We investigated patient/tumor characteristics/inherited variants, hypoxia inducible factor 1 and 2 alpha (HIF1A/HIF2A) protein expression, and patient survival among Central European (CE) and United States (US) clear cell renal cancer (ccRCC) patients from two case-control studies. VHL inactivation, HIF1A, and HIF2A expression have been implicated in RCC and angiogenesis. GWAS studies have identified EPAS1 variants encoding the protein HIF2A associated with RCC risk. We conducted a hospital-based case-control study in Central/Eastern Europe (CE) and a population-based study in the US (Detroit, Chicago) that included whites and blacks. We used data on: i) patient/tumor characteristics, ii) inherited tagging single nucleotide polymorphisms (SNPs) in genes involved in the VHL-HIF pathway (HIF1A, EPAS1, VHL), HIF1A and HIF2A protein expression using immunohistochemical (IHC) methods, and survival from 696 CEERCC and 328 US ccRCC cases. ccRCC patients from CE Europe were older, presented at a higher grade, stage, with larger tumors, had lower BMI, less family history and smoked less (all p<0.0001) compared to US cases. US cases demonstrated higher intensity HIF1A and HIF2A protein expression compared to CE cases (p<0.0001). Black US ccRCC cases were more likely to be hypertensive (p<0.0001) and have lower HIF2A protein expression compared to white US cases. HIF1A and HIF2A were examined for associations with patient/tumor characteristics. In the US study, younger patients had higher levels of HIF2A expression compared to older cases and high BMI was associated with HIF1A expression. In both studies, tumor grade, stage and size at diagnosis were associated with lower HIF1A and HIF2A expression. In analyses adjusted for center, race, sex, age, hypertension, BMI, smoking, tumor grade and stage, HIF1A expression was significantly associated with HIF2A expression (P-trend<0.0001). We assessed associations of variants in EPAS1 (N=16), HIF1A (N=11), and VHL (N=9) with HIF1A and HIF2A expression in ccRCC tissue using tissue microarrays. Seven HIF1A SNPs were significantly associated with HIF1A expression and one EPAS1 SNP (rs1374748) with HIF2A expression. Median survival time was longer in CE compared to USRCC cases (100.3 vs. 86.0 months, p=0.001), women than men (97.1 vs 91.0 months, p=0.02) but similar among whites and blacks in the US study (86.0 vs 87.0 months). In Cox proportional hazard models, in both studies combined, risk of death was higher for those with large tumors (>4cm, p<0.0001) and with a higher stage 1 vs 2, 3+4 (p<0.0001, both) In contrast, ccRCC-specific survival was higher among USRCC than CE patients (19.8 vs 38.0 months, p=0.04) but similar among white compared to black US ccRCC patients (37.0 vs 40.0 months, p=0.50).

Citation Format: Lee Moore, Petra Lenz, Meredith Yeager, Ruth Pfeiffer, Ghislaine Scelo, Mark Purdue, David Zaridze, Kendra Schwartz, Neonilia szeszenia-Dabrowska, Faith Davis, Joanne Colt, vladimir Janout, Marie Navritalova, Paolo Boffetta, Laurie Burdette, Sara Karami, Paul Brennan, Jon Hofmann, Michael Nickerson, Wong-Ho Chow, Margaret Tucker, Stephen Chanock, Stephen Hewitt, Jorge Toro, Nat Rothman. Molecular characteristics and predictors of poor prognosis in sporadic clear cell renal cancer among central/eastern European and United States patients. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-31.