DNA Repair, p53 and Apoptosis Phenotypes in Lung Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00339859
First received: June 19, 2006
Last updated: March 14, 2014
Last verified: November 2013
  Purpose

The Laboratory of Human Carcinogenesis and the Pharmocogenetics Section of the Genetic Epidemiology Branch will conduct a lung cancer case-control study in Baltimore, Maryland. The primary hypothesis of the study is to determine if mutagen sensitivity, p53 induction and apoptosis in cultured lymphocytes will be predictive of lung cancer risk. While there are some studies that examine mutagen sensitivity, none of these assays has been well-studied in an epidemiological setting. Because of methodological issues described herein, and the proposed development of new assays, this study will be viewed as a pilot and therefore hypotheses generating. The design of this molecular epidemiology study has been specifically developed to test the reliability and validity of the mutagen sensitivity assay, where a case-control study is needed to assess the possibility of case bias (i.e., results vary due to the concurrent presence of lung cancer rather than risk). Importantly, this protocol will establish a resource that will allow for the validation of these assays and also for the study of other biomarkers and gene-environment interactions, especially those related to DNA repair. Th secondary goals of this study are to 1) demonstrate gene-neuro-behavioral interactions for smoking addiction in controls and 2) assess the relationship of sex-steroid metabolism an and estrogen exposure to lung cancer risk. Cases will have histologically confirmed lung cancer and reside in Baltimore an and surrounding areas. They will be identified through six hospitals in Baltimore. Cases will be recently diagnosed and blood will be collected prior to chemotherapy or radiation therapy. Because of this requirement to obtain samples before treatment (or for surgical cases at least two months after surgery), we recognize that case ascertainment will be reduced, but critical data to assess differences between eligible and ineligible subjects will be collected through tumor registries. Two control groups will be used, the first will be hospital-based (frequency matched by age, gender, race, smoking and hospital) and the second will be population-based (frequency matched by age-, gender and race). The first control group will allow us to examine risk factors for lung cancer independent of smoking (odds ration for smoking = 1.0), and the second will allow the results to be extrapolated to the general population and also will be used to validate the phenotyping assays. The strategy for recruitment will allow us to over-sample for women and African Americans, so that after examination of data for the entire study group, we can assess differences by these subgroups. Cases and controls will receive a structured, in person interview assessing prior medical and cancer history, tobacco use, alcohol use, current medications, occupational history, family medical history, menstrual history and estrogen use, recent nutritional supplements and caffeine intake, and socioeconomic status. The questionnaire also will include the Fagerstrom index for nicotine dependence (FTND), Center for Epidemiologic Studies Depression (CES-D) scale, and a modified version of the Horn-Waingrow Reasons for Smoking (RFS) Scale. The phenotypic markers to be studied will assess DNA repair with cellular response by using lymphocyte cultures exposed in vitro to radiation, bleomycin, benzo(a)pyrene-diol-expoxide and N-methyl-nitrosurea and then measuring induction of chromosomal aberrations, p53 induction and apoptosis. DNA from cases and controls also will be used for genetic polymorphism analysis of carcinogen metabolism, and those relating to the dopaminergic system and nicotinic receptors. Tumors from cases will be evaluated for estrogen and progesterone receptors. The target accrual number of total subjects will be 1,200 where there will be 100 cases for each combination of gender and race (Caucasian- and African Americans), matched to 100 each of the hospital-based and population-based controls.


Condition
Lung Cancer

Study Type: Observational
Official Title: DNA Repair, p53 and Apoptosis Phenotypes in Lung Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 5000
Study Start Date: June 1995
Detailed Description:

The Laboratory of Human Carcinogenesis is conducting an observational lung cancer case-control study in Baltimore, MD. This molecular epidemiology study has been specifically developed to test the reliability and validity of the mutagen sensitivity assay, where a case-control study is needed to assess the possibility of case bias (i.e., results vary due to the concurrent presence of lung cancer rather than risk). Importantly, this protocol establishes a resource that allows for the validation of these assays and also for the study of other biomarkers and gene-environment interactions. In 2010, IRB approval was received to include this study in a multi-institution genome-wide association study (GWAS) of lung cancer in African Americans. The target accrual number is 4000 total subjects, consisting of 360 cases of each gender in African Americans and 640 cases for each gender in Caucasians. An equal number of controls will be selected for each category of cases based on the combination of gender and race. Upon recruitment, cases and controls receive a structured, in person interview assessing prior medical and cancer history, tobacco use, alcohol use, current medications, occupational history, family medical history, menstrual history and estrogen use, recent nutritional supplements and caffeine intake, and socioeconomic status. Specimen collection consists of a one-time blood sample and/or mouthwash to collect cheek cells (oral cells) and a one-time urine sample. In addition, cancer and surrounding non-cancer tissue that was surgically removed and not needed for diagnosis may be obtained for cases, as well as current medical information from medical records. The phenotypic markers to be studied will assess proficiency of DNA repair by using lymphocyte cultures exposed in vitro to radiation, bleomycin, benzo(a)pyrene-diol-expoxide and then measuring induction of chromosomal aberrations, p53 induction and apoptosis. DNA from buffy coats or cheek cells will be used for analysis of genetic polymorphism in the form of Single Nucleotide Polymorphisms (SNPs) in genes involved in DNA repair, innate immunity, cell cycle control, angiogenesis, apoptosis, cytokines, nicotine addiction, inflammation, hormone metabolism and microRNA. Tumors from cases will be evaluated for estrogen and progesterone receptors. Urine, plasma and serum samples will be analyzed using an untargeted metabolomics approach.

PRIMARY OBJECTIVES:

  • To determine if mutagen sensitivity, p53 induction, and apoptosis in cultured lymphocytes are predictive of lung cancer risk.
  • To investigate and develop phenotypic or predictive markers of lung cancer risk and survival, based on mutagen sensitivity, polymorphic markers, gene expression, and metabolomics.
  • To determine the relationship between sex-steroid metabolism, estrogen exposure, and lung cancer risk.

ELIGIBILITY:

  • Meets one of the following criteria:
  • Histologically confirmed non-small cell lung cancer (case), diagnosed within the past 6 months.
  • Frequency matched to cases according to age (5-year intervals), gender, and race (population-based control).
  • Resides in the state of Maryland.
  • Subject Characteristics:
  • Speaks English well enough to be interviewed
  • Born in the United States
  • Physically and mentally capable of performing the interview (i.e., must be able to hear the interviewer, mentally comprehend the interviewers questions, and verbally respond)
  • Has never been interviewed as a control for this study
  • Does not currently reside in an institution such as a prison, nursing home, or shelter
  • No history of cancer other than nonmelanoma skin cancer or carcinoma in situ of the cervix (population-based control)
  • Has a residential working phone within the home (population-based control)
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Case Subject Selection:

Diagnosis of non-small cell lung cancer made pathologically (with confirmation by a second pathologist).

Must reside in Maryland.

Have a residential working phone within their home.

Be born in the United States.

Speak English well enough to be interviewed.

Be physically and mentally capable of performing the interview (i.e., must be able to hear the interviewer, mentally comprehend the interviewers questions and verbally respond).

Never have been interviewed as a control for the study.

Consent by the physician from the clinic where the subject was identified, or listed as the treating physician by the tumor registry or surgical pathology report.

Hospital-Based Control Selection:

Stratified to frequency match cases by age (5 year intervals), gender, race, smoking (20 pack year intervals -- non-smokers, 0-20, 20-40, 40-60 and greater than 60 and ex-smokers [greater than 5 yrs]) and hospital.

Must reside in Maryland

Have a residential working phone within their home.

Be born in the United States.

Speak English well enough to be interviewed.

Be physically and mentally capable of performing the interview (i.e., must be able to hear the interviewer, mentally comprehend the interviewers questions and verbally respond).

Never have been interviewed as a control for the study.

Physician consent by physician from clinic with subject is identified.

Selection of Population-Based Controls:

Stratified to match cases by age (5 year intervals), gender, and race.

Must reside in Maryland

Have a residential working phone within their home.

Be born in the United States.

Speak English well enough to be interviewed.

Be physically and mentally capable of performing the interview (i.e., must be able to hear the interviewer, mentally comprehend the interviewers' questions and verbally respond).

Never been interviewed as a control for the study.

EXCLUSION CRITERIA:

Case Subject Selection:

More than 6 months after initial diagnosis.

Currently residing in an institution such as prison, nursing home or shelter.

Severely ill in an intensive care unit (after discharge from ICU, then can be reconsidered).

Subjects is unable to give informed consent.

Hospital-Based Control Selection:

History of cancer other than non-melanotic skin cancer or in situ cervical cancer.

Currently residing in an institution such as a prison, nursing home or shelter.

Severely ill in an intensive care unit (after discharge from ICU, the can be reconsidered).

Subject is unable to give informed consent.

Selection of Population-Based Controls:

History of cancer other than non-melanotic skin cancer or in situ cervical cancer.

Currently residing in an institution such as a prison, nursing home or shelter.

Subjects unable to give informed consent.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00339859

Contacts
Contact: Curtis C Harris, M.D. (301) 496-2048

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
University of Maryland, Baltimore Recruiting
Baltimore, Maryland, United States, 21201-1595
Sinai Hospital of Baltimore Recruiting
Baltimore, Maryland, United States, 21215-5271
Sponsors and Collaborators
Investigators
Principal Investigator: Ana I Robles, Ph.D. National Cancer Institute (NCI)
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00339859     History of Changes
Obsolete Identifiers: NCT00559325
Other Study ID Numbers: 999998027, OH98-C-N027
Study First Received: June 19, 2006
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Genetic Risk Factors
Molecular Epidemiology
Carcinogenesis Metabolism
Gender
Race
Lung Cancer

Additional relevant MeSH terms:
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on July 23, 2014