for-profit
and nonprofit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State and
Local governments, and eligible agencies of the Federal government.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this
program will be a Resource Related Support cooperative agreement
(U24), an "assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NCI scientific and/or programmatic
involvement with the awardee is anticipated during performance of
the activity.  Under the cooperative agreement, the NCI purpose is
to support and/or stimulate the activity of recipient(s), to
generate a publicly available high quality resource, by involvement
in and otherwise working jointly with the award recipient(s) in a
partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity. NCI staff will
also be involved with the coordination of different groups, should
there be more than one award recipient (e.g., with each PI focused
on specific chromosomes).

Details of the responsibilities, relationships and governance of
the study to be funded under cooperative agreement(s) are discussed
later in this document under the section "Terms and Conditions of
Award."

The total project period for an application submitted in response
to this RFA may not exceed two years.  The anticipated award date
is no later than September 30, 1998.  This RFA is a one-time
solicitation.

Because the nature and scope of projects proposed in response to
this RFA may vary, it is anticipated that the sizes of awards will
vary also.  The number of awards and level of support depend on
receipt of a sufficient number of applications of high scientific
merit.

FUNDS AVAILABLE

Approximately $500,000 in total costs will be available for this
initiative in Fiscal Year 1998, and $500,000 in total cost for the
remaining year. It is anticipated that one to three awards will be
made.  If more than one award is made, the NCI Program Director
will work with all awardees to avoid overlap and to ensure that the
maximum number of reliable mapped clones will be generated. 
Proposed funding levels are subject to change due to budgetary,
administrative and/or scientific considerations, and are dependent
upon the 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 issuance of awards pursuant to this
RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

One major goal in cancer genetics is to identify every gene that is
involved in cancer development. The concept that proto-oncogenes or
tumor suppressor genes are involved in the various forms of
microscopically discernible aberrant chromosomes has been fully
supported by the numerous molecular studies that have defined many
such tumor-specific changes.  The investigation of balanced
chromosomal rearrangements in different tumor types, primarily
leukemias but also solid tumors, in particular malignant
mesenchymal neoplasms, has led to the identification of many genes
that are involved in cancer development.  There is growing
appreciation of the clinical usefulness of the identification of a
recurring chromosome abnormality, by cytogenetic or molecular
means, in the diagnosis, subclassification and prognosis of a
neoplastic disorder, and, hence, in the selection of the
appropriate treatment.

Cytogenetic studies over the past few decades have revealed clonal
chromosomal aberrations in almost 27,000 human neoplasms,
representing 75 different types of neoplasms (Mitelman et al.,
Nature Genetics, 1997 Supplement).  Furthermore, chromosome
breakpoints in 25,547 cases analyzed showed that virtually all
chromosomal bands are involved, and, presumably, are important in
recurrent tumor-associated abnormalities.  Thus the origin of human
cancer is due to the activity of a remarkably large spectrum of
different genes, all of which can contribute to malignancy.
Resolution intervals of cytogenetic analyses are usually in the
range of 5-10 megabases, with significant variations among
different laboratories.

The idea for a resource of mapped human large-insert Bacterial
Artificial Chromosome (BAC) clones across the whole human genome,
stems from a DCB-sponsored workshop on Cancer Chromosome
Aberrations (Bethesda, March 4-5, 1997).  The availability of
mapped human BAC clones across the whole genome at approximately 1
megabase intervals for FISH analysis will allow the mapping of all
chromosome aberrations into 1 megabase "bins."

Generation of a resource of mapped human BAC clones will allow the
integration of physical and cytogenetic maps, providing the ability
to extrapolate from clinical data on chromosome aberrations, as
established by classical cytogenetic analyses or comparative genome
hybridization (CGH), and to obtain candidate BAC clone sets for
gene isolation.  Currently, some individual laboratories are
conducting the mapping of large-insert clones, including BAC and P1
artificial chromosome (PAC) clones, to specific cytogenetic regions
of interest.  Progress in the Human Genome Project is providing
ordered  large-insert clones for all chromosomes.  However, only a
handful of chromosomes (e.g., 1,6,7,20,22 and X) are currently
associated with anything approaching a mapped large-insert clone
every 1 megabase.  Very few of the currently mapped BAC/PAC clones
are derived from the human large-insert clone library that was
constructed with DNA from donors with appropriate informed consent
according to the 1996-National Human Genome Research Institute
(NHGRI)-Department of Energy (DOE) Guidance (see below). 
Furthermore, large-insert clones for the remaining chromosomes will
have to be selected from the libraries.

The purpose of the development of a high density large-insert clone
map and a centralized mapped large-insert clone resource is to
eliminate the need for individual laboratories to map from scratch
regions of interest with overlapping large-insert clones, thereby
reducing duplication of effort on some chromosome regions. It  will
also ensure that appropriate probes will be available for the whole
genome.  Furthermore, once the large-insert clones are arrayed by
chromosome map order, they may be used to define more precisely the
boundaries of cytogenetic abnormalities in clinical samples.  With
the explosion of information now available on chromosome
aberrations, it will be necessary to establish a database for that
information.  The mapped large-insert clones can be used to provide
the reference points for the development of such a cancer
chromosome aberrations database.  It is imperative that the results
of this project and the arrayed clones be made available to the
research community.  Strong emphasis will be placed on developing
means of sharing data and biological reagents with investigators
who need to identify particular genes or to conduct gene transfer
experiments to verify the function of those genes.

NCI plans to establish an Advisory Committee on "Cancer Chromosome
Aberrations."  The Committee will be comprised of the NCI Program
staff responsible for this RFA, NCBI scientists responsible for the
setting up of a public database on "Cancer Chromosome Aberrations,"
and NIH intramural and extramural experts on cancer chromosome
aberrations.  It is envisioned that the mapped large insert-clones
generated under this RFA will be useful in providing the reference
points for the development of such a database.

Objectives and Scope

The main objective of this RFA is to solicit applications for
projects that will use state-of-the-art methods to generate a high
quality resource of mapped human large-insert clones that can be
used for FISH mapping studies and to do so rapidly, efficiently,
and at low cost.  BAC clones will be the preferred resource.  PAC
clones may also be included in the arrayed resource.  However,
mapping funded under this RFA should exclusively be BAC clones
selected from libraries constructed with DNA from donors with
appropriate informed consents according to the 1996-NHGRI-DOE
Guidance.  The clones selected should have immediate utility as
FISH mapping reagents.  Beyond this immediate utility, this
resource ultimately can be used in Comparative Genome Hybridization
(CGH) arrays or as the starting point of contig assembly around
regions with chromosome aberrations.

The availability of mapped Sequence Tag Sites (STSs) across the
human genome ordered by Yeast Artificial Chromosomes (YACs) and
human radiation hybrid (RH) mapping makes it possible to derive BAC
clones every 1 megabase.  An example of approach is to generate the
arrayed BAC resource across the whole genome by hybridization of
mapped STSs with known cytogenetic band location.  These in turn
could be verified, analyzed for size and rearrayed by chromosome
map order in microtiter dishes.  The human large-insert clone
resources generated by this RFA will serve as anchors on a physical
human large-insert clone map, and it is essential the mapped clones
should have no restrictions in terms of their availability for
sequencing.  Any newly-mapped clones generated under this RFA MUST
be derived from large-insert clone libraries that are constructed
with DNA from donors with appropriate informed consent.  The
confidentiality and anonymity of donors must be ensured to the
extent possible (recognizing that, because each individual's DNA
sequence is unique, anonymity cannot ultimately be guaranteed). 
These issues have been addressed in a "Guidance for the Use of DNA
in Large-Scale Sequencing" that was jointly issued by the NHGRI and
the DOE Human Genome Program in August 1996 (Guidance available
upon request from NCI Program Director).  Currently, one human
large-insert BAC library constructed according to the NHGRI-DOE
Guidance is publicly available.  It is anticipated that additional
libraries will be available in the near future.

Applicants should discuss in their applications the rationale for
their approach.  They must also describe plans to accommodate
requirements and criteria stated in this RFA. State-of-the-art
approaches other than the whole genome approach described above may
be proposed.  However, this RFA is focused on the generation of a
high quality mapped BAC clone resource and is not designed to
support technology development.  Some laboratories may already have
BAC/PAC clones mapped to large regions of a chromosome and will
only need MINIMAL funding to identify "landmark" clones at 1
megabase intervals and generate a high quality arrayed resource. 
The BAC/PAC clones for such a resource should still have the
appropriate informed consents in terms of their availability for
sequencing.

SPECIAL REQUIREMENTS

Data and Resource Dissemination

The sharing of materials and data in a timely manner has been an
essential element in the rapid progress that has been made in
genome research.  Public Health Service (PHS) policy requires that
investigators make the results and accomplishments of funded
activities publicly available.  The advisors to the NIH and the DOE
genome programs have encouraged more rapid sharing, and this has
become the norm in the genome community.  NCI encourages applicants
who respond to this RFA to develop and propose specific plans for
sharing data and materials generated through the cooperative
agreement.  Dissemination of mapping data from individual
laboratory web sites is not sufficient.  It is anticipated that
data obtained, upon verification that the clones are true
positives, should be placed in a public database.  For example, the
National Center for Biotechnology Information, National Library of
Medicine (NCBI, NLM) has already in place a database that links the
BAC/PAC physical map with the cytogenetic map and will be willing
to include in that database the mapping information generated under
this RFA.  Applicants need to describe plans for dissemination of
their mapping data, and the compatibility of their database with
other public databases.

Where appropriate, awardees may work with the private sector in
making the mapped clones available to the larger biomedical
research community at a reasonable cost.  The plans proposed for
sharing and data release will be reviewed for adequacy by reviewers
as well as NCI staff prior to award of the cooperative agreement
and will be considered as a criterion for award.  Funds to defray
the costs of submitting data and distribution of reagents may be
included in the application.  Such requests must be adequately
justified.

The following terms and conditions will be incorporated into the
award statements(s).

Terms and Conditions of Award

A.  Applicability

These special Terms of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Parts 74 and 92, and other
HHS, PHS, and NIH Grant Administration policy statements.  Part 92
applies when state and local governments are eligible to apply as
a "domestic organization."

The administrative and funding instrument used for this program is
a Resource Related Support Cooperative Agreement (U24), an
"assistance" mechanism (rather than an "acquisition" mechanism) in
which substantial NCI scientific and/or programmatic involvement
with the awardee is anticipated during performance of the activity. 
Under the cooperative agreement, the NCI purpose is to support
and/or stimulate the recipient's activity by involvement in and
otherwise working jointly with the award recipient in a partner
role, but it is not to assume direction, prime responsibility, or
a dominant role in the activity.  Consistent with this concept, the
dominant role and prime responsibility for the activity resides
with the awardee(s) for the project as a whole, although specific
tasks and activities in carrying out the studies will be shared
between the awardees and the NCI Program Director.

B.  Awardee Rights and Responsibilities

1)  Awardees will have primary and lead responsibilities for  the
project as a whole, including research design and the actual
performance of the experiments, final data analysis, interpretation
and submission to a public database, preparation of publications,
as well as collaboration with other awardees, with assistance from
the NCI Program Director.  The Principal Investigator(s) is
expected to make any necessary adjustments in the overall research
strategies to accommodate the changing environment resulting from
improved technologies during the course of the project period.

2) If there is more than one awardee, a Steering Committee will be
formed, consisting of the NCI Program Director and individual
Principal Investigators.  Through the Steering Committee, awardees
will meet, at the beginning of the Award period and after the first
year of research, with the Program Director and other Principal
Investigators funded under this RFA in the Washington D.C. area to
plan the details of the project and to  report progress. Ongoing
collaboration between multiple awardees and NIH staff is described
in item 5 below.

3)  Awardees will retain custody of and have primary rights to the
data and reagents developed under these awards, subject to
Government rights of access consistent with current HHS, PHS, and
NIH policies.

4) Multiple awardees are expected to collaborate on common research
designs to avoid duplications of efforts in specific chromosome
regions.

C.   NIH Staff Responsibilities

1) The NCI Program Director will have substantial scientific-
programmatic involvement during the conduct of this activity,
through technical assistance, advice and coordination above and
beyond normal program stewardship for grants, as described below.

2) The NCI Program Director will have substantial scientific-
programmatic involvement in ensuring the maximum number of mapped
clones will be generated across the genome.  However, applicants
are expected to include in the applications the proposed mapping
approach, strategies and the scope of mapping (e.g. whole genome or
specific chromosomes).  The dominant role and prime responsibility
for the activity resides with the awardee(s) for the project as a
whole,  although there should be frequent interactions between the
awardees and the NCI Program Director regarding the progress and
focus of the project.

3)  NCI intends to foster extramural-intramural partnership in
research.  For example, intramural scientists who are experts in
fluorescence in situ hybridization (FISH) mapping techniques may
participate in the generation of the mapped large-insert clone
resource by the cytogenetic verification of mapped clones generated
under this RFA.  The NCBI scientists may participate by the
incorporation of the mapping data of the large-insert clones in the
public database established by the NCBI.  The NCI Program Director
will facilitate such partnership.

4)  The NCI reserves the right to terminate or curtail the study
(or an individual award) in the event of inadequate progress, data
reporting, or willingness to release materials at reasonable costs.

D.  Collaborative Responsibilities

1)  During the course of the award period, the awardee(s) may be
invited to meet with the NCI Program Director, other Principal
Investigators and/or other uninvolved experts in Bethesda, MD, to
review scientific progress.

2)  Applicants are expected to be willing to redirect efforts to
ensure that the maximum number of  reliable human large-insert
clones may be mapped across the whole genome.

E.   Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the
NCI may be brought to arbitration.  An arbitration panel will be
composed of three members -- one selected by the Steering Committee
(with the NCI member not voting) or by the individual awardee in
the event of an individual disagreement, a second member selected
by NCI, and the third member selected by the two prior selected
members.  This special arbitration procedure in no way affects the
awardee's right to appeal an adverse action that is otherwise
appealable in accordance with the PHS regulations at 42 CFR Part 
50, Subpart D and HHS regulation at 45 CFR Part 16.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 19, 1998,
a letter of intent that includes a descriptive title of the
proposed research, name, address, and telephone number of the
Principal Investigator, identities of other key personnel and
participating institutions, and number and title of the RFA in
response to which the application may be submitted.

Although a letter of intent is not required, is not binding, and
does not enter into the review of subsequent applications, the
information allows NCI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

Grace L. Shen, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 501
Bethesda, MD  20892-7381
Rockville, MD  20852 (express/courier service)
Telephone:  (301) 435-5226
FAX:  (301) 496-8656

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/95) is to be
used in applying for these projects.  Applications kits are
available at most institutional offices of sponsored research and
may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, Email: ASKNIH@od.nih.gov.

The RFA label available in the PHS 398 (rev.9/95) application form
must be affixed to the bottom of the face page of the application. 
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 title and number must be typed on
line 2 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 photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application
must also be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7399
Rockville, MD  20850 (for express/courier service)

Applications must be received by March 27, 1998.  If an application
is received after that date, it will be returned to the applicant
without review.  The Center for Scientific Review (CSR) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The CSR will not
accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an
application must follow the guidance in the PHS Form 398
application instructions for the preparation of revised
applications, including an introduction addressing the previous
critique.

Budget and Related Issues

Applicants are expected to provide a detailed breakdown of the
proposed budget to include categorical breakdown of such items as
personnel, supplies, consultants, etc.  Additional breakdown of
such items as set-up cost, cost per STS screening,  cost per
verified clone, etc. should also be provided.  Applicants should
include travel funds for the Principal Investigator and the other
key investigators on the grant to meet annually with the NCI
Program Director, other awardees and maybe the Advisory Committee
on "Cancer Chromosome Aberrations" in the Washington D.C. area.
Applicants are required to submit a statement about willingness to
participate in such activities.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific
merit of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  The
technical merit of the proposed approach for generating the large-
insert clone resource is extremely important, although it will not
be the sole criterion for evaluation of an application.  Other
considerations, such as feasibility and merit of the strategy, the
timeliness of the release of data and  plans for making the mapped
large-insert clones accessible, the source of large-insert clones
(BAC clones from "approved" libraries are preferred) will be part
of the evaluation criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by the
CSR and for responsiveness by the NCI.  Incomplete and/or non-
responsive applications will be returned to the applicant without
further consideration.  Applications may receive a preliminary
scientific review by an NCI peer review group to determine their
relative competitiveness. The NCI will withdraw from further
competition those applications judged to be noncompetitive for an
award and notify the applicant Principal Investigator and
institutional official.  Those applications that are complete and 
responsive, and judged to be competitive, will undergo further
scientific merit review in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NCI.  The second level of review will be
provided by the National Cancer Advisory Board (NCAB).

Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how best to meet the goals of the RFA and their specific
protocols, and are expected to address issues identified under
SPECIAL REQUIREMENTS of the RFA.

The review group will assess the scientific merit of the
application and related factors, including:

--scientific and technical merit of the proposed project;

--appropriateness and adequacy of the experimental approach and
methodology proposed to generate a high quality arrayed large-
insert clone resource;

--qualifications and experience of the Principal Investigator and
staff, particularly, but not exclusively, in the area of the
proposed research;

--availability of the resources/scientific environment necessary to
perform the research in a cost effective manner;

--appropriateness of methods and demonstrated willingness to work
as part of the cooperative production of resource and with the NCI
Program Director;

--plans to distribute forthcoming resources in a timely manner,
preferably with track-record of willingness to release data and
reagents;

--adequacy of the proposed protection for human subjects;

--appropriateness of the proposed budget and duration in relation
to the proposed research.

AWARD CRITERIA

Applications will be considered for award based upon (1) scientific
and technical merit; (2) program balance including, in this
instance, sufficient compatibility of features to make a successful
collaborative resource a reasonable likelihood and, (3)
availability of funds.

Schedule

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 27, 1998
Review by NCAB                  September 1998
Anticipated Award Date:         September 30, 1998

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged. 
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Grace L. Shen, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, 501
Rockville, MD  20892-7381
Rockville, MD  20852 (express/courier service)
Telephone:  (301) 435-5226
FAX:   (301) 496-8656
Email:  gs35r@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD  20892
Rockville, MD  20852 (express/courier service)
Telephone:  (301) 496-7800, ext. 250
FAX:  (301) 496-8601
Email:  WW14J@NIH.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.396.  Awards are made under authorization of the
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 grants policies and Federal Regulations 42 CFR Parts 52
and 45 CFR Part 74 [and Part 92 when applicable for State and Local
governments.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems
Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities ( or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.


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