Telomere Length Studies in PLCO
Principal Investigator
Name
Shahinaz Gadalla
Degrees
M.D., Ph.D.
Institution
National Institute of Health
Position Title
Principal Investigator
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
2017-1019
Initial CDAS Request Approval
May 1, 2018
Title
Telomere Length Studies in PLCO
Summary
Telomeres are long (TTAGGG)n tandem nucleotide repeats and an associated protein complex located at chromosome ends to maintain chromosomal stability. They shorten with each cell division and therefore are markers of cellular replicative capacity and aging. Patients with rare mutations in telomere-biology genes have very short telomeres and are at very high risk of bone marrow failure, certain cancers, and severe pulmonary complications. In the general population, telomere abnormalities have been linked to risk of early death, cancer, cardiovascular diseases, pulmonary fibrosis, and infections. Furthermore, telomere length (TL) genome-wide association studies identified associations between genomic variations in some known telomere biology genes (TERT, TERC, and OBFC1) and TL suggesting a heritable component. Also, single-nucleotide polymorphisms (SNPs) in key telomere-biology genes such as TERT or RTEL1 have been associated with several cancers, RTEL1 with idiopathic pulmonary fibrosis, and TERT and TEP1 with male infertility. TL has also been linked to lifestyle factors such as smoking, physical activities, and dietary habits in several studies.
Despite abundance of studies, the TL literature has suffered from methodological limitations and a lack of consistency in association studies with disease. Examples include: measurement errors related to the use of different DNA extraction and handling methods in qPCR TL assay; reverse-causation in case-control studies; and a lack of accurate information on attrition rates during the lifespan due to a lack of studies using serial samples. Here, we propose to use samples extracted for the PLCO GSA project (n~100,000) to better understand the relationship of TL genetic and epidemiological variation with cancer. We propose to use a robust and high throughput standardized qPCR assay at the NCI Center for Genomic Research (CGR) in combination with highly accurate flow FISH assay for a subset with viable crypopreserved samples. Flow FISH measurements will be used to calibrate the qPCR assay, facilitating robust interpretation. This work will generate a unique resource for investigators interested in telomere length studies.
Despite abundance of studies, the TL literature has suffered from methodological limitations and a lack of consistency in association studies with disease. Examples include: measurement errors related to the use of different DNA extraction and handling methods in qPCR TL assay; reverse-causation in case-control studies; and a lack of accurate information on attrition rates during the lifespan due to a lack of studies using serial samples. Here, we propose to use samples extracted for the PLCO GSA project (n~100,000) to better understand the relationship of TL genetic and epidemiological variation with cancer. We propose to use a robust and high throughput standardized qPCR assay at the NCI Center for Genomic Research (CGR) in combination with highly accurate flow FISH assay for a subset with viable crypopreserved samples. Flow FISH measurements will be used to calibrate the qPCR assay, facilitating robust interpretation. This work will generate a unique resource for investigators interested in telomere length studies.
Aims
1. Improve the understanding of telomere length genomic through a large-scale telomere length genome-wide association study.
2. Develop and validate an absolute telomere length calibration equation in a subset of participants receiving both qPCR and flow-FISH measurements.
3. Integrating both telomere length and GWAS data to understand the contribution of telomere length genetics in the risk of cancer development.
Collaborators
Shahinaz Gadalla (National Cancer Institute, NIH)
Sharon Savage (National Cancer Institute, NIH)
Hourmuzd Katki (National Cancer Institute, NIH)
Mitchell Machiela (National Cancer Institute, NIH)