title: 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.
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan; Department of Human Genetics, University of Health Sciences (UHS), Lahore, Pakistan.
authors.forename: Shagufta
authors.initials: S
authors.lastname: Khaliq
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Sadia
authors.initials: S
authors.lastname: Ajaz
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Firasat
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Saba
authors.initials: S
authors.lastname: Shahid
authors.affiliation: Department of Oncology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Asad Shahzad
authors.initials: AS
authors.lastname: Hasan
authors.affiliation: Department of Oncology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Gauhar
authors.initials: G
authors.lastname: Sultan
authors.affiliation: Department of Oncology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Rehan
authors.initials: R
authors.lastname: Mohsin
authors.affiliation: Department of Oncology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Altaf
authors.initials: A
authors.lastname: Hashmi
authors.affiliation: Department of Histopathology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Muhammed
authors.initials: M
authors.lastname: Mubarak
authors.affiliation: Department of Urology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Syed Ali Anwar
authors.initials: SA
authors.lastname: Naqvi
authors.affiliation: Department of Urology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Syed Adib-Ul-Hasan
authors.initials: SA
authors.lastname: Rizvi
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan.
authors.forename: Syed Qasim
authors.initials: SQ
authors.lastname: Mehdi
authors.affiliation: Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan. Electronic address: aiyshaabid@gmail.com.
authors.forename: Aiysha
authors.initials: A
authors.lastname: Abid
mesh_terms: D000328:Adult; D000367:Age Factors; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D010154:Pakistan; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Cancer genetics; Epigenetic silencing; Papillary RCC; Renal cell carcinoma; von Hippel-Lindau gene