GENETIC REGULATION OF SUSCEPTIBILITY TO TOBACCO-RELATED CARCINOGENESIS

Release Date:  July 29, 1998

PA NUMBER:  PA-98-095

P.T.

National Cancer Institute
National Institute of Environmental Health Sciences

PURPOSE

The Chemical and Physical Carcinogenesis and Genetics Branches, Division of
Cancer Biology (DCB), and Division of Cancer Control and Population Sciences
(DCCPS), National Cancer Institute (NCI), and the National Institute of
Environmental Health Sciences (NIEHS) invite investigator-initiated grant
applications for multidisciplinary research on Genetic Regulation of
Susceptibility to Tobacco-Related Carcinogenesis.

It is believed that 90 percent of all lung cancers are related to smoking.
Exposure to second-hand smoke increases the risk for non-smokers as well. Other
risk cofactors include alcohol, diet, prior medical treatment, exposure to
industrial substances, such as asbestos, and exposure to radiation from
occupational and environmental sources.  Exposure to radon may also increase
risk, especially among cigarette smokers, where a several-fold synergism has been
reported.  Tobacco usage has also been linked to other cancers such as those of
the pancreas, the urinary tract, the cervix, the oral cavity, the esophagus, the
head and neck, and perhaps the breast.

The goal of this initiative is to stimulate the investigation, at the basic
experimental level, of the mechanism of differential genetic susceptibility to
tobacco-related carcinogenesis in the context of lung cancer and other tobacco-
related cancers.  The classes of carcinogenic compounds of interest found in
tobacco and smoke include the aromatic amines, nitrosamines and polycyclic
aromatic hydrocarbons.  Appropriate studies include, but are not limited to, the
investigation of the possible genetic mechanisms underlying the observed familial
linkage of lung cancer susceptibility, identifying the basis of the observed
interaction of smoking and hormone status, the interaction of dietary, medicinal
and environmental cofactors and the polymorphism of enzymes involved in the
activation, deactivation and repair of DNA damage resulting from tobacco-derived
carcinogens and their metabolites.  Interdisciplinary collaborations between
geneticists, molecular biologists, environmental health scientists and others
with tobacco chemical carcinogenesis knowledge are especially encouraged.  The
use of animal models, cell cultures, and human tissue specimens are encouraged,
but studies on addiction, population screening and behavior are outside the scope
of this PA.

New knowledge about genetic polymorphisms in tobacco-metabolizing enzymes now
present an opportunity for better understanding the molecular basis for
differential susceptibility to tobacco-related cancers.  This PA is intended to
indicate to the scientific and peer-review communities the increased NCI and
NIEHS interest in supporting research in this area.

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 Program Announcement (PA), Genetic
Regulation of Susceptibility to Tobacco-Related Carcinogenesis, 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 202-512-1800).

ELIGIBILITY REQUIREMENTS

Research grant 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.  Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be through individual or interactive research
project grants (R01), competing supplemental awards to currently active research
project grants (R01), and the exploratory/developmental (R21) grant mechanism. 
The R21 grant mechanism is utilized for pilot projects or feasibility studies to
support creative, novel, high risk/high payoff research that may produce
innovative advances in science.  The exploratory grant program provides limited
funds (maximum of $100,000 direct costs per year not including facilities and
administrative costs of any collaborating institutions) for short-term (up to two
years) research projects.  Awards will be administered under PHS grants policy
as stated in the PHS Grants Policy Statement.

RESEARCH OBJECTIVES

The purpose of this program is to provide support for investigators to pursue
promising avenues of research addressing all areas of basic, clinical and applied
research relevant to genetic susceptibility to tobacco-related carcinogenesis,
including etiology, biomarkers, and metabolic polymorphism relating to lung and
other cancers.

Background

In 1998, an estimated 180,100 Americans will die from lung cancer and 171,500 new
cases will be diagnosed.  Although the incidence of this disease has declined in
men, it continues to increase in women.  Since 1987, lung cancer has been the
major cause of cancer death in women, surpassing the death rate for breast
cancer, which since the 1940's had been the leading cause of cancer death in
women.  In both men and women, cancers of the oral cavity and head and neck are
also on the rise, primarily due to the markedly increased use of smokeless
tobacco.

Within the class of aerodigestive tract cancers, alcohol and smoking are
certainly the major contributors.  Only a fraction of exposed individuals,
however, develop cancer suggesting that host specific (primarily genetic and
environmental) factors are involved.  There are also marked differences observed
in different cultural and ethnic groups.  These differences are attributed to
genetically influenced alterations in the absorption, distribution, activation
and detoxification of tobacco carcinogens, their interaction with DNA and
proteins, the recognition and repair of genetic damage, and the degree of prior
genetic damage to the individual.

A marked familial association between the prevalence of smoking and other
tobacco-use and cancer occurrence suggests a strong genetic influence. This may
imply an enhanced cancer susceptibility or actual predisposition in some
population groups.  Some of the genetic susceptibility is due to the existence
of polymorphism among the enzymes involved in the activation (phase 1) and
deactivation (phase 2) of the tobacco carcinogens, including aromatic amines,
nitrosamines and polycyclic aromatic hydrocarbons.  Nearly every enzyme in the
carcinogen metabolism pathways exists in multiple forms.  The polymorphic enzymes
vary in binding affinity, turnover efficiency or their very presence or absence
in an individual.  Among animals, there is also an observed difference between
species for some of these genes which partially explains species specificity in
carcinogen-induced tumor response.  The efficient recognition of DNA damage and
subsequent DNA repair may also be under similar genetic influence.  Indeed, alkyl
guanine transferase (three polymorphic forms) removes large bulky adducts from
DNA.  Preexisting inherited mutations in tumor suppressor genes or mutational
hypersensitivity may also be major factors in determining whether an individual
or family group has an unusually high susceptibility to tobacco-related cancers.

Several genetically controlled polymorphic enzymes and enzyme systems have been
recognized which are linked to tobacco carcinogen activation and deactivation. 
Their interaction and control as well as their contribution to cancer
susceptibility and tumor development are not well understood.  Many of these
enzymes involved in tobacco carcinogen metabolism are also induced by
environmental factors such as alcohol usage, dietary constituents, pesticide and
xenobiotic exposure, hormonal status and occupation.  Induction of activation
(P450s) stimulates carcinogenesis, while induction of detoxification enzymes
(epoxide hydrolase, glutathione transferase, N-acetyl transferase,
sulfotransferase, UDPG transferase) decreases tumorigenic response.  Polymorphism
in genes that code for the synthesis of metabolizing enzymes may result in lower
affinity or differential specificity.  Polymorphism in DNA repair genes and the
influence of fragile sites or mutational hot spots in the genome may also be
involved.  Some of these genes have been identified and characterized but others
remain to be discovered.  The interaction of these genes with each other and the
effect of environmental factors are as yet an enigma.

The incidence and types of lung tumors observed as well as tumor location have
changed over the years.  Centrally located squamous cell carcinomas used to be
the primary tumors observed among smokers.  Peripheral adenocarcinoma and other
non-small-cell lung cancers predominate today. There are also marked intergroup
differences in the lung cancer incidence among African Americans, Asians,
Caucasians, and Hispanics and between males and females.  Besides the known
genetic polymorphism in populations, these differences are believed to be also
related to the types of cigarettes available (filtered versus unfiltered, high
versus low tar), smoking habits, smoking behavior and tobacco usage (smoking and
smokeless tobacco, cigarettes versus cigars, the way cigarettes are smoked, the
degree and depth of inhalation, mentholated versus regular), the nature of the
tobacco (high and low nicotine, high and low nitrosamine levels in specific types
of products), and most importantly genetic, environmental and life style
differences among individuals and populations.  The importance of environmental
(second hand) tobacco smoke is also a current topic of debate, however, there is
very little research being done at the basic experimental level.

NIH supports a range of research on tobacco-related diseases including
experimental tobacco carcinogenesis, alcohol and tobacco co-carcinogenesis,
animal mechanistic studies using tobacco related carcinogens as model compounds,
chemoprevention of lung and other tobacco related cancers, tobacco usage and
smoking behavior, tobacco usage among youth, smoking cessation and intervention,
nicotine addiction, etc.  This PA addresses the basic carcinogenesis, co-
carcinogenesis and chemoprevention issues as regulated by the genetics of
susceptibility.  It includes basic laboratory research as well as population and
epidemiological studies.  Studies may include both current and former users of
all tobacco products. Understanding the genetic basis of tobacco-related cancers
may also help lead to more effective cancer prevention interventions.  Inclusion
of the development of biomarkers and measurement techniques for tobacco and
qualitative and quantitative tobacco smoke exposure, where appropriate, are
permissible.  Studies on susceptibility to carcinogenesis and potential
chemoprevention of the effects of second hand smoke and smokeless tobacco are
also encouraged.

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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

Basic research in which human tissues cannot be identified or linked to
individuals are excluded from the policy on women and minorities.  However, every
effort should be made to include human tissues from women and racial/ethnic
minorities when it is important to apply the results of the study broadly, and
this should be addressed by applicants.

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are clear and compelling scientific and ethical reasons not to
include them.  This policy applies to all initial (Type 1) applications submitted
for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  Application 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 301/710-0267, E-mail:
[email protected].  Application kits are also available on the web at: 
http://www.nih.gov/grants/funding/phs398/forms_toc.html.

The title and number of the program announcement must be typed in Section 2 on
the face page of the application.

For competing supplements to grants, the specific instructions in the PHS 398
application kit must be followed.

The completed original application and five legible copies must be sent or
delivered 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be reviewed for scientific and technical merit by
study sections of the Center for Scientific Review, NIH in accordance with the
standard NIH peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and may undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national advisory
council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that the
application does not need to be strong in all categories to be judged likely to
have a major scientific impact and thus deserve a high priority score.  For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced? What
will be the effect of these studies on the concepts or methods that drive this
field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements? Is there evidence of institutional support?

The initial review group will also examine the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  Awards will be made primarily on the basis of scientific merit,
overall program balance, and the availability of resources.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope of this PA,
or inquiries about whether or not specific proposed research would be responsive,
are encouraged and may be directed to:

Dr. Harold E. Seifried
Division of Cancer Biology
National Cancer Institute
6006 Executive Boulevard, Room 220
Bethesda, MD  20892
Telephone:  (301) 496-5471
FAX:  (301) 496-1040
Email:  [email protected]

Dr. Susan Nayfield
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 214
Rockville, MD  20892
Telephone:  (301) 594-7344
FAX:  (301) 402-4079
Email:  [email protected]

Dr. Jose Velazquez
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 541-4937
Email:  [email protected]

Written and telephone inquiries of a budgetary, administrative, and/or policy
nature may be directed to:

Ms. Marie Moyer
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 225
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 the
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 or 45
CFR Part 92.  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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