NIH GUIDE, Volume 21, Number 27, July 31, 1992


P.T. 34



  Biological Markers 


  Risk Factors/Analysis 

National Cancer Institute

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  October 22, 1992

Application Receipt Date:  November 19, 1992






The Extramural Programs Branch, Division of Cancer Etiology, National

Cancer Institute (NCI), and the Scientific Programs Branch, Division of

Extramural Research and Training, National Institute of Environmental

Health Sciences (NIEHS), invite investigator-initiated research grant

applications to further the effective use of biomarkers of exposure or

susceptibility in future epidemiologic studies of cancer etiology.


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,

Biotechnology Transfer to Epidemiologic Studies in 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

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 non-profit and

for-profit institutions, public and private, such as colleges,

universities, hospitals, research laboratories, units of State and

local governments, and eligible agencies of the Federal Government.

Applications from minority individuals and women are encouraged.


This program will be supported by traditional research project (R01)

grants and Interactive Research Project grants (IRPG).  Awards will be

administered under PHS grants policy as stated in the PHS Grants Policy

Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1,


The earliest anticipated date of award is July 1, 1993.

This RFA is a one-time solicitation.  The total project period for

applications submitted in response to the present RFA may not exceed

three years.  Responsibility for the planning, direction, and execution

of the proposed project will be solely that of the applicant.

Competitive continuation applications will compete with all other

unsolicited applications and be reviewed by standing Division of

Research Grants study sections.  If the NCI and NIEHS determine that

there is a sufficient continuing program need, a request for renewal

applications may be announced.


The estimated funds (total costs) available for the first year of

support for this initiative is $1.5 million.  The expected number of

awards is five to seven.  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 and the NIEHS, the award of grants pursuant to this RFA is also

contingent upon the availability of funds for this purpose.


Successful grant awardees under this RFA are strongly encouraged to

participate in an annual program meeting of one or two days' duration

in Bethesda, Maryland, during the first and third years and in Research

Triangle Park, North Carolina during the second year.  Program

directors from the NCI and the NIEHS will coordinate the meeting that

will review and assess overall progress and provide the opportunity for

investigators to exchange information and discuss methodological

issues.  The respondents must request sufficient funds within the

budget to accommodate expenses for one to two participants at these

meetings.  The application should include a statement indicating a

willingness to comply with this requirement.



A large proportion of human cancers are thought to be attributable to

environmental factors, some of which may interact with host

susceptibility states.  The problem of identifying the effects of

specific risk factors and evaluating their relative importance is a

challenging one.  Multiple exposures to a variety of agents over

extended periods are the rule rather than the exception, and many

populations are exposed to low levels of carcinogens.  A wide range of

susceptibility mechanisms may be involved in processes of

carcinogenesis, and the long latency period of many cancers may make

cause-effect relationships elusive.

Traditional methods in epidemiology have estimated exposure to

carcinogens on the basis of surrogate measures.  These have included,

for instance, questionnaire data on lifestyle factors such as diet and

smoking, record of job titles or past employment in a particular

industry, or interview information on use of medications.  Discovery of

the association between smoking and lung cancer is a classical example,

demonstrating the merit of these techniques.  In etiological studies,

the addition of measured parameters in the form of biological markers

(biomarkers) can strengthen epidemiologic findings, especially where

there may be a weak causal effect, differences in exposure level,

complex mixtures of agents, or interactions of risk factors.

Appropriate biomarkers can reduce misclassification of exposures,

increase accuracy, and enhance study power to resolve exposure-cancer


Exciting opportunities have emerged from the recent revolution in

molecular biology and genetics.  Laboratory advances offer

unprecedented capabilities to measure carcinogenic factors at the

cellular or molecular level and to detect their interaction with

cellular constituents.  A variety of biomarkers (e.g., biochemical,

molecular, genetic, immunologic) show significant promise of improving

exposure assessments (e.g., hemoglobin or DNA adducts), identifying

inherited and acquired host susceptibility (e.g., p53 gene mutations),

and detecting cellular and subcellular events representing predisposing

disease states, intermediate outcomes, and early stages of cancer

(e.g., sister chromatid exchanges).  To date, most of the evidence

about biomarkers has been derived from experimental systems, with only

limited testing in human subjects in well-controlled field studies.

Pilot studies in small populations of humans have demonstrated the

utility of certain biomarkers:  cellular assays indicating

pathobiological responses to carcinogens (e.g., cytogenetic changes)

and techniques that assess inherited or acquired host susceptibility

factors (e.g., metabolic polymorphic phenotyping).  However, a wide

range of interindividual variability and methodological issues remain

to be resolved before these procedures can be applied to large-scale

epidemiologic investigations.


The goal of this initiative is to stimulate investigations designed to

validate and apply biomarkers of exposure or susceptibility in

epidemiologic research in cancer etiology.  For biomarkers demonstrated

to have utility, assessment of the extent of intra- and

inter-individual variability is important.  Validation procedures

should consider determinations of range of normal values, as well as

sensitivity, specificity, and predictive value.  The influence of

biological variables such as age, sex, race, ethnicity, nutritional

status, preexisting disease, and lifestyle should be appropriately


Inter-institutional collaborations between laboratory scientists from

several disciplines and epidemiologists are encouraged to promote

integrated planning of study protocols and experimental methods as well

as the conduct of research.  Extension of an ongoing epidemiologic

study by the addition of a laboratory component can be proposed.

Laboratory investigations will be acceptable if human subjects or

specimens are being tested.  Whenever possible, research design should

utilize shared laboratory and specimen resources.  Ease of study

conduct and expense, as well as collection, storage, and transport

problems should be considered.  Projects will be evaluated on their

potential for enhancing the understanding of cancer etiology and

strategies for prevention.  We particularly encourage studies with

relevance to breast, ovarian, prostate, and cervical cancers.

The initiative permits a range of investigations in molecular

epidemiology relevant to cancer etiology, including, but not limited


o  Demonstration of the feasibility of developed biomarkers for

epidemiologic research (e.g., heterocyclic amine food mutagens,

benzene-DNA adducts, thymine glycol, mutation of the hypoxanthine

guanine phosphoribosyl transferase (HGPRT) gene);

o  Validation of biomarkers in exposed and unexposed population

subgroups (e.g., ethnic and minority populations, family units,

occupational cohorts, patients taking chemotherapeutic agents or other

medicinal compounds);

o  Determination of levels of agreement of mutually confirmatory

methods of analyses for measuring the same biomarker (e.g., DNA adducts

by physico-chemical, immunoassay, and postlabelling methods) with

consideration of inter-and intra-laboratory variability;

o  Comparison of biomarkers or combinations of biomarkers in different

sources of specimens such as human cells, tissues, organs, and body


o  Determination of specific sampling conditions (e.g., timing,

seasonality, repetitive or serial testing) in a chronobiologic fashion

including host/environmental factors with/without interactions (e.g.,

dietary, viral, hormonal) that may influence validity, reliability, and


o  Establishment of background or reference levels in normal or

unexposed populations (e.g., cytochrome P450 isoenzymes,

glucuronyltransferase, covalent RNA or protein adducts,

arylamine-macromolecular adducts).




For projects involving clinical research, NIH requires applicants to

give special attention to the inclusion of women and minorities in

study populations.  If women or minorities are not included in the

study populations for clinical studies, a specific justification for

this exclusion must be provided.  Applications without such

documentation will not be accepted for review.


Prospective applicants are requested to submit, by October 22, 1992, a

letter of intent that includes a descriptive title of the proposed

research, the name and address of the Principal Investigator, the names

of other key personnel, the participating institutions, and the number

and title of the RFA in response to which the application is being


Although a letter of intent is not required, is not binding, and does

not enter into the review of subsequent applications, the information

that it contains is helpful in planning for the review of applications.

It allows NCI and NIEHS staff to estimate the potential review

workload.  The letter of intent is to be sent to Dr. Kumiko Iwamoto at

the address under INQUIRIES.


Applications are to be submitted on form PHS 398 (rev. 9/91), available

at most institutional business offices and from the Office of Grants

inquiries, Division of Research Grants, National Institutes of Health,

Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892,

telephone 301/496-7441.  The format and instructions applicable to

research grant applications must be followed.  Applications must be

received by November 19, 1992.


Each application submitted in response to the RFA will be given dual

institute assignment to the NCI and the NIEHS.  The primary assignment

will be determined later by mutual agreement of the Program Directors

from the supporting programs.  Applications judged to be competitive

will be reviewed by an appropriate review panel of the Division of

Extramural Activities, NCI.  Second level review will be by the

National Cancer Advisory Board or the National Advisory Environmental

Health Sciences Council.  All applications will be reviewed in

competition with each other.

The factors that will be considered in evaluating grant applications

that are responsive to this RFA will include:  scientific, technical,

or medical significance and originality of proposed research;

appropriateness and adequacy of the experimental approach and

methodology proposed to carry out the research; qualifications and

research experience of the Principal Investigator and staff,

particularly but not exclusively in the area of the proposed research;

availability of resources necessary to perform the research; and

appropriateness of the proposed budget and duration in relation to the

proposed research.


Written and telephone inquiries concerning the RFA and the opportunity

to clarify any issues or questions from potential applicants are


Direct inquiries regarding programmatic issues and requests for the RFA


Dr. Kumiko Iwamoto

Extramural Programs Branch

Epidemiology and Biostatistics Program

Division of Cancer Etiology

National Cancer Institute

Executive Plaza North, Suite 535

Rockville, MD  20892

Telephone:  (301) 496-9600


Dr. William A. Suk

Scientific Programs Branch

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

Research Triangle Park, NC  27709

Telephone:  (919) 541-0797

Direct inquiries regarding fiscal matters to:

Ms. Jean M. Cahill

Supervisory Grants Management Specialist

National Cancer Institute

6120 Executive Boulevard

Executive Plaza South, Suite 216

Rockville, MD  20892

Telephone:  (301) 496-7800, ext. 47


Mr. David L. Mineo

Grants Management Officer

Grants Management Branch

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

P.O. Box 12233

Research Triangle Park, NC  27709

Telephone:  (919) 541-1373


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 the Public Health Service Act, Section 301(c)

and Section 402 (Public Law 78-410, as amended; 42 USC 241; 42 USC 282)

and administered under PHS grant policies and Federal Regulations 42

CFR Part 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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