Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma.

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Thoracoscopic Lobectomy Blooms in the VIOLET Trial.

Thoracoscopic Lobectomy Blooms in the VIOLET TrialLung cancer is currently the deadliest malignancy worldwide. Societal stigma, poor survival rates, and comparatively low funding for lung cancer research all contribute to lingering therapeutic nihilism. But there are reasons for optimism. Recent advances in precision oncology with targeted therapies, immunotherapy, life-saving lung cancer screening efforts, and curative surgery for early stages are improving outcomes. The VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy (VIOLET) study, a large multicenter randomized controlled trial (RCT) by Lim et al. from the United Kingdom, reports the benefit of minimally invasive surgical resection with video-assisted thoracoscopic surgery (VATS) versus open thoracotomy for lung cancer.

Therapeutic Synergy in Esophageal Cancer and Mesothelioma Is Predicted by Dynamic BH3 Profiling.

Approximately 20,000 patients per year are diagnosed with esophageal adenocarcinoma (EAC) and malignant pleural mesothelioma (MPM); fewer than 20% survive 5 years. Effective therapeutic strategies are limited although patients receive a combination of chemotherapeutics. These tumors harbor thousands of mutations that contribute to tumor development. Downstream of oncogenic driving mutations, altered tumor mitochondria promote resistance to apoptosis. Dynamic Bcl-2 homology-3 profiling (DBP) is a functional assay of live cells that identifies the mitochondrial proteins responsible for resistance to apoptosis. We hypothesized that DBP will predict which protein to target to overcome resistance thereby enhancing combinatorial therapy.DBP predicted that targeting either Mcl-1 or Bcl-xL increases the efficacy of the chemotherapeutic agent, cisplatin, whereas targeting Bcl-2 does not. We performed these assays by treating EAC and MPM cells with a combination of Bcl-2 homology-3 (BH3) mimetics and cisplatin. Following treatments, we performed efficacy assessments including apoptosis assays, IC50 calculations, and generation of a combinatorial index. DBP confirmed that targeting mitochondria with BH3 mimetics alters the threshold of apoptosis. These apoptotic effects were abolished when the mitochondrial pathway was disrupted. We validated our findings by developing knockdown models of antiapoptotic proteins Mcl-1, Bcl-xL, and the mitochondrial effector proteins Bax/Bak. Knockdown of Mcl-1 or Bcl-xL recapitulated the results of BH3 mimetics. In addition, we report an approach for BH3 profiling directly from patient tumor samples. We demonstrate that the DBP assay on living tumor cells measures the dynamic changes of resistance mechanisms, assesses response to combinatorial therapy, and provides results in a clinically feasible time frame.