Peterson, Gloria

Abstract Exposure to polycyclic aromatic hydrocarbons (PAHs), a byproduct of incomplete combustion, and its effects on the development of cancer needs further evaluation. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history and levels of PheT in plasma were collected from 400 participants (202 cases and 198 control) and evaluated based on pancreatic adenocarcinoma diagnosis. A two-stage analysis was completed to identify 1) SNPs that were significantly associated with pancreatic cancer and 2) Dietary intake and PheT variables significantly associated with pancreatic cancer. A univariate analysis for variables with OR≠1 and p-value < 0.05 suggests significant relationship with pancreatic cancer and were carried forward to a multiple regression model for either food items or SNPs. Backward stepwise selection was used to eliminate non-significant variables. A collection of 5 SNPs were observed to form several of the most significant (adjusted p-value <0.05) interaction pairs across different SNP models. These were rs566979 (gene: CAT), rs28540420 (gene: PTGER4), rs12029406 (gene: none), rs730368 (gene: PTGER4), and rs3181077 (gene: CCR1). A final multiple regression model combined the significant food items and SNPs. Final significant factors associated with pancreatic cancer after backward selection included: Type 2 Diabetes [7.66 (3.46, 17.76)], corrected percent recovered version of the PAH (cPheT) [1.03 (1.02, 1.05)], very well done red meat [0.90 (0.84, 0.96)], recessive(rs12203582) [3.58 (1.50, 8.83)], recessive(rs56679) [0.25 (0.06, 0.80)], overdominant(rs3784605) [3.42 (1.81, 6.66)], overdominant(rs721430) [0.42 (0.21, 0.83)]. Of note by design, the level of smoking did not differ between our cases and controls. This study provides evidence that a metabolite PheT could be a biomarker of pancreatic cancer independent of dietary intake, smoking, and select metabolism SNPs. Citation Format: Sierra Nguyen, Heather Carlson, Andrea Yoder, William R. Bamlet, Ann L. Oberg, Gloria M. Peterson, Steven Hecht, Rick Jansen. Polycyclic aromatic hydrocarbons and pancreatic cancer: An analysis of blood biomarker PheT as an exposure identifier [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B005.

AbstractIt is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene‐by‐environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data‐adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case–Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome‐wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking‐related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.

Abstract Hyperactivation of the oncogenic K-RAS pathway leads to increased cell proliferation, tumor growth, and oxidative stress associated with increased ROS production, heightened mitochondrial bioenergetics, and altered cancer metabolisms. Downstream of the K-RAS pathway, Seven-In-Absentia human Homolog (SIAH) is required for proper ERBB/RAS signal transduction. Human peroxiredoxin (PRDX) is an antioxidant protein, whose precise role in modulating oxidative stress during oncogenesis remains to be elucidated. Increased levels of oxidative stress alter the bioenergetics and functional integrity of mitochondrial biology under cellular stress. This study aims to elucidate the biological interaction previously detected between PRDX and SIAH2 via biochemical assays. We plan to investigate the functional role of SIAH2-PRDX interaction in modulating the stress response and adaptive cell survival in K-RAS-driven tumors. Also, we would like to investigate the biological significance of SIAH2-PRDX interaction in response to increased cellular stress in K-RAS-driven human cancer cells treated with standard chemotherapies. Mitochondrial tracking (MITO-tracker®) was used to evaluate mitochondrial integrity of SIAH-proficient and SIAH-deficient human lung (A549) and cervical (HeLa) cancer cells over six days. Immunofluorescence staining and bright field imaging were performed using DOX-inducible human breast (MDA-MB231) and cervical (HeLa) cancer cells to compare changes in organelle integrity and mitochondrial morphology, altered expression of the oxidative stress biomarker and cell death biomarkers in response to induction of the SIAH- proficient and SIAH-deficient states in highly aggressive human cancer cells. By using human pancreatic cancer tissue microarrays (TMAs), we found that the antioxidant protein PRDX is significantly upregulated and co-expressed with SIAH in human pancreatic tumor biospecimens. It seems that PRDX is an indicative biomarker of cellular and oncogenic K-RAS-induced oxidative stress in human pancreatic cancer. By blocking SIAH2 function downstream of the K-RAS signaling pathway, oxidative stress levels were markedly increased, evidenced by mitochondrial aggregations and dysfunction in both human lung and cervical cancer cells. In response to anti-SIAH2 therapy, human TNBC, NSCLC and cervical cancer cells underwent dramatic morphological changes due to the significant loss of cell junction, focal adhesion and cell attachment. These data have shown that anti-SIAH2-based anti-K-RAS and anticancer therapy is highly effective in inducing massive cell death in several highly invasive and metastatic cancer lines. Further investigation into the molecular mechanisms of anti-SIAH2-induced cellular stress and cell death may contribute to the future drug development and validation of a new and effective anti-SIAH2-based targeted therapy against metastatic human cancer in the future. Citation Format: Zena M. Urban, Lauren van Reesema, Minglei Bian, Thomas C. Smyrk, Gloria Peterson, Amy H. Tang. Inhibition of SIAH E3 ligase function leads to increased cell death in metastatic human cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2014-4442