20 Apr Study Targets Obesity Genes That May Raise Risk of Kidney Cancer
MedicalResearch.com Interview with:
Dr. Xifeng Wu, MD PhD
Department Chair, Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences
Director, Center for Translational and Public Health Genomics
Professor, Department of Epidemiology
Division of Cancer Prevention and Population Sciences
The University of Texas MD Anderson Cancer Center, Houston, Texas
Medical Research: What is the background for this study? What are the main findings?
Dr. Wu: Obesity is a well-established risk factor for renal cell carcinoma (RCC), the most common form of kidney cancer. It has been estimated that more than 40% of RCC incident cases in the US may be attributed to excessive body weight. Growing body of evidence suggests that obesity may also influence clinical outcome of RCC; however, the findings are sometimes conflicting. So far, the molecular mechanism linking obesity to RCC risk or prognosis is not well understood. In this study, we evaluated the promoter CpG site methylation of 20 candidate obesity-related genes and their association with RCC risk and recurrence in a two-phase study of 240 newly diagnosed, previously untreated RCC patients. Pyrosequencing was conducted on paired RCC tumor and normal adjacent tissues to measure promoter methylation. Among the 20 markers, we found NPY, LEP and LEPR showed significant differential methylation levels between tumors and normal adjacent tissues, and methylation was significantly higher in tumors in both discovery and validation groups. Consistent with our findings, we also found lower expression of LEPR in tumor tissues compared to normal adjacent tissues in data obtained from The Cancer Genome Atlas. Additionally, high LEPR methylation in tumors was associated with more advanced tumor features, such as high pathologic stage, high grade and clear cell RCC histology, and increased risk of recurrence compared to the low methylation group. These results suggest that tissue changes in promoter methylation in obesity-related genes may provide some biological basis for the association between obesity and RCC outcome, and that LEPR may be an independent prognostic indicator of recurrence in RCC patients. Further research in larger study population and functional studies are warranted to validate our findings and to elucidate the underlying causal mechanisms.
Medical Research: What should clinicians and patients take away from your report?
Dr. Wu: The take-home message from this study is that clinicians and patients should be aware that obesity may contribute to increased risk of kidney cancer, and that the development of this disease may involve changes at the DNA level in genes related to obesity, which may lead to altered gene expression or function. For patients with RCC, increased methylation of an obesity-related gene LEPR may lead to poor outcome.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Wu: Future studies with larger independent population are necessary to confirm these results. Since the biological basis of increased promoter methylation in LEPR and other obesity-related genes in tumors is unknown, detailed functional studies are needed to characterize the etiologic mechanisms. Once validated, patients may be tested with epigenetic drugs targeting DNA methylation or chromatin modification to lower the risk of RCC recurrence.
MedicalResearch.com: Is there anything else you would like to add?
Dr. Wu: To our knowledge, this is the first two-stage study of RCC patients using paired tumor and normal tissues to evaluate the role of methylation in obesity-related genes and RCC prognosis. We found for the first time the association between higher methylation levels in LEPR gene with risk of recurrence in RCC patients, which may contribute toward building a prognostic tool for future personalized risk stratification and therapy.
AACR abstract: April 2016
Prognostic value of obesity-related genes methylation in localized renal cell carcinoma patients