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Curated Journal Articles on Mesothelioma

Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective stud

Journal of Thoracic Oncology 2014 December 15 [Epub ahead of spring] [Link]

Lo Iacono M, Monica V, Righi L, Grosso F, Libener R, Vatrano S, Bironzo P, Novello S, Musmeci L, Volante M, Papotti M, Scagliotti GV.

Abstract

Introduction

Malignant pleural mesothelioma (MPM) is a rare malignant disease and the understanding of molecular pathogenesis has lagged behind other malignancies.

Methods

A series of 123 formalin-fixed, paraffin embedded (FFPE) tissue samples, with clinical annotations was retrospectively tested with a commercial library kit (Ion AmpliSeq Cancer Hotspot Panel v.2) to investigate 50 genes plus other two, BRCA1 associated protein-1 (BAP-1) and Neurofibromatosis-2 (NF2), frequently altered in MPM. DNA was obtained from tissues after manual microdissection and enriched for at least 50% cancer cells. Variations affecting protein stability or previously correlated to cancer, more frequently identified (≥25 patients with at least 10% of allelic frequency), were subsequently evaluated by Sanger sequencing. Immunohistochemistry staining for BAP1 and NF2 proteins was also performed.

Results

The commonest genetic variations were clustered in two main pathways: the p53/DNA repair (TP53, SMACB1, and BAP1) and PI3K-AKT pathways (PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, and NF2). PIK3CA:c.1173A>G mutation, STK11:rs2075606 (T>C) or TP53:rs1042522 (Pro/Pro) were significantly associated to time to progressive disease (TTPD) (all p-values<0.01). Furthermore, the accumulation of genetic alterations correlated with shorter TTPD and reduced OS, respectively (TTPD p-value=0.02, OS p-value=0.04). BAP1 genetic variations identified were mainly located in exons 13 and 17 and BAP1 non-synonymous variations were significantly correlated with BAP1 protein nuclear localization.

Conclusion

NGS was applied to a relatively large retrospective series of MPM using FFPE archival material. Our results indicate a complex mutational landscape with a higher number of genetic variations in the p53/DNA repair and Pi3K pathways, some of them with prognostic value.

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