A germline mutation in PBRM1 predisposes to renal cell carcinoma

J Med Genet. 2015 Jun;52(6):426-30. doi: 10.1136/jmedgenet-2014-102912. Epub 2015 Apr 24.

Abstract

Background: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC.

Methods: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene.

Results: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours.

Conclusions: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.

Keywords: Cancer: urological; Molecular genetics; PBRM1; predisposing genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / diagnosis
  • Carcinoma, Renal Cell / genetics*
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Kidney Neoplasms / diagnosis
  • Kidney Neoplasms / genetics*
  • Male
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pedigree
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Nuclear Proteins
  • PBRM1 protein, human
  • Transcription Factors