Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma.

Francesco Piva,Matteo Giulietti,Giulia Occhipinti,Roberto Iacovelli,Luciano Burattini,Matteo Santoni,Giovanni Principato,Stefano Cascinu,Valeria Sotte,Daniele Santini,Rodolfo Montironi,Francesco Massari

doi:10.18632/oncotarget.5147

Abstract

Clear cell Renal Cell Carcinoma (ccRCC) is due to loss of von Hippel-Lindau (VHL) gene and at least one out of three chromatin regulating genes BRCA1-associated protein-1 (BAP1), Polybromo-1 (PBRM1) and Set domain-containing 2 (SETD2). More than 350, 700 and 500 mutations are known respectively for BAP1, PBRM1 and SETD2 genes. Each variation damages these genes with different severity levels. Unfortunately for most of these mutations the molecular effect is unknown, so precluding a severity classification. Moreover, the huge number of these gene mutations does not allow to perform experimental assays for each of them. By bioinformatic tools, we performed predictions of the molecular effects of all mutations lying in BAP1, PBRM1 and SETD2 genes. Our results allow to distinguish whether a mutation alters protein function directly or by splicing pattern destruction and how much severely. This classification could be useful to reveal correlation with patients' outcome, to guide experiments, to select the variations that are worth to be included in translational/association studies, and to direct gene therapies.

Highlights

Human Renal Cell Carcinoma (RCC), both sporadic and hereditary forms, comprises different histological subtypes
The first carcinogenic step leading to clear cell RCC is the inactivation of the von Hippel–Lindau (VHL) tumour suppressor gene, mapped on 3p25
We considered as severe a mutation predicted to be severe according to either NNSPLICE or SpliceAid 2

Summary

Introduction

Human Renal Cell Carcinoma (RCC), both sporadic and hereditary forms, comprises different histological subtypes. The first carcinogenic step leading to clear cell RCC (ccRCC) is the inactivation of the von Hippel–Lindau (VHL) tumour suppressor gene, mapped on 3p25. One VHL allele is usually damaged by a point mutation, while the other allele is lost owning to a large deletion. This deletion can remove one allele of the near chromatin regulating genes BRCA1associated protein-1 (BAP1), Polybromo-1 (PBRM1). We considered as severe a mutation predicted to be severe according to either NNSPLICE or SpliceAid 2. For protein effect, we graded as severe a mutation if either PredictSNP or DDIG-in claimed the severity

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Conclusion