The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n=144) and ccB (n=106) cases and 1,476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male [case-only odds ratio (OR) 2.68, 95% confidence interval (CI) 1.43-5.03]. In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs. <25 kg/m2 ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs. unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs. 10th percentile). In a meta-analysis of case-only results including three patient cohorts we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors. This article is protected by copyright. All rights reserved.
International journal of cancer. 2021 May 31 [Epub ahead of print]
Mark P Purdue, Jongeun Rhee, Lee Moore, Xiaohua Gao, Xuezheng Sun, Erin Kirk, Vladimir Bencko, Vladimir Janout, Dana Mates, David Zaridze, Stacey Petruzella, A Ari Hakimi, W Marston Linehan, Stephen J Chanock, Paul Brennan, Helena Furberg, Melissa Troester, Nathaniel Rothman
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA., University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic., Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic., Institute of Public Health, Bucharest, Romania., Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia., Memorial Sloan Kettering Cancer Center, New York, NY, USA., Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA., International Agency for Research on Cancer, Lyon, France.