Unique molecular alteration patterns in von Hippel-Lindau (VHL) gene in a cohort of sporadic renal cell carcinoma patients from Pakistan.

Abstract Background Renal cell carcinoma (RCC) is the most frequent form of kidney cancer in adults. Somatic mutations that inactivate the von Hippel-Lindau ( VHL ) gene are the most common cause of RCC. The frequencies of molecular changes in the VHL gene in RCCs vary among different populations. So far, a single chromosomal-based study has been reported from a South Asian population. This report presents, for the first time, the somatic changes and promoter hypermethylation in VHL in a cohort of 300 RCC patients from Pakistan. Methods To identify mutations in the VHL gene, direct DNA sequencing was carried out. Epigenetic silencing was investigated by using methylation-specific polymerase chain reaction. Results Our data showed molecular alterations in the VHL gene in 163 (54%) renal cell carcinoma patients. Somatic mutations were found in 87 (29%) patients and 35 novel mutations were identified. VHL promoter hyper-methylation analysis showed epigenetic changes in 106 (35%) out of 300 patients. Patients who had no evidence of molecular alterations in the VHL gene were significantly younger than patients who carried some molecular change. Molecular alterations in the VHL gene were not restricted to clear-cell RCCs (ccRCCs). Conclusions This is the first report that identifies molecular aberrations in the VHL gene from a South Asian population. The frequency of somatic mutation is lower and that of promoter hypermethylation is higher when compared with data from other parts of the world. The data has important implications in the population-specific application of tailored preventive and therapeutic regimens in non-familial RCCs.