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

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.

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.

EGFR-Mutated Breast Metastasis of Lung Adenocarcinoma: A Case Report.

Breast metastasis from other primary carcinoma is very rare and could be difficult to identify despite immunohistochemistry analysis. Breast metastasis from lung adenocarcinoma can mimic triple-negative breast cancer. Given the prognosis and therapeutic challenges, a correct diagnosis appears essential, and molecular biomarkers could be useful. We report the case of a 52-year-old woman with a breast mass initially diagnosed as primary breast cancer and secondarily attached to breast metastasis from an EGFR-mutated lung adenocarcinoma. The same activating EGFR mutations were identified in both the primary lung carcinoma and the breast metastasis.

Asymptomatic pelvic metastasis from thymic carcinoma: a case report.

Thymic epithelial tumors are rare and often occur somewhere local. Metastatic sites of thymic carcinomas (Masaoka-Koga stage IVb) are mostly seen in the lung, liver and brain. We report a 64-year-old female with an initial diagnosis of thymoma B3 who first showed thoracic recurrences and then an asymptomatic isolated pelvic metastasis from her thymic carcinoma.