Genetic characterization of Polish ccRCC patients: somatic mutation analysis of PBRM1, BAP1 and KDMC5, genomic SNP array analysis in tumor biopsy and preliminary results of chromosome aberrations analysis in plasma cell free DNA

Abstract

BackgroundMutation analysis and cytogenetic testing in clear cell renal cell carcinoma (ccRCC) is not yet implemented in a routine diagnostics of ccRCC.Material and methodsWe characterized the chromosomal alterations in 83 ccRCC tumors from Polish patients using whole genome SNP genotyping assay. Moreover, the utility of next generation sequencing of cell free DNA (cfDNA) in patients plasma as a potential tool for non-invasive cytogenetic analysis was tested. Additionally, tumor specific somatic mutations in PBRM1, BAP1 and KDM5C were determinedResultsWe confirmed a correlation between deletions at 9p and higher tumor size, and deletion of chromosome 20 and the survival time. In Fuhrman grade 1, only aberrations of 3p and 8p deletion, gain of 5q and 13q and gains of chromosome 7 and 16 were present. The number of aberrations increased with Fuhrman grade, all chromosomes displayed cytogenetic changes in G3 and G4. ccRCC specific chromosome aberrations were observed in cfDNA, although discrepancies were found between cfDNA and tumor samples. In total 12 common and 94 rare variants were detected in PBRM1, BAP1 and KDM5C, with four potentially pathogenic variants. We observed markedly lower mutation load in PBRM1.ConclusionsCytogenetic analysis of cfDNA may allow more accurate diagnosis of tumor aberrations and therefore the correlation between the chromosome aberrations in cfDNA and clinical outcome should be studied in larger cohorts. The functional studies on in BAP1, KDM5C, PBRM1 mutations in large, independent sample set would be necessary for the assessment of their prognostic and diagnostic potential.

Genetic alteration of histone lysine methyltransferases and their significance in renal cell carcinoma

“…Several studies indicated that aberrations of chromosome 3p deletion and gain of chromosome 5q were uncovered in ccRCC patients and presented their prognostic and diagnostic potential (Nagao et al, 2005; Kluzek et al, 2017; Togo et al, 2016). Taking chromosome 3p as an illustration, ccRCC was characterized by a high frequency of allelic deletion or loss of heterozygosity on chromosome 3p, causing biallelic mutation or promoter hypermethylation of von Hippel-Lindau (VHL) gene.…”

Transcriptomic characterization and innovative molecular classification of clear cell renal cell carcinoma in the Chinese population

“…PBRM1 was previously reported to be associated with slightly worse stage and grade tumors by immunohistochemistry [ 46 ], however, the domination of early stage (78.4%) and low grade (66.1%) samples in our dataset might bias the observation. Nevertheless, remarkably low frequency of PBRM1 mutation frequency (11%) was also reported in Polish population with a samples size of 83 patients and no bias in early stage and low grade [ 47 ]. PBRM1 is involved in the regulation of genes of metabolic pathways that is known to be essential for driving ccRCC, including the hypoxia response related PI3K signaling pathway [ 48 ], high percentage of wild type PBRM1 could be one reason why better treatment outcome of PI3K inhibitor was observed in the Chinese population (data not shown).…”

Somatic Mutation of BAP1 Can Lead to Expression Loss in Non-Small Cell Lung Carcinoma: Next Generation Sequencing and IHC Analysis in A Large Single Institute Cohort

“…Several different alterations in the BAP1 gene have been described, including large deletions of exons, frameshift mutations, splice site mutations and the base substitution leading to nonsense and missense mutations. 2,17,18 Frameshift mutations, missense and nonsense substitutions are the most common sequence alterations. In our study, we also found missense and frameshift mutations are the most common BAP1 alterations in NSCLC cases and have the potential to result in expression loss of BAP1.…”

“…2,7,8 It has been hypothesized that BAP1 mutations may yield different tumor phenotypes, depending on the cell types and the co-existing oncogenic mutations. 7 Germline mutations of BAP1 are known to confer increased susceptibility for a variety of tumors including uveal melanoma, 3,9,10 atypical Spitz tumors, 3,10 cutaneous melanoma, 3,10 mesothelioma, [11][12][13][14][15][16][17] renal cell carcinoma 7,[18][19][20] and possibly other epithelial, mesenchymal and neural tumors. 7,21 In addition to germline BAP1 mutations, sporadic, non-familial tumors may harbor somatic mutations.…”