An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma

Abstract

Background: Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features.

Methods: Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal-Wallis or Fisher exact tests. All statistical tests were two-sided.

Results: Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox.

Conclusions: Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.

Figure 2.

Box plots of genomic alterations stratified by body mass index (BMI). A) Boxplots of nonsilent mutations stratified by BMI (two-sided P value from Kruskal–Wallis test) and recurrent cancer gene nonsilent mutations by BMI. *Indicates statistically significant higher mutation rate of KDM5C in the obese group (P = .03) but not when controlling for multiple testing (P = .34). B) Boxplots of genome-wide amplifications, losses, and DNA hypermethylation stratified by BMI (two-sided P value from Kruskal–Wallis test).

Figure 1.

Cancer-specific mortality curves. A) Cancer-specific mortality stratified by body mass index (BMI). B) Cancer-specific mortality stratified by by combinations of BMI and albumin (ALB) (P _interaction between BMI and albumin = .69). Two-sided P values are from Gray’s test.

Figure 3.

Gene expression analysis linking body mass index (BMI), fatty acid metabolism, and survival from The Cancer Genome Atlas (TCGA) dataset. A) Heat map of gene expression by BMI. B) Cancer-specific mortality stratified by fatty acid synthase (FASN) in Memorial Sloan-Kettering Cancer Center (MSKCC) TCGA cohort (n = 122) Two-sided P value is from Gray’s test. C) Diagram illustrates the relationship between BMI, survival, and FASN pathway expression. Red color indicates gene or protein upregulation. Blue color indicates downregulation. Rectangle indicates mRNA expression. Diamond indicates protein expression.