Full Text PA-96-008


NIH GUIDE, Volume 24, Number 41, December 1, 1995

PA NUMBER:  PA-96-008

P.T. 34

  Pulmonary Diseases 

National Cancer Institute
National Institute of Environmental Health Sciences


The Division of Cancer Epidemiology and Genetics of the National
Cancer Institute (NCI) invites grant applications for innovative
interdisciplinary studies to better understand the etiology of
adenocarcinoma and small cell carcinoma of the lung and the means of


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), Epidemiology of Lung Cancer: Interdisciplinary
Studies, 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.
017-001000473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).


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, eligible agencies of the Federal government, and small
businesses.  Racial/ethnic minority individuals, women and persons
with disabilities are encouraged to apply as Principal Investigators.


Support of this program will be through individual research project
grants (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the



Lung cancer is now a leading cause of cancer death in industrialized
countries and is rising in many developing countries.  Thun et al.
(1), who examined changes in smoking-specific death rates from the
1960s to the 1980s in the U.S. reported that lung cancer surpassed
coronary heart disease as the largest single contributor to
smoking-attributable death among White middle-class smokers.  In
1930, the age-adjusted lung cancer death rate among U.S. males was
about 5/100,000 per year; it rose to 55.9 in 1970 and to 74.9 in
1987.  Among females in the U.S., the corresponding lung cancer death
rates were 3.0, 12.2 and 28.5, respectively (2).  In 1994, lung
cancer accounted for an estimated 172,000 incident cases (100,000
males and 72,000 females) and 153,000 deaths (94,000 males and 59,000
females) (3).

Cigarette smoking is the leading cause of lung cancer.   While
smoking cessation programs are critical to reduce the burden of lung
cancer in our society, additional research is also warranted to
clarify the reasons for changes in the distribution of the major
histologic types during the last 40 years and gender and racial
differences in risk.  Our lack of understanding of the reasons for
these patterns reflects the inadequacy of our knowledge of lung
carcinogenesis at the histology-specific level. This level of
understanding will also impact clearly on our ability to prevent the

Several investigators have reported on time trends.  Vincent (4)
found adenocarcinoma and squamous cell carcinoma to be the more
common histologic types among lung cancer patients presenting to the
thoracic surgery department of Roswell Park Memorial Institute
between 1962 and 1975.  Adenocarcinoma increased progressively from
17.6 percent of the total cases in 1962 to 29.8 percent by 1975,
while squamous cell carcinoma represented 48.6 percent of the total
cases in 1962 but decreased to 25.5 percent in 1975.

Devesa et al. (5), reporting on changing patterns of lung cancer by
histologic type for the period 1969-1986 for five geographic areas
(Atlanta, Connecticut, Detroit, Iowa and San Francisco- Oakland)
covering seven percent of the U.S. population, indicated that for all
sex-race groups combined, age-adjusted incidence of lung cancer
increased three percent per year from 38.6/100,000 person-years
during 1969-71 to 58.4/100,000 person-years during 1984-86.  The rate
rose 25 percent among white men, about 50 percent among black men,
and over 150 percent among both black and white women.  Squamous cell
carcinoma rates increased 50 percent or less among men and more than
doubled among women.  Adenocarcinoma and small cell carcinoma rates
doubled among men and more than tripled among women.  As a result,
the histologic distribution of lung cancer changed over time.
Squamous cell carcinoma remains the most common type among men.
Among women, however, adenocarcinoma is the most frequent type; the
rates of small cell carcinoma exceeds slightly those of squamous cell
carcinoma among white women only.

Recently, Travis et al (6) reported analyses of Surveillance,
Epidemiology, and End Results (SEER) Program data on lung cancer for
the period 1973-1987.  The percentage of lung cancers that were
adenocarcinoma in all race-sex groups combined increased to 32
percent, surpassing squamous cell carcinoma as the most frequently
occurring histologic type.  Squamous cell carcinoma, however,
continues to constitute a large proportion (29 percent) of lung

The race, gender and time patterns of adenocarcinoma and small cell
carcinoma cannot be readily explained.  It has been suggested that
advances in techniques for establishing the diagnosis of lung cancer
should be considered in interpreting temporal trends of incidence by
histologic type.  Changing patterns of classification by pathologists
may also have influenced the reported increase in frequency of
adenocarcinoma. Cigarette smoking is a stronger risk factor for
squamous cell carcinoma and small cell carcinoma than for
adenocarcinoma of the lung (5).  Smoking intensity, duration, types
of cigarette smoked, cessation, or different degree of susceptibility
to carcinogens present in tobacco smoke may differentially affect the
development of the various histologic types of lung tumors. Newer
cigarettes containing lower amounts of tar, as determined by the
Federal Trade Commission method, may be more harmful than older
brands.  Women may be at a higher elevated risk of lung cancer than
men due to greater exposure to newer brands and/or to gender-related
susceptibility (7,8).  The greater lung cancer risk in blacks
compared to that in whites may be due to racial differences in
carcinogen metabolism or for reasons similar to those responsible for
gender differences.

Occupational determinants of lung adenocarcinoma have not been well
investigated.  Few studies have examined the differences in
occupational risks for histologic types of lung cancer, but
associations between occupations and specific histologic types have
been suggested.  Adenocarcinoma of the lung was elevated among
carpenters, and cabinet and furniture makers (9). Occupational
exposure to bischloromethyl ether (10) and radon (11) preferentially
influence  small cell carcinoma.  With regard to diet, positive
associations have been seen with lipid consumption, fat and
cholesterol, and inverse associations with various carotenoids,
vitamin C, and retinol, and with fruits and vegetables as a group
(12).  Immunologic and hormonal factors have been suggested to affect
risk of adenocarcinoma (13,14), and familial patterns have been
observed (15).

Findings from a multicenter case-control study of lung cancer in
nonsmoking women indicated an overall 30 percent increased risk
associated with exposure to environmental tobacco smoke from a
spouse, with a 50 percent elevated risk of lung adenocarcinoma (16).
Other adult life exposures in household, occupational and social
settings were each associated with a 40 to 60 percent increased risk
of lung adenocarcinoma (16).  Approximately half of all lung cancers
among current nonsmokers could be attributed to a history of smoking,
dietary intake of saturated fat, nonmalignant lung disease,
environmental tobacco smoke, occupational exposures including
asbestos, a family history of lung cancer and domestic radon (17).
Thus half of the lung cancer incidence among nonsmokers remains

Research Scope and Goals

The reasons for the increases in adenocarcinoma and small cell
carcinoma of the lung in the U.S. remain to be fully explained.
Changing diagnostic trends should be considered as one possible
reason, and examined through standardized review of a sample series
of cases that are representative of those occurring since the 1950s.
There is a paucity of understanding of the environmental and host
factors and the mechanisms of induction for specific types of lung
cancer.  In particular, further research is needed to elucidate the
etiologic factors that influence the upwards time trends in lung
adenocarcinoma and small cell carcinoma.

The areas of research listed below are not intended to be all-
inclusive, but are designed to give the applicant some direction for
the types of research that the NCI is interested in stimulating to
enhance knowledge about the etiology of lung adenocarcinoma and small
cell carcinoma and means for their prevention.

1. Epidemiologic studies of lung adenocarcinoma and/or small cell
carcinoma in smokers, with detailed collection of tobacco use data,
assessment of risk modifiers, and evaluation of susceptibility
factors; pooled analysis of existing data sets for lung
adenocarcinoma and small cell carcinoma; studies of non- tobacco
environmental/occupational exposures and lung adenocarcinoma and
small cell carcinoma risk.

2. Studies of host susceptibility factors in relation to lung cancer
type, such as P450 expression/polymorphisms, glutathione
S-transferase enzymes, hormonal factors, and diet.

3. Studies of the molecular mechanisms of lung adenocarcinoma and/or
small cell carcinoma in laboratory animals and humans to assess the
role of novel oncogenes or tumor suppressor genes; investigation of
carcinogen metabolic activation and detoxification in human pulmonary
cells; development of biomarkers of chemicals in tobacco products, in
the general environment or in occupational settings that induce lung
adenocarcinoma, and small cell carcinoma, including DNA adducts.
Consideration should also be given to DNA adduct repair in human
pulmonary cells.


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH- sponsored
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 and 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 on 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 under INQUIRIES.  Program
staff may also provide additional relevant information concerning the


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 Office of Grants Information, Division of Research
Grants, National Institutes of Health, 6701 Rockledge Drive, Room
3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301-710-0267.

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

BETHESDA, MD 20892-7710
BETHESDA, MD, 20817 (for courier/overnight service)


Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with the standard NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and 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

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

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The Initial review group will also examine the provisions for the
protection of human subjects and animal welfare and the safety of the
research environment.


Applications will compete for available funds with all other approved
applications assigned to the NCI.  The following will be considered
in making funding decisions: quality of the proposed project as
determined by peer review, availability of funds, and program


Inquiries are encouraged, particularly during the planning phase of
the grant applications.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. A.R. Patel
Division of Cancer Epidemiology and Genetics
National Cancer Institute
6130 Executive Boulevard, Suite 535, MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279

Dr. Gwen W. Collman
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O, Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4980
FAX:  (919) 541-2843
Email:  collman@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. E. C. Melvin
Grants Administration Branch
National Cancer Institute
Executive Plaza South
6120 Executive Boulevard, Suite 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, EXT 258
FAX:  (301) 496-860

David L. Mineo
Grants Management Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  MELVINE@gab.nci.nih.gov


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 78-140, as
amended by Public Law 99.158, 42 USC 241 and 285) and administered
under HHS policies and grant regulations.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health System Agency review.

The Public Health Service (PHS) strongly encourages all grant
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.


1.Thun, M.J., Day-Lally, C.A., Calle, E.E., et al. Excess mortality
among cigarette smokers: changes in a 20-year interval. Am. J Public
Health, 85: 1223-1230, 1995.

2. Wynder, E.L. and Hoffmann, D. Smoking and lung cancer: scientific
challenges and opportunities. Cancer Res., 54: 5284- 5295, 1994.

3. Boring, C.C., Squires, T.S., Tong, T., et al. Cancer statistics,
1994. Ca. Cancer J. Clin., 44: 7-26, 1994.

4. Vincent, R. G., Pickren, J.W., Lane, W.W. et al. The changing
histopathology of lung cancer: a review of 1682 cases. Cancer, 39:
1647-1655, 1977.

5. Devesa, S. S., Shaw, G.L., and Blot, W.J. Changing patterns of
lung cancer by histologic type. Cancer Epidemiol., Biomarkers Prev.,
1: 29-34, 1991.

6. Travis, W.D., Travis, L.B., and Devesa, S.S. Lung cancer. Cancer,
75: 191-202, 1995.

7. Risch, H.A., Howe, G.R., Jain, M., et al. Are female smokers at
higher risk of lung cancer than male smokers? A case-control analysis
by histologic type. Am. J. Epidemiol., 138: 281-293, 1993.

8. Harris, R.E., Zang, E.A., Anderson, J.I., et al. Race and sex
differences in lung cancer risk associated with cigarette smoking.
Int. J. Epidemiol., 22: 592-599, 1993.

9. Zahm, S.H., Brownson, R.C., Chang, J.C., et al. Study of lung
cancer histologic types, occupation and smoking in Missouri. Am. J.
Ind. Med., 15: 565-578, 1989.

10. Pasternack, B.S., Shore, R.E., and Albert, R.E.  Occupational
exposure to chloromethyl ethers.  J. Occup. Med., 19: 741-746, 1977.

11.  Samet, J.M.  Radon and lung cancer.  J. Natl. Cancer Inst., 81:
745-757, 1989.

12.  Patel, A.R. and Obrams, G.I. Meeting Report: Adenocarcinoma of
the lung. Cancer Epidemiol., Biomarkers Prev., 4: 175-180, 1995.

13.  Fraumeni, J.F. Jr., Wertelecki, W., Blattner, W.A., et al.
Varied manifestations of a familial lymphoproliferative disorder. Am.
J. Med., 59: 145-151, 1975.

14. Gao, Y.T., Blot, W.J., Zheng, W., et al. Lung cancer among
Chinese women. Int. J. Cancer, 40: 604-609, 1987.

15. Mulvihill, J.J. Host factors in human lung tumors: an example of
ecogenetics in oncology. J. Natl. Cancer Inst., 57: 3-7, 1976.

16. Fontham, E. T. H., Correa, P., Wu-Williams, A., et al. Lung
cancer in nonsmoking women: a multicenter case-control study. Cancer
Epidemiol., Biomarkers Prev., 1: 35-43, 1991.

17.  Alavanja, M.C.R., Brownson, R.C., Benichou, J., et al.
Attributable risk of lung cancer in lifetime nonsmokers and long-term
exsmokers.  Cancer Causes and Control, 6: 209-216, 1995.


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