PMID- 31570769 OWN - NLM STAT- MEDLINE DCOM- 20210125 LR - 20230210 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 33 IP - 2 DP - 2020 Feb TI - Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma. PG - 217-227 LID - 10.1038/s41379-019-0371-0 [doi] AB - The aim of this study was to assess the performance of fluorescence in situ hybridization (FISH) in identifying the copy number profiles of the three key peritoneal mesothelioma tumor suppressor genes BAP1, CDKN2A, and NF2, with particular emphasis on minute homozygous deletions, a copy number abnormality recently unveiled at the 3p21 (BAP1) chromosomal region using high-throughput methods. FISH was performed on 75 formalin-fixed-paraffin-embedded peritoneal mesotheliomas and recognized two types of monoallelic loss (monosomy, and hemizygous deletion) and two types of biallelic loss (canonical homozygous deletion with a complete loss of FISH signal and homozygous deletion with diminished signal). Diminished FISH signals revealed deletions occurring within the genomic region covered by the gene-specific probe and affected all three tumor suppressors. BAP1 homozygous deletions with diminished signal outnumbered canonical homozygous deletions (13 vs 3): conversely, canonical homozygous deletions were prevalent for CDKN2A (2 vs 14). Diminished signal homozygous deletion was the only pattern of biallelic loss observed for NF2 (2 cases). Hemizygous deletion mainly affected BAP1 (21 vs 6), while monosomy was prevalent for CDKN2A (14 vs 7) and particularly for NF2 where it accounts for all monoallelic losses. FISH/immunohistochemistry (BAP1, CDKN2A, and MTAP) correlation showed that all homozygous deletions, including those with diminished signals, resulted in a null BAP1 and CDKN2A immunophenotype but only canonical CDKN2A homozygous deletions resulted in MTAP loss of expression. BAP1 hemizygous deletion, but not monosomy, was also invariably associated with loss of protein expression whereas neither type of CDKN2A monoallelic loss correlated with p16 or MTAP immunohistochemistry. Array comparative genomic hybridization performed on a spontaneously emerging peritoneal mesothelioma cell line provided support for the interpretation of the FISH patterns and allowed us to extend the number of chromatin remodeling factors involved in mesothelioma to SETD7 and PCGF5, two previously unreported genes. FAU - Brich, Silvia AU - Brich S AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Bozzi, Fabio AU - Bozzi F AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Perrone, Federica AU - Perrone F AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Tamborini, Elena AU - Tamborini E AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Cabras, Antonello Domenico AU - Cabras AD AD - Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. FAU - Deraco, Marcello AU - Deraco M AD - Peritoneal Surface Malignancies Unit, Colon and Rectal Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. FAU - Stacchiotti, Silvia AU - Stacchiotti S AD - Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. FAU - Dagrada, Gian Paolo AU - Dagrada GP AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. gianpaolo.dagrada@istitutotumori.mi.it. FAU - Pilotti, Silvana AU - Pilotti S AD - Department of Pathology, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. LA - eng PT - Journal Article DEP - 20190930 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 0 (BAP1 protein, human) RN - 0 (Biomarkers, Tumor) RN - 0 (CDKN2A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (NF2 protein, human) RN - 0 (Neurofibromin 2) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.4.2.1 (Purine-Nucleoside Phosphorylase) RN - EC 2.4.2.28 (5'-methylthioadenosine phosphorylase) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) SB - IM MH - Adult MH - Aged MH - Biomarkers, Tumor/*genetics/metabolism MH - Cell Line, Tumor MH - Comparative Genomic Hybridization MH - Cyclin-Dependent Kinase Inhibitor p16/*genetics/metabolism MH - Female MH - *Gene Deletion MH - Genetic Predisposition to Disease MH - Hemizygote MH - Homozygote MH - Humans MH - Immunohistochemistry MH - *In Situ Hybridization, Fluorescence MH - Male MH - Mesothelioma/*genetics/metabolism/pathology MH - Middle Aged MH - Neurofibromin 2/*genetics MH - Peritoneal Neoplasms/*genetics/metabolism/pathology MH - Phenotype MH - Purine-Nucleoside Phosphorylase/genetics/metabolism MH - Tumor Cells, Cultured MH - Tumor Suppressor Proteins/*genetics MH - Ubiquitin Thiolesterase/*genetics MH - Young Adult EDAT- 2019/10/02 06:00 MHDA- 2021/01/26 06:00 CRDT- 2019/10/02 06:00 PHST- 2019/02/04 00:00 [received] PHST- 2019/08/29 00:00 [accepted] PHST- 2019/08/29 00:00 [revised] PHST- 2019/10/02 06:00 [pubmed] PHST- 2021/01/26 06:00 [medline] PHST- 2019/10/02 06:00 [entrez] AID - S0893-3952(22)00926-7 [pii] AID - 10.1038/s41379-019-0371-0 [doi] PST - ppublish SO - Mod Pathol. 2020 Feb;33(2):217-227. doi: 10.1038/s41379-019-0371-0. Epub 2019 Sep 30.