bims-mesote 2021-07-11 papers

Issue of 2021–07–11
seven papers selected by
Laura Mannarino, Humanitas Research

Comb Chem High Throughput Screen. 2021 Jul 06.

KIAA0101 in Malignant Pleural Mesothelioma: a Potential Diagnostic and Prognostic Marker.

Ping Lin, Yuean Zhao, Xiaoqian Li, Zongan Liang.

BACKGROUND: Currently, there are no reliable diagnostic and prognostic markers for malignant pleural mesothelioma (MPM). The objective of this study was to identify hub genes that could be helpful for diagnosis and prognosis in MPM by using bioinformatics analysis.
MATERIALS AND METHODS: The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA), LASSO regression analysis, Cox regression analysis, and Gene Set Enrichment Analysis (GSEA) were performed to identify hub genes and their functions.
RESULTS: A total of 430 up-regulated and 867 downregulated genes in MPM were identified based on the GSE51024 dataset. According to the WGCNA analysis, differentially expressed genes were classified into 8 modules. Among them, the pink module was most closely associated with MPM. According to genes with GS > 0.8 and MM > 0.8, six genes were selected as candidate hub genes (NUSAP1, TOP2A, PLOD2, BUB1B, UHRF1, KIAA0101) in the pink module. In the LASSO model, three genes (NUSAP1, PLOD2, and KIAA0101) were identified with non-zero regression coefficients and were considered hub genes among the 6 candidates. The hub gene-based LASSO model can accurately distinguish MPM from controls (AUC = 0.98). Moreover, the high expression level of KIAA0101, PLOD2, and NUSAP1 were all associated with poor prognosis compared to the low level in Kaplan-Meier survival analyses. After further multivariate Cox analysis, only KIAA0101 (HR = 1.55, 95% CI = 1.05-2.29) was identified as an independent prognostic factor among these hub genes. Finally, GSEA revealed that high expression of KIAA0101 was closely associated with 10 signaling pathways.
CONCLUSION: Our study identified several hub genes relevant to MPM, including NUSAP1, PLOD2, and KIAA0101. Among these genes, KIAA0101 appears to be a useful diagnostic and prognostic biomarker for MPM, which may provide new clues for MPM diagnosis and therapy.

Keywords: GEO; Malignant pleural mesothelioma; TCGA; WGCNA; biomarker

DOI: https://doi.org/10.2174/1386207324666210707105634

Front Oncol. 2021 ;11 704295

Lurbinectedin in Refractory Diffuse Malignant Peritoneal Mesothelioma: Report of Two Cases.

Louis Gros, Petr Szturz, Antonella Diciolla, Volker Kirchner, Solange Peters, Niklaus Schaefer, Martin Hubner, Antonia Digklia.

Mesothelioma is a malignancy of serosal membranes. Parietal pleura is the most common site, with peritoneum being the second most frequent location. Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. The prognosis is often very poor with median overall survival ranging from 6 to 18 months in patients who are not candidates for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) due to non-resectable disease or comorbid conditions. For patients with resectable disease, CRS and HIPEC have become the standard of care. However, for patients with unresectable malignant mesothelioma there is unfortunately no effective systemic treatment beyond the first line. Based on the results of a recent phase II trial, lurbinectedin has clinical activity and acceptable toxicity in the second- and third-line treatment of malignant pleural mesothelioma. However, until present, no data have been available for patients with MPM and for patients who become refractory after multiple treatment lines. We report on two patients with metastatic MPM who achieved durable disease control of 10+ and 8 months with lurbinectedin in the fourth and fifth treatment line, respectively.

Keywords: case report; durable response; lurbinectedin; palliative chemotherapy; peritoneal mesothelioma; peritoneal tumor

DOI: https://doi.org/10.3389/fonc.2021.704295

Respir Med. 2021 Jun 29. pii: S0954-6111(21)00233-X. [Epub ahead of print]186 106527

Mesothelioma in immigrants from Turkey: Genes have a minor role.

Selma Metintas, Muzaffer Metintas, Guntulu Ak, Gunnar Hillerdal, Hirsh Koyi.

OBJECTIVE: To examine the incidence and epidemiology of malignant mesothelioma in immigrants from Karain where there is an extraordinarily high incidence of mesothelioma, Cappadocia, Turkey, to Stockholm, Sweden, and their children over 20 years of age born in Stockholm, i.e. two genetically similar populations with and without erionite exposure.
METHODS: This survey was conducted as a retrospective cohort study. Standardized average annual mesothelioma incidence rates (AAMIRs) and mesothelioma standardized incidence ratio (mSIR) were calculated. Cox regression analysis was used to determine the importance of different factors related to mesothelioma risk.
RESULTS: The cohort consisted of 337 people, 203 of whom were born and/or lived in Karain before immigrating to Sweden (erionite-exposed), and 134 who were born in Stockholm (erionite-unexposed). There were 69 deaths, 42 (61%) due to mesothelioma, and two patients with the disease who were still alive. Of these 44 patients, 22 were men. All mesothelioma patients were in the erionite-exposed group. In the age group 30-49 years, mesothelioma developed in 11 of 38 (29%) with erionite exposure, while there were no cases among 86 persons in the non-exposed group. For men, the AAMIR was 253.9 per 100,000 persons in the whole cohort, and for women, it was 350.9. The mSIR was 71.9 for men and 393.1 for women. Exposure to erionite exceeding 20 years and age over 40 years were associated with increased mesothelioma risk.
CONCLUSION: Exposure to erionite is the leading cause of mesothelioma in Karain villagers, and genetic factors are probably of minor importance.

Keywords: Environmental exposure; Epidemiology; Erionite; Genetic; Mesothelioma

DOI: https://doi.org/10.1016/j.rmed.2021.106527

Eur Rev Med Pharmacol Sci. 2021 Jun;pii: 26129. [Epub ahead of print]25(12): 4236-4246

Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond.

F Pagliuca, F Zito Marino, F Morgillo, C Della Corte, M Santini, G Vicidomini, G Guggino, G De Dominicis, S Campione, M Accardo, I Cozzolino, R Franco.

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

DOI: https://doi.org/10.26355/eurrev_202106_26129

Pathol Int. 2021 Jul 09.

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Kenzo Hiroshima, Di Wu, Eitetsu Koh, Yasuo Sekine, Daisuke Ozaki, Toshikazu Yusa, Tadao Nakazawa, Shoutaro Tsuji, Yohei Miyagi, Ann E Walts, Alberto M Marchevsky, Aliya N Husain, Kohzoh Imai.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.

Keywords: HEG1; immunohistochemistry; mesothelial marker; mesothelioma

DOI: https://doi.org/10.1111/pin.13140

Br J Cancer. 2021 Jul 05.

Biological basis for novel mesothelioma therapies.

Joanna Obacz, Henry Yung, Marie Shamseddin, Emily Linnane, Xiewen Liu, Arsalan A Azad, Doris M Rassl, David Fairen-Jimenez, Robert C Rintoul, Marko Z Nikolić, Stefan J Marciniak.

Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

DOI: https://doi.org/10.1038/s41416-021-01462-2

Front Oncol. 2021 ;11 679609

How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers.

Kiarash Behrouzfar, Kimberley Burton, Steve E Mutsaers, Grant Morahan, Richard A Lake, Scott A Fisher.

Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC-MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.

Keywords: Collaborative Cross; MexTAg; host genetics; mesothelioma; thoracic malignancies; tumor immune microenvironment

DOI: https://doi.org/10.3389/fonc.2021.679609