Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Occupations and industries in France at high risk for pleural mesothelioma: A population-based case-control study (1998-2002).

BACKGROUND: Occupational exposure to asbestos, widely used in various industries for decades, is the most important risk factor for pleural mesothelioma. We report here the ranking of occupations and industries in France at high risk for this cancer among men and women. METHODS: A population-based case-control study, conducted from 1998 to 2002, included 462 cases (80.3% men) and 897 controls. Data were collected in face-to-face interviews with a standardized questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each occupation and industry; subjects never employed in each category were the reference. RESULTS: For men, risks were high for several occupations and industries. Besides the expected high risks for non-metallic mineral product makers and manufacturing asbestos products, occupations such as plumbers (OR = 5.57, 95% CI: 2.90-10.69), sheet-metal workers, welders, metal molders, coremakers, and cabinetmakers were also at high risk. Elevated risks were found in the industries of shipbuilding (OR = 9.13, 95% CI: 5.20-16.06) and construction, but also in the manufacturing of metal products, chemicals, and railroad and aircraft equipment. The results for women showed increased but not significant risks in several occupational activities. CONCLUSIONS: This report provides new insight into the epidemiology of mesothelioma, confirming risks for occupational activities reported earlier and pointing out risks in activities never previously reported. It offers guidance to authorities for the compensation of asbestos victims and for prevention in at-risk activities still involving asbestos-containing products.

Lymphohistiocytoid variant of malignant mesothelioma of the pleura: a series of 22 cases.

The lymphohistiocytoid variant of diffuse malignant mesothelioma is rare with very few cases described in the literature. It is characterized by mesothelial cells with a histiocytelike appearance and an associated dense lymphoid infiltrate. We studied clinicopathologic features and immunohistochemical patterns of a series of 22 cases. The histiocytelike cells had a mesothelial immunophenotype: AE1/AE3 (100%), calretinin (100%), CK5/6 (46%), and EMA (52%). The prominent lymphoid component showed a cytotoxic T-cell immunophenotype. Prognosis was similar to that of a large series of epithelioid diffuse malignant mesotheliomas. Formely, it was classified within the sarcomatoid type. We suggest that it should be reclassified as an epithelioid variant because of its similar behavioural characteristics. There was no evidence of Epstein-Barr virus-related infection.

Plasma cell membrane localization of c-MET predicts longer survival in patients with malignant mesothelioma: a series of 157 cases from the MESOPATH Group.

INTRODUCTION: By regulating cell functions such as growth, survival, motility/migration, and invasion, the c-mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase/hepatocyte growth factor (HGF) axis accounts for a critical pathway in malignant pleural mesothelioma. METHODS: Overall survival correlations of c-MET and phospho-c-MET immunostainings were investigated in 157 malignant pleural mesothelioma patients for whom paraffin-embedded specimens were referred to our center for pathological diagnosis certification (MESOPATH French National group). Subcellular localization of the activated c-MET receptor after HGF stimulation was assessed in nontumorogenic cell lines. RESULTS: Positive c-MET expression was found in 119 samples (75.8%), more frequently in the epithelioid subtype (p < 0.0001). Among those 119 positive c-MET specimens, 77 (64.7%) were also positive for phospho-c-MET. Both c-MET and phospho-c-MET scoring were independent of patient gender or age. Phospho-c-MET scoring or localization did not associate with survival. Conversely, patients with a c-MET immunohistochemical staining intensity higher than 1, but exclusively confined to plasma membrane, had a median overall survival of 25 months versus 13 months for all other patients. Only exclusive plasma membrane staining remained significantly associated with a worse prognosis in multivariate analysis (hazard ratio = 2.9, 95% confidence interval 1.0-8.2, p = 0.043). Using the HBEC3 immortalized epithelial cell lines treated with HGF, we showed the physiological relevance of phospho-c-MET nuclear translocation. CONCLUSIONS: Our results lighten that, disregarding the intracellular c-MET receptor traffic, only c-MET plasma membrane localization could be a relevant prognosis biomarker in malignant pleural mesothelioma. Whether patients with c-MET plasma membrane immunostaining could beneficiate from c-MET-targeted therapies remains to be established in prospective trials.