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Targeted Next-Generation Sequencing of Cancer Genes in Advanced Stage Malignant Pleural Mesothelioma: A Retrospective Study  Marco Lo Iacono, PhD, Valentina.

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Presentation on theme: "Targeted Next-Generation Sequencing of Cancer Genes in Advanced Stage Malignant Pleural Mesothelioma: A Retrospective Study  Marco Lo Iacono, PhD, Valentina."— Presentation transcript:

1 Targeted Next-Generation Sequencing of Cancer Genes in Advanced Stage Malignant Pleural Mesothelioma: A Retrospective Study  Marco Lo Iacono, PhD, Valentina Monica, PhD, Luisella Righi, MD, Federica Grosso, MD, Roberta Libener, MD, Simona Vatrano, BS, Paolo Bironzo, MD, Silvia Novello, MD, Loredana Musmeci, MD, Marco Volante, MD, Mauro Papotti, MD, Giorgio V. Scagliotti, MD  Journal of Thoracic Oncology  Volume 10, Issue 3, Pages (March 2015) DOI: /JTO Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Summary of genetic variations identified by next-generation sequencing. In the left panel, the variations identified in the top 20 genes (≥25 patients mutated with at least 10% of allelic frequency) are summarized: in red the malignant pleural mesothelioma (MPM) samples (pts) with at least a variation (intronic, synonymous, nonsynonymous, and regulative), whereas in blue the MPM samples with at least one nonsynonymous/regulative variation in the top 20 genes. The right panel shows the heatmap of MPM samples with only the nonsynonymous/regulative variations at ≥10% AF. The blue blocks identify variations, although the color intensity is proportional to number of mutations observed in each MPM sample. Journal of Thoracic Oncology  , DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 BAP1/NF2 panel: BAP1 variations were enriched mainly in exons 13 and 17. Loci of BAP1 and NF2 are shown. The blue blocks represent the exons, whereas the red blocks indicated the regions amplified and sequenced with BAP1/NF2 custom panel. The red and yellow circles indicate the regions with at least 10 variations (red) or mutated samples (yellow). The size of circles is proportional to variations/samples counted for each region. The genetic variations identified in NF2 were distributed throughout the sequenced exons. Conversely, the BAP1 genetic variations were enriched mainly in exons 13 and 17. Journal of Thoracic Oncology  , DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 BAP1 nuclear protein localization correlates with next-generation sequencing results. Top panel: contingency tables show the correlation between nuclear BAP1 protein expression and nonsynonymous variations detected by BAP1/NF2 custom panel. The lack of BAP1 protein expression was significantly correlated with the detection of nonsynonymous variations identified with allelic frequency of 10% or 25% (Fisher test p value < 0.01 for both 10% and 25% of allelic frequency). Bottom panel: BAP1 immunohistochemistry. A, malignant pleural mesothelioma with nuclear expression of BAP1 (arrow). B, malignant pleural mesothelioma with loss of BAP1 nuclear expression in neoplastic cells (thick arrow) and maintained BAP1 expression in endothelial and stromal normal cells (thin arrows; immunoperoxidase staining, ×400). Journal of Thoracic Oncology  , DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 TP53 and PIK3CA genetic variations identified by next-generation sequencing (NGS) and correlation with time to progressive disease or overall survival (OS) of malignant pleural mesothelioma patients. A, TP53 rs genotype and time to progressive disease/OS. In left part of panel, the genotypes of three patients identified by NGS are shown and confirmed by Sanger sequencing. In details, the left panel shows Sanger electropherograms for rs homo- (C:C), hetero- (C:G), and homo-zygote (G:G) samples. In the middle panel, the same samples were represented by NGS sequence BAM files uploaded in IGV software. In the right panel, KaplanMeier curves show the association between rs genotype and the early disease progression or reduced survival (log-rank p value indicated in figure). B, PIK3CA mutation I391M and patient progression/OS. Left part of panel shows the high correlation between Sanger and NGS data when the allelic frequency for mutation was ≥15% at NGS. In the right part of the figure. KaplanMeier curves and contingency table show associations between PIK3CA p.I391M mutation and early disease progression (log-rank and Fisher test p values indicated in the figure). Journal of Thoracic Oncology  , DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Correlation between the number of identified genetic variations and time to progressive disease (TTPD) or overall survival (OS). KaplanMeier curves show associations between one or more genetic validated variations identified (STK11: rs , TP53: rs , PIK3CA: COSM328028, KIT: COSM28026, and KDR: COSM149673) and TTPD or OS. In particular, an inverse correlation between the number of alterations identified in these genes (0, 1, 2, and ≥3 genetic variations) and TTPD or OS was observed (log-rank p value = 0.02 and 0.04, respectively). Median TTPD group with more than three genetic variations, 5 months; two genetic variations, 7.4 months; one genetic variation, 10.3 months; zero genetic variation, 22 months. Median OS group with more than three genetic variations, 12.8 months; two genetic variations, 16.6 months; one genetic variation, 19.7 months; zero genetic variation, 20.8 months. Journal of Thoracic Oncology  , DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

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