Abstract 903: Circulating inflammatory proteins associated with mortality from causes other than the index cancer in older adult cancer survivors in the atherosclerosis risk in communities study
Authors: Ugoji Chinenye C. , Walker Keenan A. , Dean Lorraine T. , Gross Alden , Ballantyne Christie M. , Butler Ken , Hoogeveen Ron C. , Joshu Corinne , Mosley Thomas H. , Prizment Anna , Sharrett A. Richey , Tin Adrienne , Varadhan Ravi , Coresh Josef , Platz Elizabeth A. 
Published: July 2021

Abstract
Background: Inflammation is hypothesized to underlie premature mortality in cancer survivors, yet little is known about the inflammatory proteins and pathways involved.
Methods: 474 long-term (≥5 years) older adult survivors of prostate, breast, colorectal, endometrial or bladder cancers in the ARIC study were followed from visit 5 (2011-13) to 12/2018. At visit 5, 580 plasma inflammatory proteins were assayed using the SomaScan platform, a modified aptamer-based assay. We modeled sub-distribution hazards (sHR) of non-index cancer-related death per log2 increase in each protein, adjusting for age, sex, race, years since cancer diagnosis, renal function, anti-inflammatory drug use, and cancer/CVD shared risk factors. We also investigated these proteins with mortality in survivors of the two most common cancers, prostate and breast. To account for multiple testing, we used Bonferroni correction and false discovery rate. Using Ingenuity Pathway Analysis (Qiagen®) and principal components analysis, we identified protein pathways and upstream regulators most strongly associated with mortality.
Results: Survivors were 21% Black, 56% male, had a mean age of 77 yrs, and median time since diagnosis of 11 yrs. 95 non-cancer (50% CVD) and 34 non-index cancer deaths occurred in 2740 person-yrs of follow-up. After FDR correction, 49 proteins were significantly associated with risk of death. VEGF sR3, complement C1RL, CD9 antigen, insulin-like growth factor-binding protein 7 (IGFBP7), platelet-derived growth factor D (PDGFD) and interferon-induced protein (IFIT2) were most strongly positively associated, with sHR: 2.1-4.4 per two-fold increase. Transmembrane protein (TMEM230), plasminogen, TNFSF12, APOL1, serum amyloid P-component and von Willebrand factor (VWA2) were most strongly inversely associated, with sHR:0.34-0.42. Only IFIT2 remained significant after Bonferroni correction. Associations of some inflammatory proteins differed by cancer site survived. However, 2 proteins, telomeric repeat binding factor (TERF1) and toll-like receptor (TLR2), were associated with increased mortality in all, prostate, and breast cancer survivors. Proteins associated with mortality were enriched for 5 major signaling pathways - MSP-RON, IL-8, glioma/coagulation, glucocorticoid receptor, atherosclerosis, and hepatic fibrosis, and were activated or inhibited by upstream regulators: SOX7, ERG, MYC, and IL4.
Conclusion: Several circulating inflammatory proteins and signaling pathways were associated with premature death in cancer survivors independent of cancer/CVD risk factors. If confirmed, these proteins/pathways may warrant evaluation as potential biomarkers for screening for risk of premature mortality, and possibly as therapeutic targets to prolong lives of cancer survivors. Funding: NHLBI, NCI, NPCR
Citation Format: Chinenye C. Ugoji, Keenan A. Walker, Lorraine T. Dean, Alden Gross, Christie M. Ballantyne, Ken Butler, Ron C. Hoogeveen, Corinne Joshu, Thomas H. Mosley, Anna Prizment, A. Richey Sharrett, Adrienne Tin, Ravi Varadhan, Josef Coresh, Elizabeth A. Platz. Circulating inflammatory proteins associated with mortality from causes other than the index cancer in older adult cancer survivors in the atherosclerosis risk in communities study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 903.