Shannon Lynch

PhD, MPH

Fox Chase Cancer Center

Assistant Professor

PLCO (Learn more about this study)

2013-0031

May 1, 2013

Repeated Measures of Telomere Length and Pancreatic Cancer

Exocrine pancreatic cancer is among the most fatal cancers worldwide and one for which few preventable risk factors have been established(e.g., smoking, diabetes mellitus, obesity). Telomeres are structures at the end of chromosomes that are critical in maintaining the integrity of the genome by protecting against chromosomal break-fusions in dividing cells. Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length(TL). Recent studies have shown that TL can potentially serve as a pancreatic cancer biomarker. A hospital-based study showed an association between short telomeres and pancreatic cancer at time of diagnosis. We showed that long TL, prior to disease diagnosis, may serve as an early marker for pancreatic cancer. We propose to conduct a nested case-control (~350 cases; 700 matched controls) study within the PLCO Trial using DNA extracted from T0, T3, T5 blood samples(buffy coat). The purpose of this study is: 1) to describe the natural history of telomere length change from T0 to T5 in cases and controls; 2) to test whether change in telomere length (TLC) is associated with pancreatic cancer incidence and survival 3) to explore whether the relationship between TLC and pancreatic cancer is affected by telomere genetic variants associated with TL and pancreatic cancer, namely TERT. We hypothesize that observing TLC over time and determining whether telomeres lengthen, shorten, or maintain length in cases and controls can provide insights into pancreatic carcinogenesis and mortality and the potential use of TL as an early detection marker. Including genetic variants in this analysis will allow us to more comprehensively assess the utility of TL as a biomarker. The PLCO Trial provides an opportunity to test our hypothesis in a prospective setting, avoiding the biases of retrospective research, particularly reverse-causation bias. The results may have important implications for pancreatic cancer prevention/detection.

This proposed nested case-control study within the PLCO study cohort aims to examine whether telomere length change over time (TLC) and the magnitude of change (e.g. lengthening, shortening, maintenance) measured in PBCs is associated with pancreatic cancer risk and mortality. The primary aims of this study are to:

To test the hypothesis that baseline telomere length, as well as change in telomere length(TLC-over T0, T3, T5) in normal somatic cells (i.e., PBCs) is associated with pancreatic cancer risk. We hypothesize that baseline telomere length and TLC (either shortening or lengthening) telomere length will be positively associated with pancreatic cancer.

Our secondary aims are:

1. To examine the trajectory of TLC in cases and controls separately, and to test the hypothesis that TLC, specifically shortening and lengthening of TL, in normal somatic cells (i.e., PBCs) is related to pancreatic cancer survival. We hypothesize that telomere lengthening will be associated with longer survival once diagnosed with pancreatic cancer, and telomere shortening will be associated with metastatic pancreatic cancer risk and shorter survival.

2. To determine if the relationship between baseline telomere length (n~350 cases and 700 controls), TLC and pancreatic cancer is modified by telomere genetic variants from GWAS, namely TERT.