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Insulin resistance and lung cancer risk

Principal Investigator
Name
Pamela Goodwin
Degrees
-
Institution
University of Toronto
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2012-0001
Initial CDAS Request Approval
Apr 27, 2012
Title
Insulin resistance and lung cancer risk
Summary
We propose a case-control study nested in PLCO that will explore the association of markers of insulin resistance with lung cancer risk. Changing patterns of tobacco use have led to a changing epidemiology of lung cancer as fewer smoking associated cancers are diagnosed. We hypothesize that insulin resistance and associated factors may contribute to lung cancer risk, the effect being greater in non-smoking associated cancers. Recent reports suggest that lung cancer may be associated with components of the insulin resistance syndrome (IRS), including insulin resistance as evidenced by Homeostasis Model Assessment (HOMA), central obesity, higher leptin (an adipocytokine implicated in lung cancer risk) and higher C-reactive protein (CRP, a systemic marker of chronic inflammation implicated in lung cancer risk. Risk of lung cancer is higher is diabetics (who are insulin resistant), particularly in those receiving insulin; risk is lower in diabetics who receive metformin or thiazolidenediones, agents that lower insulin levels. Based on these observations and previous reports that nicotine use (inhaled or gum) is associated with insulin resistance, we hypothesize that lung cancer patients will be more insulin resistant than controls. Because blood specimens were collected in the non-fasting state in PLCO, we will measure C-peptide (released when insulin is cleaved from proinsulin), which is an accepted marker of insulin resistance in non-fasting blood. We also plan to measure two additional factors associated with insulin resistance - C-reactive protein (a systemic marker of chronic inflammation) and leptin (a marker of adiposity) that have also been implicated in lung cancer risk. We will utilize specimens from 552 lung cancer cases and 1657 control subjects without lung cancer and will measure our analytes in a CAP/CLIO certified laboratory at Mount Sinai Hospital, University of Toronto (under the supervision of Dr. Azar Azad, Laboratory Director). Statistical analyses will be conducted to examine (i) correlations amongst our analytes and key PLCO data (e.g. age, gender, body mass index, smoking history, family history of lung cancer, caloric intake, chronic obstructive lung disease, socioeconomic status) and (ii) the associations of C-peptide (primarily) and leptin and C-reactive protein (secondarily) with lung cancer risk before and after adjustment for key co-variates. If important associations are identified we may request additional access to tumor specimens and to more proximate and distal blood specimens to examine the time course of associations to investigate biologic mechanisms (such as insulin/IGF-1 receptor activation) that may mediate an association of insulin resistance with lung cancer risk.
Aims

Our hypotheses are as follows: 1. Higher non-fasting C-peptide (reflecting insulin resistance) is associated with increased lung cancer risk THIS IS OUR PRIMARY HYPOTHESIS; this association is strongest in non-smokers, intermediate in former smokers and weakest in current smokers. 2. Leptin associations with lung cancer risk follow the same pattern as C-peptide. 3. C-reactive protein associations with lung cancer risk follow the same pattern as C-peptide. 4. Lung adenocarcinoma is associated with non-smoking status (lifetime non-smoker, or former smoker with a long duration of smoking cessation), higher C-peptide and higher leptin levels compared to other histologies. In essence, we are hypothesizing that lung cancer will be associated with higher C-peptide, leptin and CRP levels in smokers but that smoking will be the strongest risk factor for lung cancer in smokers. We also hypothesize that higher C-peptide, leptin and CRP will be the strongest risk factors for lung cancer in non-smokers and that former smokers will show associations between those seen in smokers and non-smokers, depending on time since smoking cessation. We have not included BMI associations in our hypotheses because they have already been examined in the control arm of the PLCO dataset (Tammemagi JNCI 2011 and personal communication), however, we plan to replicate these findings in the screening arm and to explore the extent to which BMI modifies any associations we identify between markers of insulin resistance and lung cancer risk. Our specific aims are as follows: Using a nested case-control design, to: 1. Examine the association of non-fasting C-peptide (reflecting insulin resistance) with lung cancer risk in overall (OUR PRIMARY OBJECTIVE) and, in secondary exploratory analyses in current smokers, former smokers and non-smokers. Blood samples used to measure C-peptide ideally will have been drawn at entry onto PLCO to minimize effects of a developing and/or undiagnosed lung cancer on insulin resistance. 2. Examine the association of leptin (an adipocytokine secreted by adipose cells, a marker of obesity) with lung cancer risk overall and in current smokers, former smokers and non-smokers. 3. Examine the association of CRP (a marker of systemic inflammation, often elevated when insulin resistance is present) with lung cancer risk in current smokers, former smokers and non-smoke. 4. Evaluate the univariate and multivariable independent associations between C-peptide, CRP, leptin, BMI and lung cancer risk, stratified by smoking status. 5. Evaluate the aforementioned associations in histologic subtypes of lung cancer: adenocarcinomas, small cell and non-adenocarcinoma non-small cell lung cancers.

Collaborators

C. Martin Temmemagi (Brock University)
Frances A. Shepherd (Princess Margaret Hospital, University Health Network, University of Toronto)
Geoffrey Liu (Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto)
Ming-Sound Tsao (Princess Margaret Hospital, Ontario Cancer Institute, University of Toronto)
Natasha B. Leighl (Princess Margaret Hospital, University Health Network, University of Toronto)
Pamela J. Goodwin (Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto)
Vuk Stambolic (Ontario Cancer Institute, University Health Network, Princess Margaret Hospital, University of Toronto)