Full Text CA-93-020


NIH Guide, Volume 22, Number 15, April 16, 1993

RFA:  CA-93-020

P.T. 34

  Environmental Effects 
  Biomedical Research, Multidiscipl 

National Cancer Institute
National Center for Human Genome Research

Letter of Intent Receipt Date:  May 20, 1993
Application Receipt Date:  July 22, 1993


The Extramural Programs Branch, Division of Cancer Etiology, National
Cancer Institute (NCI) and the Ethical, Legal, and Social Implications
(ELSI) Branch of the National Center for Human Genome Research (NCHGR),
invite investigator-initiated Collaborative Research Project Grant
applications to encourage and facilitate collaborative and
interdisciplinary genetic epidemiology investigations designed to
evaluate the interaction of genetic and environmental factors in cancer

The special feature of this program is the concurrent submission of
research grant applications by investigators who wish to collaborate
within the common theme of genetic epidemiology of cancer, but do not
require extensive shared physical resources or core functions to
conduct their research.  In order to be responsive to this RFA, a
minimum of three investigators with related research objectives should
submit concurrent, collaborative, cross-referenced individual research
grant applications that address a common theme.


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 Request
for Applications (RFA), Interdisciplinary Collaborative Studies in the
Genetic Epidemiology of 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) 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).


Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, research laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications from minority institutions, individuals, and women are


The support mechanism for this program will be the individual research
grant (R01).  Multi-institutional collaborative arrangements are
encouraged and should be discussed with the program staff prior to the
submission of the applications.

The collaborative research grant program encourages the coordinated
submission of related research project grants (R01) from investigators
who wish to collaborate on their research efforts, but do not require
extensive shared physical resources.  These applications must share a
common theme and describe, in section 7 of each application, the
objectives and scientific importance of the interchange of ideas, data,
materials, etc. among the collaborating investigators.  A minimum of
three independent investigators with related research objectives are
encouraged to submit concurrent, collaborative, cross-referenced
individual R01 applications.  Applicants may be from one or several
institutions.  Applications will be reviewed independently for
scientific merit.  Applications judged to have significant and
substantial merit will be considered for funding both as independent
awards and in the context of the proposed R01 collaboration.
 Responsibility for the planning, direction, and execution of the
proposed projects will be solely that of the applicants.  The total
project period for applications submitted in response to the present
RFA must not exceed five years.  Since a variety of approaches would
represent valid responses to this announcement, a range of costs is
expected among individual grants awarded.  However, a collaborative
group must not exceed $800,000 total request costs (direct and
indirect) per year.

This RFA is a one time-solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer-review
procedures.  If the NCI determines that there is a sufficient
continuing program need, the NCI may announce a request for renewal


The estimated funds (total costs) available for the first year of the
support for the entire program is $2,250,000.  It is expected that two
to three collaborative group awards will be supported under this
program.  This funding level is dependent on 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
awards of grants pursuant to this RFA is also contingent upon the
availability of funds for this purpose.



Genetic epidemiology has classically been defined as the discipline
studying the role of genetic factors and their interaction with
environmental factors in the distribution and determinants of diseases
within human populations.  However, for many years, human geneticists
have mostly focused on the genetic components of disease with less
consideration of the effect of environment on phenotype.  On the other
hand, epidemiologists have primarily paid attention to the association
of environmental factors with illness, often being unable to account
for the role of genetic endowment.  Classical epidemiology studies to
identify specific environmental factors (such as diet, smoking,
exposure to radiation, etc.) mostly failed to collect data or specimens
that could be used to address genetic hypotheses of disease etiology.

This dichotomy has been true as well for the rapidly advancing field of
cancer research.  The pursuit of an integrated, cross-disciplinary
approach to the understanding of cancer etiology within the framework
of genetic epidemiology studies has been constantly hampered by an
insufficient integration of the underlying concepts and methods, by the
lack of a common scientific language, and by the shortage of
appropriate supporting technology and biostatistical methods.
Therefore, a workshop entitled "Genetic Epidemiology of Cancer: a
Multidisciplinary Approach" was convened by the National Cancer
Institute in May 1992, with the goals of developing scientific and
programmatic recommendations for cross-disciplinary studies and for
facilitating technological, methodological and conceptual transfer
within the framework of genetic epidemiology of cancer.

The participants emphasized that the field of molecular genetics has
enormous potential for application to epidemiologic studies, but it has
developed a vocabulary and methodology that may sound very foreign to
epidemiologists.  Conversely, laboratory scientists and clinical
oncologists are often unfamiliar with epidemiologic principles and
study designs.  Epidemiologists should consider collecting family
histories and extending pedigrees identified in cohort and case-control
studies, and storing blood and tissue specimens for present and future
use.  Geneticists should benefit from epidemiological expertise in
matters of proper sampling, data management, sources of population
information of special interest, selection of controls and proper
development of denominators.

During the last decade, revolutionary advances in molecular biology and
their applications to human genetics have provided new ways to analyze
the human genome and to look at the relationship between phenotype and
genotype.  The Human Genome Project effort, leading to continuous
improvement of the human genome map, has facilitated localization of
genes in restricted chromosomal areas.  Investigators in genetic
epidemiology can now incorporate developments in molecular genetics
into population studies, and greatly increase their insights into the
genetic and environmental determinants of cancer.  In addition,
traditional statistical methods used in genetics are yielding to new
methodologies developed to encompass both genetic and environmental
factors.  As genes are identified, mapped and cloned, the possibility
of describing the distribution of various genes in the general
population, as well as the ways in which environmental factors and
genes interact, becomes feasible.  This approach has been used
successfully in the study of cardiovascular and psychological
disorders, and is being explored for the study of cancer etiology.

Genetic determinants have been recognized to play a role in cancer
etiology through studies at the cell and population levels; at least 8
percent of the known or suspected Mendelian traits in humans have
neoplasia as a feature or a complication.  Several syndromes of
familial aggregation of cancer have been recognized, and others still
remain to be characterized.  On the other hand, epidemiologic studies
have demonstrated that a wide array of environmental factors (e.g.,
smoking, diet, environmental pollutants) substantially contribute to
cancer development.

Current theories of carcinogenesis hypothesize that most forms of
cancer result from the variable effects of environmental influences on
a broad range of genetic susceptibilities, in a multistage process that
can be delineated and modified at each step by environmental and host
factors.  Supportive evidence for this theory has been provided in
recent years by molecular, genetic and epidemiologic studies of
specific cancers, such as colon, breast and lung, in which
susceptibility genes and environmental factors are involved.  Because
of the complex nature of these diseases, it is important that genetic
epidemiology studies be performed by multidisciplinary research groups
capable to investigate both environmental and genetic determinants of
cancer in well-defined pedigrees and in case-control studies.  As the
genetic and environmental contributions to cancer become further
defined, there will be the potential to test individuals for genetic
factors to assess their cancer risks.  Studies regarding the benefits,
risks, and psychosocial impact of testing and counseling for genetic
contributions to cancer are needed to help elaborate professional
practice standards.

However, the road to this kind of cross-disciplinary research is not
without obstacles:  the ties among experts in the different fields of
epidemiologic, biologic, psychosocial and behavioral research that may
contribute to genetic epidemiology are still weak, and it is clear that
the elucidation of cancer etiologies will require a high level of
integration of concepts and analytical strategies developed within the
framework of these studies.  Workshop participants agreed that research
to advance knowledge into genetic and environmental risk factors for
cancer will be promoted if epidemiologists are encouraged to work
effectively with scientists from a variety of other disciplines.  The
objectives of this RFA focus on major recommendations of the NCI


The main goal of this initiative is to facilitate cross-disciplinary
technological, methodological and conceptual transfer in order to
advance research on the genetic epidemiology of cancer in families and

Interinstitutional collaborations between epidemiologists, laboratory
scientists, clinical oncologists and geneticists, epidemiologists,
biostatisticians, psychosocial and biobehavioral researchers and
experts in related disciplines working on the same cancer site/syndrome
are encouraged.

Although this research will ultimately lead to more targeted prevention
efforts and novel therapeutic designs, the latter are beyond the scope
of this RFA.  Studies of breast, ovarian, lung, prostate, and uterine
cancers are particularly encouraged.

Each component of collaborative proposals could include, but should not
be limited to:

o  Ascertainment of cancer-prone families from large, population-based
samples, and creation of extended multi-generational pedigrees with the
establishment of related epidemiological data bases and blood/tissue
specimen repositories.

o  Studies of inherited variation in genetic susceptibility to
environmental carcinogens and, conversely, studies to determine the
mode of inheritance of susceptibility to malignancies with known
environmental or endogenous risk factors.

o  Studies of loss of heterozygosity in tumors, to suggest candidate
regions for cancer-related genes and to define etiologic subgroups.

o  Development and validation of novel statistical models to evaluate
gene/environment interactions, genetic heterogeneity and alternative
modes of inheritance (e.g., gene imprinting) within existing cohort or
family datasets.

o  Feasibility and validation studies to test the applicability of
developing experimental laboratory techniques to genetic epidemiology

o  Studies to test innovative hypotheses on the molecular mechanisms
underlying the genetic components of cancer etiology using the
biological resources made available through family and case-control

o  Genetic epidemiology studies of precancerous lesions in familial
clusters, including the analysis of heritable and environmental factors
affecting the progression of the precursor state to malignancy.

o  Studies to evaluate the potential benefits, risks, and psychosocial
impact of testing and counseling for individuals at increased risk to
develop cancer and their families.


Applicants must state clearly, in section 7 of the application form PHS
398, how they plan to collaborate.  Applicants who already have ongoing
collaborations must indicate how their response to this RFA will
augment their current collaboration.  Applicants are encouraged to
establish collaborations that will enable them to use established
resources and facilities (e.g., cancer registries and/or designated
cancer centers) to facilitate the collection of patients and pedigrees
and to increase cost effectiveness.

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 Principal Investigator could be included with the

Successful grant awardees under this RFA are strongly encouraged to
participate in an annual program meeting of one or two days duration
which may be held in Bethesda, Maryland, or in other convenient
locations.  The program director from NCI will coordinate the meeting
to review and assess overall progress and provide the opportunity for
investigators to exchange information and discuss research issues.  The
respondents should request sufficient funds within the budget to
accommodate expenses for one participant per R01 to these two-day



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk for the disease, disorder or condition under study;
special emphasis must be placed on the need for the inclusion of
minorities and women in studies of diseases, disorders and conditions
that disproportionally affect them.  This policy is intended to apply
to males and females of all ages.  If women and minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale must be

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the research plan AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans, including American Indians or Alaskan Natives, Asian/Pacific
Islanders, Blacks, Hispanics).  The rationale for studies on single
minority population groups should be provided.

For the purpose of this policy, clinical research is defined as human,
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including, but not limited to, clinical

The usual policies concerning research on human subjects also apply.
Basic research or clinical studies in which human tissues cannot be
identified or linked to individuals are excluded.  However, every
effort should be made to include human tissue from women and
racial/ethnic minorities when it is important to apply the result of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on the inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
populations groups to the United States populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.


Prospective applicants are asked to submit, by May 20, 1993, a letter
of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Principal Investigator,
the identification of any other participant investigators and
institutions, and the 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 in the review of subsequent applications, the information
that it contains 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 Dr. Daniela Seminara at the
address listed under INQUIRIES.


Applications are to be submitted on form PHS 398 (rev. 9/91), available
at most institutional offices of sponsored research and from the Office
of Grants Inquiries, Division of Research Grants, National Institute of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

Submit a signed, typewritten original of the application, including the
Checklist and three signed, exact, clear and single-sided photocopies
in one package to:

Division of Research Grants
National Institute of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of the
application to:

Ms. Toby Friedberg, Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 650
6130 Executive Boulevard
Rockville, MD  20892

Applications must be received by July 22, 1993.  If an application is
received after that date, it will be returned.  If the application
submitted in response to this RFA is substantially similar to a
research grant application already submitted to the NIH for review, but
has not yet been reviewed, the applicant will be asked to withdraw
either the pending application or the new one.  Simultaneous submission
of identical applications will not be allowed, nor will essentially
identical applications be reviewed by different committees.  Therefore,
an application cannot be submitted in response to this RFA which is
essentially identical to one that has already been 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.

The RFA label available in the application form PHS 398 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 number and
title of the RFA must be typed on line 2a of the face page of the
application and YES must be checked.


Upon receipt, applications will be reviewed by the Division of Research
Grants (DRG) for completeness.  Incomplete applications will be
returned to the applicant without further consideration.  Evaluation
for responsiveness to the program requirements and criteria stated in
the RFA is an NCI program staff function.  Applications that are judged
non-responsive will be returned by the NCI, but may be submitted as
investigator-initiated collaborative research grants at the next
regular receipt date.  Questions concerning the responsiveness of
proposed research to the RFA should be directed to program staff.

If the number of applications is large compared to the number of awards
to be made, the NCI may conduct a preliminary scientific peer review to
eliminate those which are clearly not competitive.  The NCI will remove
from 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 according to 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 by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National
Cancer Program.

Applications should be responsive to the stated purpose and objectives
of the RFA.  Applicants are encouraged to submit and describe their own
ideas on how to best meet the goals of this announcement.  Applications
will be judged according to the criteria stated below:

o  the availability of and access to a suitable patient population;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  the experience of the investigators in the conduct of similar
epidemiologic or interdisciplinary research and their capability to
conduct the work proposed;

o  availability of resources necessary to perform the research;

o  willingness to work cooperatively with other awardees.

For each application that is scored, the review group will assign an
adjectival descriptor that reflects the extent and effectiveness of its
collaboration(s) with the other collaborative R01 applications.  This
assessment will be documented in a brief administrative note in the
summary statement to assist the NCI in making final decisions on each
application in the context of the overall cluster of collaborative

The review group will also examine the proposed budget and will
recommend an appropriate budget and period of support for each
meritorious application.


The earliest anticipated date of award is April 1, 1994.  Applications
will compete for available funds with all other meritorious
applications.  The following will be considered for making funding

o  quality of the proposed project as determined by peer review;
o  availability of funds;
o  program balance among research areas.


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

Direct inquiries regarding programmatic issues related to the overall
RFA and address the letter of intent to:

Dr. Daniela Seminara
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Suite 535
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-9600
FAX:  (301) 4O2-4279

Direct enquiries regarding programmatic issues on the ethical, legal
and social aspects of this RFA to:

Elizabeth J. Thomson, M.S., R.N.
Ethical, Legal and Social Implications Branch
National Center for Human Genome Research
Building 38A, Room 604
Bethesda MD  20892
Telephone:  (301) 402-0911
FAX:  (301) 402-1950

Direct inquiries regarding fiscal matters to:

Ms. Lauren Newmann
Grants Administrative Branch
National Cancer Institute
Executive Plaza South, Suite 216
6120 Executive Boulevard
Rockville, MD  20892
Telephone:  (301) 496-7800, ext. 47


This program is described in the Catalog of Federal Domestic Assistance
No. 93.393.  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 52 and 45 CFR part 74.  This
program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency Review.


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