Abstract 2340: Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma in a case-control study
Authors: Purdue Mark P. , Rhee Jongeun , Moore Lee , Gao Xiaohua , Sun Xuezheng , Kirk Erin , Callahan Catherine , Bencko Vladimir , Janout Vladimir , Mates Dana , Foretova Lenka , Szeszenia-Dabrowska Neonilia , Matveev Vsevolod , Zaridze David , Petruzella Stacey , Hakimi A. Ari , Merino Maria , Linehan W. Marston , Brennan Paul , Furberg Helena , Troester Melissa , Rothman Nathaniel 
Published: September 2020

Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC, making up over 80% of cases. Two molecular ccRCC subtypes, designated ccA and ccB, have been well characterized as having prognostic relevance, with ccB tumors associated with poorer survival. However, no epidemiologic studies to date have investigated whether these molecular subtypes possess distinct risk factors. We explored the possible existence of etiologic heterogeneity for ccA and ccB tumors within a multi-center hospital-based case-control study of kidney cancer conducted in Central and Eastern Europe.
Methods: We measured mRNA expression for a 34-gene ccA/ccB classification panel (ClearCode34) in tumor samples collected from 333 ccRCC cases. Using TCGA-KIRC data as a training set, we predicted ccA/ccB status using prediction analysis of microarrays and restricted our data analysis to tumors with a predicted subtype probability &gt;70% (n=262). We used logistic and polytomous regression modeling to compute odds ratios (OR) and 95% confidence intervals (CI) to assess subtype differences by age and sex (via case-only analyses) and, through comparisons between cases and controls (N=1,476), subtype-specific ORs for established RCC risk factors. We also conducted a meta-analysis combining our case-only findings for sex and body mass index (BMI) with those from three clinical studies with ccRCC molecular classification.
Results: Cases with ccB tumors (n=111) were more likely than those with ccA tumors (n=151) to be male (OR 2.6, 95% CI 1.4-4.7 controlling for country, age at diagnosis, stage and grade). In case-control analyses, ccA tumors were more strongly associated with moderate and severe obesity (OR 2.1, 95% CI 1.3-3.5 and 2.5, 1.2-5.2 for BMI 30.0-34.9 and ≥35.0 vs. &lt;25.0 kg/m2; Ptrend = 0.001) than ccB tumors (1.6, 95% CI 0.9-2.9 and 1.8, 0.7-4.5; Ptrend = 0.08), while occupational exposure to trichloroethylene was associated with ccB (OR 1.5, 95% CI 0.5-4.5 and 3.0, 1.2-7.2 for &lt;1.58 and ≥1.58 ppm-years vs. unexposed; Ptrend = 0.02) but not ccA (0.6, 0.1-2.4 and 1.0, 0.3-3.3; Ptrend = 0.80) tumors. A polygenic risk score including all 13 GWAS-identified susceptibility loci identified to date was also more strongly associated with ccB than ccA tumors (90th vs. 10th percentile: OR 2.6, 95% CI 1.5-4.6 and 1.8, 1.1-3.0 respectively). No notable subtype differences were observed for age, smoking, hypertension or family history of RCC. In a meta-analysis of case-only results including three clinical studies we still observed the ccB excess for male sex (OR 1.8, 95% CI 1.1-2.9 vs. ccA, I2 = 67%) and the ccA excess for obesity (1.6, 1.1-2.2, I2 = 0%).
Conclusions: Our findings suggest that the etiology of ccRCC may be more complex than previously understood, with evidence of differences across molecular subtypes in their relationships with sex, obesity, trichloroethylene exposure and genetic susceptibility.
Citation Format: Mark P. Purdue, Jongeun Rhee, Lee Moore, Xiaohua Gao, Xuezheng Sun, Erin Kirk, Catherine Callahan, Vladimir Bencko, Vladimir Janout, Dana Mates, Lenka Foretova, Neonilia Szeszenia-Dabrowska, Vsevolod Matveev, David Zaridze, Stacey Petruzella, A. Ari Hakimi, Maria Merino, W. Marston Linehan, Paul Brennan, Helena Furberg, Melissa Troester, Nathaniel Rothman. Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma in a case-control study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2340.