||5R03CA091217-02 Interpret this number
||Fox Chase Cancer Center
||Lung Cancer Free Survival Among Aged Smokers
DESCRIPTION (provided by Applicant)
We are proposing the collection of pilot data for planning a more definitive
epidemiological investigation of genetic protective factors in the families of
individuals aged 70 years and older, with more than 20 pack-years of smoking
who have not been diagnosed with lung cancer, the extremely exposed extremely
resistant aged survivors (ERAS). Balmain and Nagase (1998) developed a model
of differential resistance to cancer based on studies in mice and posited
application to humans. This proposed study represents a novel genetic
epidemiologic approach to test their model in the human setting. We will
sample 100 probands from an existing registry of 216,022 elderly
Pennsylvanians >= 70 years, on a prescription plan, 7-10 percent (15,581) of
whom are current smokers (Pharmaceutical Assistance Contract for the Elderly
(PACE) Program, 1999).
We will test the feasibility of enrolling family members to participate in
this study. We will document the type and structure of the families, and
address the issues of familial aggregation of a lung-cancer resistant
phenotype. With the ERAS probands, we will ascertain a sample enriched for
'protected' persons. We will provide descriptive statistics of ERAS in the
PACE population, and in our sample.
We will genotype the Myeloperoxidase (MPO) enzyme in probands and first-degree
relatives. MPO transforms precarcinogens in tobacco smoke. Individuals who
inherit two copies of the low activity allele (-463A) are reported to be at a
reduced risk of lung cancer. Combined segregation and linkage analyses,
together with generalized estimating equations, will be used to explore the
mode of inheritance of hypothesized protective factors and characterize the
association between the ERAS phenotype, the MPO genotype and selected
demographic, medical and family history variables.
Pilot data are sought to provide: a) an indication of a putative protective
gene exhibiting Mendelian inheritance, b) an opportunity to model genetic
resistance incorporating MPO genotypic data, and c) information needed for the
efficient design of a subsequent study to examine "gene x gene" and "gene x
environment" interactions. Evidence for genetic protection is sought
primarily to increase understanding of the biology of lung cancer. The
proposal does not imply that those with the putative resistant marker can
smoke safely, an unwarranted conclusion given the other deleterious effects of
cigarette smoking. Understanding mechanisms of resistance could suggest new
The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer.
, Ivan M.
, Hawkins S.M.
Gynecologic oncology, 2017 11; 147(2), p. 481-487.