Chromatin remodeling gene PBRM1 is frequently altered somatically in epithelioid sarcomas and clear cell renal cell carcinomas, but its germline mutation had been reported only once, in a pedigree with familial clear cell renal cell carcinoma (Benusiglio et al., 2015). We present another evidence of a cancer caused by PBRM1 germline mutation in a family with two young sibs, one of whom deceased of round cell soft tissue sarcoma 13 years old.
For search of mutations we used next generation sequencing (NGS) on Ion S5 platform. For verification of mutations identified by NGS, for mutation segregation analysis and for evaluation of allelic expression expression we used DNA and cDNA Sanger sequencing.
Exome sequencing of cancer related genes identified a heterozygous germline genetic variant p.F1026L (c.3078C>G) in PBRM1 in the leucocyte DNA of the living sibling. This variant is absent from databases and bioinformatic predictors provide ambiguous estimates as to its pathogenicity. Search for this genetic variant in other family members showed that it is also being carried by the father and the older brother of the proband. Sanger sequencing of this variant in the archived tumor material of the deceased revealed its presence in the heterozygous state indicating no signs of allelic imbalance as an inactivation event that would have been consistent with Knudson’s two-hit model. Yet, further examination of allelic expression in tumor revealed loss of expression of the normal allele suggesting functional loss of heterozygosity in favor of the mutant one.
Our finding of functional two-hit inactivation of PBRM1 in the tumour supports its role as a tumour suppressor gene. Moreover, we present a second description of PBRM1 pathogenic germline mutation, and the first to be presumably causative for a soft tissue sarcoma. Absence of any tumours in other PBRM1 mutation carriers in the family described here provides the evidence of low penetrance of this mutation.
Clinical trial identification
Legal entity responsible for the study
Research Centre for Medical Genetics, Moscow.
State assignment of FASO Russia.
All authors have declared no conflicts of interest.