Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

Zhang, Min; Luo, Juan; Sun, Qianqian; Harber, James; Dawson, Alan G.; Nakas, Apostolos; Busacca, Sara; Sharkey, Annabel J.; Waller, David; Sheaff, Michael; Richards, Cathy; Wells-Jordan, Peter; Gaba, Aarti; Poile, Charlotte; Baitei, Essa Y.; Bzura, Aleksandra; Dzialo, Joanna; Jama, Maymun; Quesne, John Le; Bajaj, Amrita; Martinson, Luke; Shaw, Jacqui A.; Pritchard, Catrin; Kamata, Tamihiro; Kuse, Nathaniel; Brannan, Lee; Zhang, Pan De Philip; Yang, Hongji; Griffiths, Gareth; Wilson, Gareth A.; Swanton, Charles; Dudbridge, Frank; Hollox, Edward J.; Fennell, Dean A.

doi:10.1038/s41467-021-21798-w

Cited by 79 publications

(89 citation statements)

References 57 publications

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“…Indeed, the study of intratumor heterogeneity of MPM through an exome sequencing approach has shown that most MPMs follow a linear evolution with BAP1 being the most frequent ancestral mutation and NF2 arising mainly as a late event. Moreover, a minority of patients presented a branched evolution that was associated with a higher tumor lymphocyte infiltration and antigen burden, suggesting a possible sensitivity to immunotherapy ( 139 ).…”

Section: Therapeutic Implications Of Genomics and Transcriptomics Evidencesmentioning

confidence: 99%

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

et al. 2021

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Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

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Section: Therapeutic Implications Of Genomics and Transcriptomics Evidencesmentioning

confidence: 99%

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

et al. 2021

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“…Our study was not designed for evaluating the diagnostic sensitivity and specificity of surgical biopsy nor to compare it with less-invasive techniques, evaluated in previous analyses, like trans-bronchial or trans-esophageal biopsies [ 22 , 23 ]. However, the 3.7% rate of redo surgery for diagnostic failure highlights the complexity of pathological assessment and the usefulness of large pleural sampling, especially in the era of molecular and tumor microenvironment analyses [ 5 , 24 , 25 ]. Moreover, it should be noted that “classical” medical thoracoscopy has also been reported as a relevant and reasonable alternative for pleural biopsy and simultaneous talc poudrage, nevertheless exhibiting lower efficiency than surgical procedures in reaching both diagnostic and therapeutic objectives [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Surgical Diagnosis of Malignant Pleural Mesothelioma: 20 Years’ Experience at a High-Volume Referral Center

Iaffaldano

Charrier

Lococo

et al. 2021

JCM

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Despite advances, malignant pleural mesothelioma (MPM) remains a challenging disease in terms of diagnosis, treatment, and overall management. Herein, we analyzed, in a large-scale single-center cohort, the characteristics and perioperative course of patients undergoing surgical diagnosis of MPM. We identified a total of 514 consecutive patients, 71.4% male and 28.6% female, with mean age 71.3 +/− 13.6 years. Most exhibited pleural, respiratory, or general symptoms and American Society of Anesthesiologists (ASA) score was ≥3 in 68.3% of cases. Thoracoscopy was the most frequent approach (92.0%) and short open thoracotomy was performed in the remaining patients. Pleurodesis was simultaneously performed in 74.3% of cases. Diagnostic failure led to redo surgery in 3.7% of patients. Non-epithelioid histology was found in 19.5% of MPMs and was significantly more frequent in right-sided MPM (p = 0.04), and in patients without history of cancer (p = 0.03), or pleural nodules at thoracoscopy (p = 0.01). Minor only or major complications occurred in respectively 7.8% and 3.6% of cases. They were more frequent in patients ≥ 70 years (p = 0.05) and Performance Status > 2 (p = 0.05). The mean hospital stay was 7.5 days. The 30-day and 90-day early mortality rates were 2.3% and 6.4%, respectively. Surgical diagnosis of MPM is a reliable procedure but is associated with significant morbidity and hospital-stay duration.

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“…Chromosomal instability may result in gross karyotypic alterations. It has been related to cancer immunogenicity (27), and is a common feature of MPM (34,35). Genome-wide copy number analysis performed in 113 MPM tumors with IHC data for PD-L1, CD4, CD8, and FOXP3 was used to compute the percent genome aberration (PGA) for each sample as total count of base pairs involved in copy number gains or losses divided by the total length of the genome in base pairs (36).…”

Section: Genetic and Epigenetic Effects On The Immune Responsementioning

confidence: 99%

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

2021

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Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response.

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Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

Cited by 79 publications

References 57 publications

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Surgical Diagnosis of Malignant Pleural Mesothelioma: 20 Years’ Experience at a High-Volume Referral Center

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

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