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Circulating Leptin and Risk of Pancreatic Cancer

Circulating Leptin and Risk of Pancreatic Cancer


This pooled, nested case-control study from 3 cohorts of middle-aged and older adults showed that higher prediagnostic circulating leptin concentrations were associated with an increased pancreatic cancer risk among those with longer follow-up. In particular, a statistically significant greater than 2-fold risk for pancreatic cancer was observed among participants in the top 2 quintiles compared with those in the lowest quintile for those who developed pancreatic cancer 10 or more years after blood collection. The positive association was present in all cohorts and was independent of race, sex, smoking history, body mass index, and diabetes. To the best of our knowledge, this is the first prospective epidemiologic study that has examined prediagnostic leptin and subsequent pancreatic cancer development.

The absence of a positive association between leptin and pancreatic cancer during the earlier years of follow-up may be explained by reverse causation. Pancreatic cancer is most often diagnosed at advanced stages with metastasis to distant organs and is preceded by significant weight loss which could affect circulating leptin concentrations. Even relatively modest weight loss has been shown to substantially reduce blood leptin levels. Four small clinic–based case-control studies and 1 case series have demonstrated that prevalent pancreatic cancer cases have lower leptin concentrations than do noncases. One of these studies examined results by stage at diagnosis and found that leptin concentrations were lower among cases with distant metastasis than among cases with local disease. Consistent with the results of these case-control studies, our results included some suggestion of an association between lower leptin concentrations and higher risk of a pancreatic cancer diagnosis within 5 years of blood collection overall and among the ATBC participants diagnosed less than 10 years after blood collection. Alternatively, there might be processes independent of body mass index related to latent pancreatic cancer that could explain our observations.

There are biologically plausible reasons why higher leptin concentrations may be associated with risk of pancreatic cancer. First, serum leptin could directly influence pancreatic carcinogenesis. Leptin can promote tumor vascularization, as well as the proliferation, migration, and invasion of tumor cells. In rodent models, obesity both promotes pancreatic carcinogenesis and increases leptin concentrations, although obesity-related changes in other adipocytokines and growth factors have also been reported. Notably, in a hamster model of pancreatic carcinogenesis, diet-induced obesity resulted in fatty infiltration of the pancreas, greater leptin expression in pancreatic tissue, 2-fold higher serum leptin concentrations, and a significant increase in the number of pancreatic tumors. Recently, fatty pancreas infiltration has been associated with central adiposity, as well as pancreatic cancer in humans, although to the best of our knowledge leptin expression has not been quantified in the pancreas. Alternatively, serum leptin concentration may be a more sensitive marker for intra-abdominal or visceral adiposity compared with body mass index and even independent of body mass index. With aging, body composition changes, such that muscle mass decreases while total fat mass and intra-abdominal or visceral fat stores increase, although body mass index may stay the same or even decrease. Given the older age of our study participants, this may help to explain why we observe stronger associations between leptin and risk of pancreatic cancer in participants with a body mass index of less than 25 with longer follow-up. Additionally, in middle-aged and older adults the distribution of white adipose shifts from subcutaneous to visceral fat stores. This shift contributes to greater cytokine production, insulin insensitivity, glucose intolerance, and leptin resistance. Intra-abdominal adiposity may be particularly relevant for pancreatic carcinogenesis, given the proximity of the pancreas to visceral adipose tissue, the greater potential for fatty pancreas infiltration, and possibly lipotoxicity. Waist circumference and the waist:hip ratio, indicators of intra-abdominal fat, are positively and linearly associated with risk of pancreatic cancer.

In our study, the association between leptin and pancreatic cancer was apparent among smokers during follow-up occurring 10 or more years after blood draw. This contrasts with epidemiologic studies of body mass index and pancreatic cancer that generally report positive associations among nonsmokers but little or no association among smokers. One possible explanation is that leptin may be more strongly correlated than body mass index is with intra-abdominal adiposity, particularly among smokers. Cigarette smoking has been associated with greater intra-abdominal adiposity as characterized by the waist and waist:hip ratio, independent of body mass index. In addition, heavy smoking has been associated with intra-abdominal fat, but not subcutaneous fat, as quantified by X-ray computed tomography scans and independent of age, physical activity, and alcohol intake. Significant positive associations were also observed between leptin and pancreatic cancer among PLCO/CPS-II participants (who are mostly nonsmokers) and never smokers during lesser follow-up times (Web Table 1

Important strengths of our study include its prospective nested case-control design. As the cases and controls are from the same cohorts, our study has internal validity and no control selection bias. In addition, our study included a large number of pancreatic cancer cases occurring over a wide range of follow-up time, allowing us to detect differences in associations between the early years of follow-up, when reverse causation is plausible, and later follow-up, when it is less likely. Our case definition includes confirmed pancreatic adenocarcinoma cases, reducing the potential of misclassification of the outcome. Our study also has some limitations. A single measurement of leptin in adulthood may not represent long-term leptin concentrations, and changes in diet, smoking, and weight during follow-up were not measured and could influence the risk estimates. The influence of fasting status on our study results is unclear. Overnight fasting lowers leptin concentrations and may have contributed to differences in median leptin levels between cohorts. At the time of blood draw, all ATBC participants, some PLCO participants, and few, if any, CPS-II participants were fasting.

Some PLCO participants were likely fasting at the time of blood draw in preparation for the colonoscopy scheduled the same day, but we are unable to determine which participants were fasting. It is possible that variation in fasting time attenuated results somewhat in PLCO and CPS-II. However, the association between leptin and pancreatic cancer risk did not vary significantly (Pheterogeneity = 0.66) between ATBC and PLCO/CPS-II. Of note, significant continuous associations and trends were observed in the PLCO/CPS-II participants during follow-up 5 to <10 years after their baseline blood collection. A smaller number of cases (74 in PLCO/CPS-II vs. 209 in ATBC) and inadequate power might also explain the nonsignificant positive associations observed in the PLCO/CPS-II participants with follow-up 10 years or more. Residual confounding by cigarette smoking is possible; however, there was no significant interaction of our association by smoking status, and positive associations were observed among never, former, and current smokers. Finally, our results may be generalizable to middle-aged and older Caucasian populations but not necessarily to other ethnic groups.

In conclusion, our results support an association between serum leptin concentration and higher risk of pancreatic cancer, although this association may be obscured by reverse causation during early years of follow-up. Our findings are relevant given the obesity and diabetes epidemics and could potentially have preventive implications along with other adipokines associated with pancreatic cancer. Additional research is needed to confirm the association between serum leptin concentration and risk of pancreatic cancer and to clarify the underlying potential biological mechanisms.

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