DNA Repair, p53 and Apoptosis Phenotypes in Lung Cancer
| Status: | Recruiting |
|---|---|
| Conditions: | Lung Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 3/29/2019 |
| Start Date: | June 2, 1995 |
| Contact: | Curtis C Harris, M.D. |
| Email: | harrisc@mail.nih.gov |
| Phone: | (301) 496-2048 |
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.
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.
Background:
The Laboratory of Human Carcinogenesis is conducting an observational non-small cell lung
cancer (NSCLC) case-control study in Baltimore, MD. This molecular epidemiology study was
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. Importantly, this
protocol establishes a resource that allows for the study of additional biomarkers and
gene-environment interactions. Upon recruitment, cases and controls receive a structured, in
person interview assessing prior medical and cancer history, use of tobacco and electronic
cigarettes, 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. Primary cell cultures may be established from available fresh tumor tissue. The
phenotypic markers to be studied will assess proficiency of DNA repair in lymphocyte cultures
exposed in vitro to radiation, bleomycin, benzo(a)pyrene-diol-epoxide by measuring induction
of chromosomal aberrations, p53 and apoptosis. DNA from buffy coats or cheek cells will be
used for analysis of germline variation 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.
Additionally, IRB approval was received in 2010 to include this study in a multi-institution
genome-wide association study (GWAS) of lung cancer in African Americans. Tumors from cases
will be evaluated for estrogen and progesterone receptors, somatic mutations, and gene
expression. Urine, plasma, serum and tissue sample metabolomics will be analyzed by
untargeted approach.
Objectives:
1. To determine if mutagen sensitivity, p53 induction, and apoptosis in cultured
lymphocytes are predictive of lung cancer risk.
2. To determine the relationship between sex-steroid metabolism, estrogen exposure, and
lung cancer risk.
3. To investigate and develop phenotypic or predictive markers of lung cancer risk and
survival, based on mutagen sensitivity, polymorphic markers, gene expression, and
metabolomics.
4. To investigate racial disparities associated with lung cancer risk and survival.
5. To examine the relationship between circulating cytokines with risk and survival of lung
cancer and to establish the most robust method of cytokine detection.
6. To generate a more accurate measure of ancestry using ancestry informative marker
analysis and to integrate this variable into our studies of health disparities
7. To conduct studies of metabolomics on serum, plasma and urine for the purposes of
discovering novel markers of risk, diagnosis and prognosis. We will use ultraperformance
liquid chromatography coupled to mass spectrometry (UPLS-MS) to search for small
molecular weight endogenous metabolites that can classify cancer and predict outcome.
This is a novel approach for biomarker discovery that also leverages the non-invasive
process of biospecimen collection. Tumor and corresponding non tumor tissues from
corresponding patients will also be tested using the same methods to extend the
discovery of novel tumor metabolites. Further, metabolites of vitamin D will be examined
on serum samples from lung cancer cases and controls to assess the relationship between
circulating
levels of Vitamin D metabolites with cancer risk and survival. This analysis will be
coupled with testing of Vitamin D pathway SNPs in corresponding patients to determine if
certain SNPs are also associated with levels of vitamin D.
8. To evaluate biomarkers of cancer diagnosis and prognosis in circulating tumor DNA
9. To evaluate the microbiome (microbes) present in lung tissue using in situ hybridization
of fixed tissues to be completed at Mayo Clinic by collaborators. The collaborators will
receive no information on the samples other than their tissue of origin.
10. To collect data and biospecimens on patients that received low dose CT screening as part
of their lung cancer diagnosis. This is for the purposes of investigating non-invasive
biomarkers of lung cancer diagnosis and prognosis. Low-dose CT screening is now offered
at UMMS and the VA for the purposes of early lung cancer detection. These screening
guidelines are per CMS guidelines, i.e., age 55-77, >=30 pack-years of smoking and have
quit smoking for 15 years or less. Such high-risk patients will be offered annual
screening.
11. To culture lung cancer specific microbiome-bacteria from human lung cancers. This work
will, in part, be conducted with our collaborator Dr Paul Owrin, who is an expert in the
culture of microbial species from human tissues. These samples, approximately 10 per
year, will be de-identified of all patient information.
Eligibility:
- Histologically confirmed NSCLC diagnosed within the past 2 years (case).
- Frequency matched to cases according to age (5-year intervals), gender, and race
(population-based control).
- Born in the United States, resident of the state of Maryland
- Subject Characteristics:
- Speaks English well enough to be interviewed
- 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 non-melanoma skin cancer or carcinoma in situ of
the cervix (population-based control)
- Has a residential working phone within the home (population-based control)
Design:
- Case/Control; Observational
- Planned statistical analysis: Risk associations between the genotypes and
cancer/survival will be assessed using unconditional logistic regression model, with
covariate adjustment, as appropriate.
- Number of subjects to be enrolled: Target accrual is 6000 subjects, consisting of 450
cases/each gender in African Americans and 800 cases/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.
- For patients that undergo low dose CT screening at the participating hospitals in this
protocol, we will enroll patients that have had a "positive" scan and are attending
either UMMS or the VA hospital for further follow up.
The Laboratory of Human Carcinogenesis is conducting an observational non-small cell lung
cancer (NSCLC) case-control study in Baltimore, MD. This molecular epidemiology study was
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. Importantly, this
protocol establishes a resource that allows for the study of additional biomarkers and
gene-environment interactions. Upon recruitment, cases and controls receive a structured, in
person interview assessing prior medical and cancer history, use of tobacco and electronic
cigarettes, 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. Primary cell cultures may be established from available fresh tumor tissue. The
phenotypic markers to be studied will assess proficiency of DNA repair in lymphocyte cultures
exposed in vitro to radiation, bleomycin, benzo(a)pyrene-diol-epoxide by measuring induction
of chromosomal aberrations, p53 and apoptosis. DNA from buffy coats or cheek cells will be
used for analysis of germline variation 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.
Additionally, IRB approval was received in 2010 to include this study in a multi-institution
genome-wide association study (GWAS) of lung cancer in African Americans. Tumors from cases
will be evaluated for estrogen and progesterone receptors, somatic mutations, and gene
expression. Urine, plasma, serum and tissue sample metabolomics will be analyzed by
untargeted approach.
Objectives:
1. To determine if mutagen sensitivity, p53 induction, and apoptosis in cultured
lymphocytes are predictive of lung cancer risk.
2. To determine the relationship between sex-steroid metabolism, estrogen exposure, and
lung cancer risk.
3. To investigate and develop phenotypic or predictive markers of lung cancer risk and
survival, based on mutagen sensitivity, polymorphic markers, gene expression, and
metabolomics.
4. To investigate racial disparities associated with lung cancer risk and survival.
5. To examine the relationship between circulating cytokines with risk and survival of lung
cancer and to establish the most robust method of cytokine detection.
6. To generate a more accurate measure of ancestry using ancestry informative marker
analysis and to integrate this variable into our studies of health disparities
7. To conduct studies of metabolomics on serum, plasma and urine for the purposes of
discovering novel markers of risk, diagnosis and prognosis. We will use ultraperformance
liquid chromatography coupled to mass spectrometry (UPLS-MS) to search for small
molecular weight endogenous metabolites that can classify cancer and predict outcome.
This is a novel approach for biomarker discovery that also leverages the non-invasive
process of biospecimen collection. Tumor and corresponding non tumor tissues from
corresponding patients will also be tested using the same methods to extend the
discovery of novel tumor metabolites. Further, metabolites of vitamin D will be examined
on serum samples from lung cancer cases and controls to assess the relationship between
circulating
levels of Vitamin D metabolites with cancer risk and survival. This analysis will be
coupled with testing of Vitamin D pathway SNPs in corresponding patients to determine if
certain SNPs are also associated with levels of vitamin D.
8. To evaluate biomarkers of cancer diagnosis and prognosis in circulating tumor DNA
9. To evaluate the microbiome (microbes) present in lung tissue using in situ hybridization
of fixed tissues to be completed at Mayo Clinic by collaborators. The collaborators will
receive no information on the samples other than their tissue of origin.
10. To collect data and biospecimens on patients that received low dose CT screening as part
of their lung cancer diagnosis. This is for the purposes of investigating non-invasive
biomarkers of lung cancer diagnosis and prognosis. Low-dose CT screening is now offered
at UMMS and the VA for the purposes of early lung cancer detection. These screening
guidelines are per CMS guidelines, i.e., age 55-77, >=30 pack-years of smoking and have
quit smoking for 15 years or less. Such high-risk patients will be offered annual
screening.
11. To culture lung cancer specific microbiome-bacteria from human lung cancers. This work
will, in part, be conducted with our collaborator Dr Paul Owrin, who is an expert in the
culture of microbial species from human tissues. These samples, approximately 10 per
year, will be de-identified of all patient information.
Eligibility:
- Histologically confirmed NSCLC diagnosed within the past 2 years (case).
- Frequency matched to cases according to age (5-year intervals), gender, and race
(population-based control).
- Born in the United States, resident of the state of Maryland
- Subject Characteristics:
- Speaks English well enough to be interviewed
- 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 non-melanoma skin cancer or carcinoma in situ of
the cervix (population-based control)
- Has a residential working phone within the home (population-based control)
Design:
- Case/Control; Observational
- Planned statistical analysis: Risk associations between the genotypes and
cancer/survival will be assessed using unconditional logistic regression model, with
covariate adjustment, as appropriate.
- Number of subjects to be enrolled: Target accrual is 6000 subjects, consisting of 450
cases/each gender in African Americans and 800 cases/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.
- For patients that undergo low dose CT screening at the participating hospitals in this
protocol, we will enroll patients that have had a "positive" scan and are attending
either UMMS or the VA hospital for further follow up.
- INCLUSION CRITERIA:
- Case Subject Selection:
- Diagnosis of non-small cell lung cancer made pathologically (with confirmation by
a second pathologist).
- Must reside in Baltimore city or contiguous metropolitan counties, Prince
George's county or Anne Arundel county.
- 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.
- Report of a positive LDCT screen by a physician
- 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 Baltimore city, contiguous metropolitan counties, Prince George's
county or Anne Arundel county.
- 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.
- Known diagnosis of HIV, hepatitis B or C.
- 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.
We found this trial at
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Sinai Hospital of Baltimore Sinai Hospital of Baltimore provides a broad array of high-quality, cost-effective...
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