Gene Regulation Sheds Light On Renal Cancer ‘Obesity Paradox’

Examining body mass index in relation to stage, grade and cancer-specific mortality

medwireNews:  Alterations in Gene expression may explain the ‘obesity paradox’ phenomenon seen in patients with clear-cell renal cell carcinoma (ccRCC), suggests research published in the Journal of the National Cancer Institute.

The study of 2119 ccRCC patients confirmed a significant and inverse relationship between body mass index (BMI) and grade and American Joint Committee on Cancer (AJCC) stage, despite obesity being a known risk factor for the disease.

Overweight and obese patients were significantly less likely to have stage 3 or above disease at diagnosis than their normal weight counterparts, after adjusting for gender and age at time of surgery (odds ratio [OR]=0.61 and 0.65, respectively). The likelihood of grade 3 or greater disease was also significantly reduced (OR=0.73 and 0.81, respectively).

In addition, BMI showed an inverse relationship with cancer-specific mortality (CSM; hazard ratio=0.59 for obese versus normal weight) , although this was no longer significant after adjusting for AJCC stage and grade, according to A Ari Hakimi of the Memorial Sloan-Kettering Cancer Center, New York, USA and co-authors.

Genomic analysis of 126 patients revealed a significant difference in the pattern of gene expression in tumours taken from obese and normal weight patients.

In particular, the fatty acid synthase (FASN) Oncogene was significantly upregulated in normal weight patients but downregulated in obese patients.  Upregulation of FASN was in turn significantly associated with an increased risk of CSM, which the researchers say is in line with previous reports that increased expression of the gene is associated with aggressive disease and a poor prognosis.

“Collectively our results suggest that the decreased mortality observed among obese ccRCC patients may not merely be explained by detection bias or weight loss but that tumors developing in obese patients may be more indolent than those in normal-weight patients,” Ari Hakimi et al write.

In an accompanying editorial, Lin Li and Kamyar Kalantar-Zadeh, from the University of California Irvine Medical Center, Orange, USA, note that the study did not objectively measure visceral fat or take into account changes in patients’ body composition over time.

Nevertheless, they write that “the study is one of the first to provide a step closer to a true biologic plausibility for the obesity paradox, at least among renal cell carcinoma patients, and provides convincing evidence about a more indolent nature of the kidney cancer in obesogenic milieu, the very same condition that has predisposed to the development of the very cancer.”

Concluding that the impact of obesity on health is not a “black-and-white story”, Li and Kalantar-Zadeh emphasize that “[s]uch provocative findings… should not be considered as an attempt to undermine the legitimacy of an antiobesity campaign that is in the best interest of public health.”


Ari Hakimi A, Furberg H, Zabor E, et al. An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma. J Natl Cancer Inst2013 Nov 27. Epub ahead of print. doi: 10.1093/jnci/djt310

Li L and Kalantar-Zadeh K. Obesity That Makes Kidney Cancer More Likely but Helps Fight It More Strongly. J Natl Cancer Inst2013 Nov 27. Epub ahead of print. doi: 10.1093/jnci/djt348

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