Abstract The well validated Clearcode34 transcriptomic subtypes of clear cell renal cell carcinoma (ccRCC) are clinically distinct, with ccB tumors having poorer patient survival than ccA tumors, yet few studies have evaluated whether the subtypes possess distinct risk factor profiles. To address this question, we investigated potential etiologic heterogeneity between the ccA and ccB subtypes in two case-control studies conducted in Europe (144 ccA, 106 ccB, 1,476 controls) and the U.S. (75 ccA, 27 ccB, 1,235 controls). We measured expression levels of the 34-gene Clearcode panel to classify ccRCC tumors by subtype. For each study we conducted (1) case-only analyses (ccB vs. ccA) using logistic regression to assess subtype differences in tumor characteristics and control matching factors (e.g., age, sex, race/ethnicity) and (2) case-control analyses using polytomous regression to compute subtype-specific associations with established and suspected RCC risk factors e.g., body mass index (BMI), smoking, hypertension, polygenic risk score (PRS) derived from genome-wide association studies (European-ancestry subjects). Study-specific findings were combined through meta-analysis using random effects models. We also computed associations with additional suspected risk factors that were assessed in the US study only. In the meta-analysis of case-control findings, we found ccA tumors to be more strongly associated with obesity odds ratio (OR)=3.75, 95% confidence interval (CI)=1.14-12.35 than ccB tumors (OR=1.56, 95% CI=0.96-2.52). Conversely, ccB tumors were more strongly associated with a PRS based on 13 risk variants (90th vs. 10th percentile: ORccA=1.96, 95% CI=1.23-3.11; ORccB=3.34, 95% CI=1.83-6.11). From the U.S study, we identified that ccB tumors were more common among US Black vs. White patients (case-only OR=6.71, 95% CI=1.22-36.98), more strongly associated with chronic renal failure (ORccB=22.12, 95% CI=6.22-78.72; no exposed ccA cases), and more highly associated with a recent PRS based on 108 risk variants (90th vs. 10th percentiles: ORccA=3.26, 95% CI=1.39-7.60; ORccB=13.12, 95% CI=1.61-107.02). We did not observe any notable differences by subtype for the associations with smoking, hypertension, hysterectomy, oophorectomy, physical activity, and alcohol consumption. Our findings suggest the existence of etiologic heterogeneity between the Clearcode34 subtypes, with ccA tumors more strongly associated with excess weight and ccB tumors more common among Black patients and more strongly associated with chronic renal failure and genetic risk scores. This evidence suggesting risk factor heterogeneity across subtypes highlights the importance of accounting for tumor molecular characteristics in investigations of ccRCC etiology and risk prediction models. Citation Format: Eun Mi Jung, Kristine Jones, Diptavo Dutta, Jonathan N. Hofmann, Helena Furberg Barnes, Stephen J. Chanock, Nat Rothman, Paul Brennan, Kai Yu, Mark P. Purdue. An investigation of etiologic heterogeneity across transcriptomic subtypes of clear cell renal cell carcinoma in two case-control studies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2349.
Jung et al. (Fri,) studied this question.