High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma Masaki Nasu, Mitsuru Emi, Sandra Pastorino, Mika Tanji, Amy Powers, Hugh.

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High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma Masaki Nasu, Mitsuru Emi, Sandra Pastorino, Mika Tanji, Amy Powers, Hugh Luk, Francine Baumann, Yu-an Zhang, Adi Gazdar, Shreya Kanodia, Maarit Tiirikainen, Erin Flores, Giovanni Gaudino, Michael J. Becich, Harvey I. Pass, Haining Yang, Michele Carbone, MD, PhD Journal of Thoracic Oncology Volume 10, Issue 4, Pages 565-576 (April 2015) DOI: 10.1097/JTO.0000000000000471 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Point mutations of BAP1 genes detected by Sanger sequencing. A, Tumor NYU524. Genomic DNA sequencing shows point mutation (G → T) at the splicing site at the end of intron 14. B, cDNA sequencing revealed a 70 nucleotide insertion from part of intron 14 (c.1891_1892Ins 70, p.Glu630fsX23). C, Tumor NYU1024. Genomic sequencing displayed G insertion in exon 14 (c.1762_1763 Ins G). D, cDNA sequence of the corresponding region (p.Pro588fsx55). Journal of Thoracic Oncology 2015 10, 565-576DOI: (10.1097/JTO.0000000000000471) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Detection of BAP1 protein expression in sporadic malignant mesothelioma tumor samples by immunohistochemistry. Wild-type BAP1 tumor sample NYU047 shows strong nuclear staining in all tumor cells. All samples carrying alteration of BAP1 gene are shown (photomicrographs magnification, 400×). Journal of Thoracic Oncology 2015 10, 565-576DOI: (10.1097/JTO.0000000000000471) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Gross BAP1 gene alterations detected by MLPA and TaqMan copy number assays. MLPA assay is measured at 17 points, one each on 17 exons of BAP1 gene. TaqMan copy number assay is measured at six points on BAP1 gene; one each on exons 2, 3, 6, 12, 14, and 17. NYU540 MLPA and TaqMan data (A, B), NYU559 MLPA and TaqMan data (C, D), NYU1419 MLPA and TaqMan data (E, F), and NYU207 MLPA and TaqMan data (G, H). MLPA = multiplex ligation-dependent probe amplification. Journal of Thoracic Oncology 2015 10, 565-576DOI: (10.1097/JTO.0000000000000471) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Detection of aberrant forms of BAP1 by MLPA and cDNA sequencing. A, Tumor NYU851. MLPA assay detected deletions of exons 1, 4, and 15. B, NYU851 cDNA sequencing revealed two aberrant splicing at exons 8–9 and exons 11–17 in one allele. C, MLPA on NYU966 showed deletion of exons 1 and 4. D, Tumor NYU966 cDNA sequencing revealed a cDNA with skipping of most of exons 12, 13, 14, and 6 bp of exon 15 as well as a wild-type cDNA (exons 14 and 15 shown). E, MLPA on NYU1306 detected triplication, copy number increase to three copies, in most exons. F, NYU1306 cDNA sequencing revealed a deletion of exons 12 and 13. G, NYU1250 cDNA sequencing revealed a new splicing isoform of BAP1 due to a 121-bp deletion in exon 13. H, Aberrant usage of cryptic splicing site AG, found in NYU1250, is shown by arrow on reference DNA sequence at intron 12 and exon 13. Nucleotides in green indicate the exon sequence. MLPA = multiplex ligation-dependent probe amplification. Journal of Thoracic Oncology 2015 10, 565-576DOI: (10.1097/JTO.0000000000000471) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 BAP1 promoter and body methylation analysis. A, Sample NYU047. B, Sample NYU524. Low BAP1 promoter methylation was detected by pyrosequencing in all sporadic MM samples tested. Pyrosequencing values detected in MM tumor samples are as low as the normal control DNA. Two representative samples are shown, where yellow highlights indicate the percentage of methylation at each site. C, The Cancer Genome Atlas portal database (https://tcga-data.nci.nih.gov/tcga/) was examined for methylation at BAP1 gene, which was covered by 19 probes (data generated by use of the Infinium HumanMethylation450 BeadChip). MM = malignant mesothelioma. Journal of Thoracic Oncology 2015 10, 565-576DOI: (10.1097/JTO.0000000000000471) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions