Transcriptomic Signatures Related to the Obesity Paradox in Patients with Clear Cell Renal Cell Carcinoma

Abstract

Background: Obesity, defined as body mass index (BMI ≥ 30 kg/m2), is associated with an increased risk of developing clear cell renal cell carcinoma (ccRCC) but, paradoxically, also with improved oncologic outcomes in clinical cohorts. This obesity paradox has been described among ccRCC patients with localized disease treated with nephrectomy alone, and those with metastatic disease receiving targeted therapy. The mechanisms underlying these associations are not well understood. Methods: After confirming the inverse association between BMI and mortality among a cohort of 453 metastatic ccRCC patients treated with first-line VEGF-directed therapy, 152 predominately early stage ccRCC patients from the KIRC TCGA, and an observational cohort of 203 metastatic ccRCC patients treated with targeted immunotherapy, we evaluated gene expression differences between obese and normal weight patients. Tumor transcriptomic patterns were compared between obese and normal weight patients in COMPARZ and validated in early-stage patients from the KIRC TCGA cohort. We additionally explored gene expression differences in the peritumoral fat from a prospectively collected cohort of 62 patients with non-metastatic disease. Findings: Gene expression analyses implicate differences in angiogenic and immune cell programs in the tumor microenvironment as possible drivers of the obesity paradox. We also found increased perinephric adipose tissue inflammation near the primary tumor in obese versus normal weight patients. Peritumoral adipose tissue inflammation may be related to increased hypoxia among obese patients, which is more pronounced near the primary tumor. Interpretation: Molecular changes in both the tumor and peritumoral fat may contribute to the apparent survival advantage experienced by obese ccRCC patients. The complex interplay between the ccRCC tumor and peritumoral adipose tissue microenvironment may have clinical relevance and warrants further investigation. Funding: ASCO Young Investigator Award (AS), Chanel grant (HF) and SOAR grant (HF & AJD), Ludwig Center MSKCC (AAH, FK, HF), Ruth L. Kirschstein Research Service Award T32CA082088 (AS), and P30CA08748 MSK Center Support Grant. Declaration of Interest: M.H. Voss reports receiving commercial research grants from BMS and Genentech, is a consultant/advisory board member for Alexion Pharmaceuticals, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Natera, Novartis, and Pfizer, and has received other remuneration from Eisai, Takeda, and Novartis. N. Riaz reports receiving commercial research grants from BMS and Pfizer and honoraria from the speaker’s bureau of Illumina. Y. Cheng owns stock in Novartis Pharm Inc. M.O. Li is a consultant/advisory board member for Leap Therapeutics. T.A. Chan reports receiving commercial research grants from Illumina, BMS, Eisai, AstraZeneca, and An2H, has ownership interest (including stock, patents, etc.) in Gritstone Oncology, and is a consultant/advisory board member for Gritstone Oncology,Illumina, and Bristol Myers. R.J. Motzer reports receiving commercial research grants from Bristol-Myers Squibb, Pfizer, Novartis, Genentech/Roche, and Eisai and is a consultant/advisory board member for Genentech, Pfizer, Merck, Novartis, and Incyte. A.J. Dannenberg is a member of the scientific advisory boards of SynDevRx and Quentis. No potential conflicts of interest were disclosed by the other authors. Ethical Approval: We conducted an Institutional Review Board (IRB)-approved retrospective observational study investigating the clinical significance of pre-treatment BMI and OS in the context of targeted immunotherapy among 203 patients with metastatic ccRCC.