AS146 - A prospective study of pancreatic cancer pathogenesis

Investigator Names and Contact Information

Charles Fuchs (cfuchs@partners.org)

Introduction/Intent

Each year, 29,000 Americans die of cancer of the pancreas, making pancreatic cancer the fourth most common cause of cancer-related mortality among American men and women (1). Nonetheless, relatively little is known about the pathogenesis and epidemiology of this malignancy. In a recently funded grant to study pancreatic cancer epidemiology (Fuchs, PI, National Cancer Institute, R01-CA86102), we are utilizing prospectively collected diet and lifestyle data as well as blood and tumor specimens from two large cohort studies, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). As part this effort, we will examine the prevalence and spectrum of various molecular alterations in the tumors and assess the influence of dietary and other factors on the prevalence of these molecular changes.

In this current application, we are requesting support to expand this prospective cohort by adding blood specimens from the Women’s Health Initiative (WHI) and the Physicians’ Health Study (PHS). Moreover, we are proposing additional specific aims given the added statistical power that all four cohort studies provide. Using these resources, we propose to achieve the following specific aims:

1. To examine whether elevated levels of circulating Insulin-like growth factor-I (IGF-I) and IGF-II, elevated levels of fasting insulin and C-peptide, and reduced levels of circulating IGF binding protein-1 (IGFBP-1) and IGFBP-3 are associated with an increased risk of pancreatic cancer.

2. To examine whether biochemical indicators of methyl-group availability are inversely associated with pancreatic cancer risk and whether an influence of folate is modified by methylene tetrahydrofolate reductase (MTHFR) polymorphisms.

3. To examine whether polymorphisms of genes responsible for detoxification and activation of aromatic/heterocyclic amines influence the risk of pancreatic cancer. The specific hypotheses are:

• a) Glutathione transferase M1 (GSTM1) null genotype is associated with an increased risk of pancreatic cancer, and the associations of smoking and red meat intake with pancreatic cancer are modified by GSTM1 genotype.

• b) Polymorphisms of N-acetyltransferases 1 and 2 confer differential susceptibility to pancreatic cancer, and the associations of smoking and red meat intake with pancreatic cancer are modified by acetylation genotype.

• c) Polymorphisms of cytochrome P450 1A1 (CYP1A1) confer differential susceptibility to pancreatic cancer and the association of smoking with pancreatic cancer is modified by CYP1A1 genotype.

Through this collaboration of investigators at the Dana-Farber Cancer Institute, Children’s Hospital, Brigham and Women’s Hospital, and Harvard School of Public Health, we will establish a unique pancreatic cancer database consisting of repeated dietary and lifestyle assessments over several decades as well as archived blood and tumor specimens. This resource will allow us to examine many inter-related risk factors and biochemical factors simultaneously to better understand pancreatic cancer pathogenesis. Moreover, this effort will enhance a “nodal point” interaction among DF/HCC members and foster the development of a Gastrointestinal Program within DF/HCC. Results/Findings

Some of the publications related to this ancillary study are:

Ms482 - Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, Giovannucci E, Thomson C, Stampfer MJ, Fuchs C. Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res. 2007 Jun 1;67(11):5553-60.

Ms483 - McTiernan A, Rossouw J, Manson J, Franzi C, Taylor V, Carleton R, Johnson S, Nevitt M. Informed consent in the Women's Health Initiative Clinical Trial and Observational Study. J Womens Health. 1995;4:519-29

Ms484 - Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS. Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts. Br J Cancer. 2007 Jul 2;97(1):98-104. Epub 2007 May 29.

Ms576 - Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS. Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. Cancer Res. 2007 Aug 15;67(16):7923-8.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.