AS214 - Prospective cohort collaborative in pancreatic cancer epidemiology and pathogenesis (AS146 extension)

Investigator Names and Contact Information

Charles Fuchs (charles.fuchs@yale.edu)

Introduction/Intent

Introduction/Intent

Each year, 30,000 Americans die of cancer of the pancreas, making pancreatic cancer the fourth most common cause of cancer-related mortality. Nonetheless, relatively little is known about the pathogenesis and epidemiology of this malignancy. In a ongoing grant from the National Cancer Institute (Fuchs, PI, R01CA86102, WHI AS146), we are conducting analyses in pancreatic cancer using DNA and plasma from participants in the Women’s Health Initiative (WHI) in conjunction with specimens from the Nurses’ Health Study (NHS), Health Professionals Follow-up Study (HPFS), Women’s Health Study (WHS) and the Physicians’ Health Study (PHS). We wish to extend our analyses in pancreatic cancer among participants in the WHI (and the other cohorts) for the purpose of a competitive renewal of this grant. Continued pooling of cases from the ongoing prospective cohort studies will allow a rigorous examination of this important cancer. Blood specimens will be analyzed using a matched, nested case-control design of projected cases through 2007 to evaluate hypotheses focusing on mechanisms of pancreatic cancer pathogenesis. Using these resources, we propose to examine energy balance, insulin and insulin-like growth factor signaling, inflammation and H. pylori, and retinol and vitamin D-related pathways. By better understanding mechanisms, inter-relations between factors acting in similar pathways, and genetic variation, we can identify recommendations at reducing the incidence and mortality from this highly fatal malignancy.

Aims

Since pancreatic cancer is a relatively uncommon malignancy, it will be difficult for any individual prospective cohort to definitively study biochemical predictors of this disease. However, continued pooling of cases from the WHI and the other ongoing prospective cohort studies will create an unprecedented resource for the study of this important cancer. Using these resources, we propose the following specific aims:

1. Indicators of energy balance, insulin, and insulin-like growth factors (IGF)

• a. A marker of insulin resistance and hyperinsulinemia (C-peptide; fasting insulin) is associated with higher pancreatic cancer risk whereas markers of pancreatic beta-cell dysfunction (hemoglobin A1c; pro-insulin:insulin ratio) do not predict pancreatic cancer risk.
• b. Polymorphic variation in genes involved in the IGF and insulin pathway is associated with the risk of pancreatic cancer.
• c. Decreased plasma adiponectin and the adiponectin (ACDC) gene T45G/G276T haplotype are associated with an increased risk of pancreatic cancer, particularly among sedentary and/or obese individuals.
• d. Higher plasma leptin is associated with an increased risk of pancreatic cancer, independent of body mass index.

2. Inflammatory pathways:

• a. Inflammatory markers (increased plasma C-reactive protein, interleukin-6, and tumor necrosis factor-α-receptor II) are associated with increased pancreatic cancer risk.
• b. Genetic polymorphisms in inflammatory mediator genes are associated with the risk of pancreatic cancer. These genes include *interleukin-1-β (IL1B), interleukin-1receptor antagonist (IL1RN), interleukin-6 (IL6), interleukin-8 (IL8), interleukin-10 (IL10), tumor necrosis factor-α (TNF), transforming growth factor- β (TGFB1), peroxisome proliferator-activated receptor-g (PPARD), NFKB1, NFKBIA, NFKBIL1, COX-1 (PTGS1), and COX-2 (PTGS2). *
• c. Helicobacter pylori colonization is associated with an increased risk of pancreatic cancer and this association is mediated, in part, by the influence of hypergastrinemia on pancreatic cancer risk.
• d. Polymorphisms in the interleukin-1 gene cluster, TNF- α, and IL-10 augment the association between H. pylori and pancreatic cancer risk.

3. Retinol and Vitamin D

• a. Higher levels of plasma retinol are associated with a decreased risk of pancreatic cancer and this association is modified by polymorphisms in peroxisome proliferator-activated receptor-γ.
• b. Higher levels of plasma vitamin D are associated with a decreased risk of pancreatic cancer and this association is modified by polymorphisms in vitamin D receptor (VDR).

Results/Findings

Some of the publications related to this ancillary study are:

Ms930 - Wolpin BM, Kraft P, Gross M, Kathy Helzlsouer K, Bueno-de-Mesquita HB, Steplowski E, Stolzenberg-Solomon RZ, Arslan AA, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Allen NE, Amundadottir L, Anderson G, Boutron-Ruault MC, Buring JE, Canzian F, Chanock SJ, Clipp S, Gaziano JM, Giovannucci EL, Hallmans G, Hankinson SE, Hoover RN, Hunter DJ, Hutchinson A, Jacobs K, Kooperberg C, Lynch SM, Mendelsohn JB, Michaud DS, Overvad K, Patel AV, Rajkovic A, Sanchéz MJ, Shu XO, Slimani N, Thomas G, Tobias GS, Trichopoulos D, Vineis P, Virtamo J, Wactawski-Wende J, Yu K, Zeleniuch-Jacquotte A, Hartge P, and Fuchs CS. Pancreatic cancer risk and ABO blood group alleles: Results from the Pancreatic Cancer Cohort Consortium. Cancer Res. 2010 Feb 1;70(3):1015-23. Epub 2010 Jan 26.

Ms936 - Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS, Petersen GM, Arslan AA, Bueno-de-Mesquita HB, Gross M, Helzlsouer K, Jacobs EJ, Lacroix A, Zheng W, Albanes D, Bamlet W, Berg CD, Berrino F, Bingham S, Buring JE, Bracci PM, Canzian F, Clavel-Chapelon F, Clipp S, Cotterchio M, de Andrade M, Duell EJ, Fox Jr JW, Gallinger S, Gaziano JM, Giovannucci EL, Goggins M, González CA, Hallmans G, Hankinson SE, Hassan M, Holly EA, Hunter DJ, Hutchinson A, Jackson R, Jacobs KB, Jenab M, Kaaks R, Klein AP, Kooperberg C, Kurtz RC, Li D, Lynch SM, Mandelson M, McWilliams RR, Mendelsohn JB, Michaud DS, Olson SH, Overvad K, Patel AV, Peeters PH, Rajkovic A, Riboli E, Risch HA, Shu XO, Thomas G, Tobias GS, Trichopoulos D, Van Den Eeden SK, Virtamo J, Wactawski-Wende J, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Chanock SJ, Hartge P, Hoover RN. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep;41(9):986-90. Epub 2009 Aug 2.

Ms1075 - Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M, Helzlsouer K, Holly EA, Jacobs EJ, Klein AP, Lacroix A, Li D, Mandelson MT, Olson SH, Risch HA, Zheng W, Albanes D, Bamlet WR, Berg CD, Boutron-Ruault MC, Buring JE, Bracci PM, Canzian F, Clipp S, Cotterchio M, de Andrade M, Duell EJ, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hankinson SE, Hassan M, Howard B, Hunter DJ, Hutchinson A, Jenab M, Kaaks R, Kooperberg C, Krogh V, Kurtz RC, Lynch SM, McWilliams RR, Mendelsohn JB, Michaud DS, Parikh H, Patel AV, Peeters PH, Rajkovic A, Riboli E, Rodriguez L, Seminara D, Shu XO, Thomas G, Tjønneland A, Tobias GS, Trichopoulos D, Van Den Eeden SK, Virtamo J, Wactawski-Wende J, Wang Z, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Fraumeni JF Jr, Hoover RN, Hartge P, Chanock SJ. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224-8. Epub 2010 Jan 24

Ms1182 - Wolpin BM, Ng K, Bao Y, Kraft P, Stampfer MJ, Michaud DS, Ma J, Buring JE, Sesso H, Lee IM, Rifai N, Cochrane BB, Wactawaski-Wende J, Chlebowski RT, Willett WC, Manson JE, Giovannucci EL, Fuchs CS. Plasma 25-Hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):82-91. Epub 2011 Nov 15

Ms1408 - Bao Y, Giovannucci EL, Kraft P, Stampfer MJ, Ogino S, Ma J, Buring JE, Sesso HD, Lee IM, Gaziano JM, Rifai N, Pollak MN, Cochrane BB, Kaklamani V, Lin JH, Manson JE, Fuchs CS, Wolpin BM. A prospective study of plasma adiponectin and pancreatic cancer risk in 5 US Cohorts. J Natl Cancer Inst. 2013 Jan 16;105(2):95-103. doi: 10.1093/jnci/djs474. Epub 2012 Dec 14

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.