scholarly journals Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

2020 ◽  
Vol 14 ◽  
pp. 175346662093577 ◽  
Author(s):  
Jia Hu ◽  
Baoshi Zhang ◽  
Fangfang Yao ◽  
Yan Fu ◽  
Dianjun Chen ◽  
...  
Keyword(s):  
Case Report ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Alk Rearrangement ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Incremental Step

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

scholarly journals Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Clément Meiller ◽  
François Montagne ◽  
Theo Z. Hirsch ◽  
Stefano Caruso ◽  
Julien de Wolf ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Immunological Synapse ◽  
Side Wall ◽  
Molecular Classification ◽  
Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Methylome Analysis

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

scholarly journals Malignant pleural mesothelioma and gastric metastasis: A very rare case report and literature review

2016 ◽  
Vol 3 (2) ◽  
pp. 181
Author(s):  
Nergis Ekmen ◽  
Hadi Sasani ◽  
Levent Erdem ◽  
Özkan Demirhan ◽  
GülenBülbül Doğusoy
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Malignant Pleural Mesothelioma ◽  
Rare Case ◽  
Pleural Mesothelioma ◽  
Gastric Metastasis ◽  
Rare Case Report

scholarly journals Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2454
Author(s):  
Federica Torricelli ◽  
Filippo Lococo ◽  
Teresa Severina Di Stefano ◽  
Eugenia Lorenzini ◽  
Simonetta Piana ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Deep Sequencing ◽  
Validation Cohort ◽  
Genetic Alterations ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Specific Subset ◽  
Validation Set ◽  
Custom Panel ◽  
Deep Sequencing Analysis

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients’ survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients’ risk stratification.

scholarly journals Anaplastic lymphoma tyrosine kinase oncogene in human cancer: gene aberrations, methods of detection and therapeutic potential

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Rosalaura Sabetta ◽  
Monica Gargiulo ◽  
Marina Accardo ◽  
Federica Zito Marino ◽  
Renato Franco
Keyword(s):  
Tyrosine Kinase ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Acquired Resistance ◽  
Specific Inhibitor ◽  
Genetic Alterations ◽  
Alk Rearrangement ◽  
Detection Mechanism ◽  
Targeting Therapy ◽  
Anaplastic Lymphoma

Anaplastic lymphoma tyrosine kinase (ALK) gene could be an attractive oncotarget in human cancers, since it is involved in several genetic alterations resulting in an aberrant activity of the receptor. To date, ALK-rearrangement represents a molecular target for the treatment of ALK-rearranged Non Small Cell Lung Cancer patients, who are highly sensitive to crizotinib, a specific inhibitor. ALK-rearranged patients treated with crizotinib show relevant clinical implications, however several different resistance mechanisms have been identified. Here we review various critical issues related to ALK-targeting therapy, including ALK gene aberrations, methods of detection, mechanism of acquired resistance and second-generation ALK inhibitors.

Concomitant Presence of EGFR and ALK Fusion Gene Mutation in Adenocarcinoma of Lung: A Case Report and Review of the Literature

2017 ◽  
Vol 31 (2) ◽  
pp. 244-248
Author(s):  
Nishitha Thumallapally ◽  
Hana Yu ◽  
Mohammad Farhan ◽  
Uroosa Ibrahim ◽  
Maricel Odiami
Keyword(s):  
Molecular Mechanisms ◽  
Fusion Gene ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Adenocarcinoma Of Lung ◽  
Practical Guidelines ◽  
Oncogenic Driver

Empirical evidence has long suggested that oncogenic driver mutations in non-small-cell lung cancer are mutually independent. However, recent studies reported in pertinent literature reveal that concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement can occur in a subset of patients with NSCLC. In order to shed further light on this issue, we report a case of adenocarcinoma of lung harboring both EGFR mutation in exon 21 (L861Q) and ALK rearrangement. This allows us to speculate on likely molecular mechanisms underlying this uncommon phenomenon, while also offering some practical guidelines on the therapeutic options that could benefit patients diagnosed with this dual-positive tumor.

Malignant pleural mesothelioma showing a solitary shadow in the lung field-A case report-

2011 ◽  
Vol 50 (2) ◽  
pp. 115-119
Author(s):  
Eisaku MIYAUCHI ◽  
Keita KUDO ◽  
Rira HOSHI ◽  
Noriyuki FURUTA ◽  
Yasuo HIRAI ◽  
...  
Keyword(s):  
Case Report ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Lung Field

Malignant pleural mesothelioma with a 14-year survival: A case report and electronmicroscopic study

1982 ◽  
Vol 20 (4) ◽  
pp. 253-259 ◽  
Author(s):  
Marcella Klima ◽  
Harlan J. Spjut ◽  
Mattie I. Bossart ◽  
O. Howard Frazier ◽  
Denton H. Cooley
Keyword(s):  
Case Report ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Electronmicroscopic Study
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