Keywords
National Mesothelioma Virtual Bank, Translational Research, Biomarker, Informatics, Rare Disease Biobank, Patient Registries
Mesothelioma remains an under-researched cancerous disease due to the lack of high-quality patient samples and clinical information especially outcomes and asbestos exposure data. The National Mesothelioma Virtual Bank (NMVB) is a biobank in which mesothelioma annotated biospecimens can be made widely available to the research community. Here, we summarized the significant research findings from 20 publications that utilized the NMVB samples for novel biomarker and therapeutic discoveries. The results showed that the use of the NMVB resource was dispersed among a variety of basic science topics including, but not limited to, biomarkers, abnormal gene expression, and potential therapeutic targets. Positive biomarkers included several miRNAs and antibodies, HMGB1, ATG5, PIAS3, pancytokeratin and GATA3. Genes that had mutations or high/low levels of expression were BAP1, a human control gene of importance in this disease, as well as various cytokines, and checkpoint inhibitors TM4SF1, PKM2, ARHGDIA, COBLL1, WT1, FOXM1, and CD30. Treatments investigated include thiostrepton, interferon-β gene, and Brentuximab. Publications reviewed indicated a significant impact of the NMVB resource utilized in significant studies focusing on biomarker and therapeutic discoveries, which can act as a model for rare diseases, especially in oncology.
National Mesothelioma Virtual Bank, Translational Research, Biomarker, Informatics, Rare Disease Biobank, Patient Registries
Revised the manuscript with the guidance of the reviewer, including some singular and plural changes, rephrased some statements, and added three more references.
See the authors' detailed response to the review by Emanuela Felley-Bosco
See the authors' detailed response to the review by Brooke Mossman
Mesothelioma is commonly a cancerous tumor lining pleural and peritoneal surfaces.1 Occupational exposure to asbestos, a group of naturally occurring silicate minerals, is the leading cause of mesothelioma.2 Other mineral fibers (e.g., erionite, fluoro-edenite) are known to be carcinogenic with the potential cause to mesothelioma.2,3 Previous studies from the 1980s and 1990s suggested that long fibers of various types interact with the cell spindle in vitro inducing the mutation.4 However, mesothelioma is primarily an epigenetically regulated disease that results from interactions between cell surface receptors, protein cascades influencing transcription factors, gene expression, and the loss of tumor suppressor gene function.5,6 The most common symptoms include breathlessness, chest pain, difficulty swallowing, and pleural fluid accumulation; as disease worsens, it leads to death.3 Because mesothelioma is aggressive and fatal (approximately 8–14 months survival after diagnosis3), reduction in exposure and early diagnosis are essential. Biomarkers, especially mesothelin, have been proven useful in malignant pleural mesothelioma (MPM) diagnoses because of the over expression.3 Furthermore, sampling measures (pleural fluid), staging, immunohistochemistry (IHC), histology (epithelial, biphasic, and sarcomatoid) and imaging (chest radiography, CT imaging, PET-CT) can be used as distinguishers between the diagnosis and progression of MPM, as well as among MPM subtypes.3,7 There are both surgical and non-surgical treatment options available to prolong the survival of patients, such as chemotherapy, radiotherapy, targeted therapy, surgery, trimodality (consisting of surgery, chemotherapy and radiotherapy), and multimodality.3,7 Swiftly discovering and enhancing treatment options is imperative for researchers to provide maximum benefits to patients.
It’s challenging and sometimes impossible for biomedical researchers to obtain a sufficient number of mesothelioma patients’ high-quality samples and comprehensive clinical information for analysis. As tissue banking and annotation of specimens becomes increasingly widespread and improved in collection and storage of human biospecimens, a valuable resources can aid researchers in conducting basic and clinical science research that contribute toward personalized medical approaches in a clinical setting. The National Mesothelioma Virtual Bank (NMVB) (https://mesotissue.org/, last accessed on Oct 17th, 2022) is the largest US mesothelioma patient registry, and offers pleural and peritoneal mesothelioma biospecimens with high-quality data, which are critical for effective biomarker identification discovery and personalized medicine research. The NMVB database captures robust clinical data including patient demographics, epidemiology, and health assessment surveys; pathology, treatment, and outcomes can also be recorded and used in molecular analysis of tissue and blood specimens. Researchers can access statistical data using the public portal (https://data.mesotissue.org/data-page.html) or search the collection of mesothelioma biospecimens via the request fulfilment process (https://mesotissue.org/specimens). The NMVB serves as a leading resource for mesothelioma biospecimens by providing a sufficient number of mesothelioma cases, standardizing the data and specimen collection method, facilitating the sharing of information through the NMVB database, and addressing the issues of privacy constraint through confidentiality and de-identification.
Starting from 2006, the NMVB has collected over 2,000 archival mesothelioma and prospective mesothelioma biospecimens that have been obtained from surgical resections and biopsies, including fresh frozen and blood products. Retrospective collections include clinically collected specimens for diagnostic purposes from surgical and diagnostic biopsies, like paraffin tissue samples. Prospective collections are obtained from clinical visits in which physicians obtain permission for each NMVB study via e-informed consent. The NMVB has been supportive to researches using novel technologies, such as sequencing techniques, staining techniques (such as fluorescence), and DNA/gene expression analyses, to study potential mesothelioma inhibitors, activators, and therapies.
This manuscript aims to summarize the important research findings of key published studies that have utilized NMVB resources and to discuss the future direction of the NMVB. The innovative work discussed in this paper was conducted by a total of 320 researchers from 99 institutions or departments.
NMVB samples have allowed researchers to discover biomarkers for mesothelioma detection. This part will discuss the biomarkers under 4 categories: miRNAs, Autoantibodies, Extracellular Vesicles and Particles (EVP), and Gene Expression.
The expression of MicroRNAs can be utilized as a biomarker to determine stages of tumor progression, as well as to categorize cancer types (lung adenocarcinoma versus mesothelioma).8 Researchers have discovered that seven types of RNA—miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, and miR-429—are significantly downregulated in MPM compared to lung adenocarcinoma.8 Additionally, they identified that key downstream modulators, such as MYC and JUN, as well as effectors like VANGL1, RHOA, ROCK2, WNT5A, and PLCB1 of the Wnt pathway, are redundantly targeted by these downregulated miRNAs. This reduction in miRNA expression leads to the dysregulation of the Wnt pathway, which is a crucial process in the development of MPM. A 2013 study9 further indicated that microRNAs can be investigated in order to understand the change from non-cancerous to cancerous cell. This study found that within several mesothelioma cells, three miRNAs were under-expressed (miR-1, miR-206, and miR-133b). Specifically, miR-1 acted as an active malignant pleural mesothelioma tumor suppressor. In prior studies, SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME.10 A later study11 obtained tissues from several institutions, including the NMVB, to observe the existence of SV40 miRNA within tissue samples and failed to detect mature SV40 miRNAs, indicating that SV40 may not contribute to mesothelioma tumorigenesis.
Testing the antibodies against tumor-associated antigens in tissue and serum samples could be a reliable assay for recognition of malignant mesothelioma. Nine autoantibody biomarkers (PDIA6, MEG3, SDCCAG3, IGHG3, NADH dehydrogenase 1, BACRP11-484D18, CH507-528H12, RP11-413M2) from phage library have exhibited promising accuracy in detecting MM.12 In cell culture experiments, a prognostic marker, PIAS3, has been demonstrated to prevent mesothelioma growth through the inhibition of STAT3 activity.13 PIAS3 expression presents low or negative in the MM cells from NMVB tissue microarray slides, while it has been demonstrated to inhibit STAT3 activity and further prevent mesothelioma growth in cell culture experiments.13 PIAS3 holds promise as a potential drug target for MM.13 Another biomarker, cytoplasmic and extracellular HMGB1, is a mediator of autophagy. A study from the Hawaii Cancer Center14 found that asbestos exposure directly releases HMGB1 and impacts the Beclin 1/PI3K-III complex. HMGB1-mediated autophagy was induced by RAGE receptor and Beclin-1 pathway. That autophagy caused the upregulation of phosphorylated Beclin-1, whereas the silencing of HMGB1 caused p-Beclin-1 levels to greatly decrease, and autophagy was inhibited. Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells through autophagy. As an autophagy marker, ATG5 was detected high in the serum from asbestos-exposed individuals, which can be used as a prognostic biomarker as well.
Interestingly, EVP derived biomarkers are able to distinguish various cancer types. EVP proteins, HSPA8, and CD63 are commonly seen in EVPs. Two other EVP proteins, THBS1 and VCAN, and other less significant biomarkers, such as metabolic enzymes.15 More importantly, immunoglobulins are a key EVP protein for mesothelioma detection in plasma-derived EVP samples compared to other cancers. Specific EVP proteomes can aid in the classification of 16 cancer types including but not limited to: breast, lung, pancreatic carcinoma, etc.15
A research study,16 isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity, verified a six-peptide biomarker signature (intercellular adhesion molecule 1, basement membrane-specific heparan sulfate proteoglycan core protein, serum paraoxonase/arylesterase 1, mesothelin, hypoxia up-regulated protein 1, thrombospondin-1) that can be used to detect MPM. Since MPM has a poor prognosis, the tool has the potential to decrease the risk of false negatives when diagnosing individuals. The MPM signature has a higher sensitivity than the SMRP ELISA test.16 A case report17 dealing with a deceased sarcomatoid mesothelioma patient uncovered a loss of p16 cyclin-dependent kinase inhibitor 2A, which is a prominent feature of desmoplastic malignant mesothelioma. Additionally, CK7 and CK5/6 expression is essential in the diagnosis of sarcomatoid mesothelioma. Calretinin, D2-40, and WT-1 are likely elevated in certain central locations (especially the lung). Diffuse sarcomatoid mesothelioma is sensitive for GATA3 expression, but it has been showed that this mesothelioma type was improbable to present large levels of TTF-1 and carcinoembryonic antigen.7 Pleural-based sarcomas are commonly seen to have a loss of pancytokeratin and CD31, a vascular biomarker.
Previously, miRNAs were identified as potential biomarkers for the progression of non-cancerous cells to mesothelioma cancerous cells. The NMVB tissue bank has facilitated studies on new biomarkers (e.g., PIAS3 and HMGB1) that may have a role in mesothelioma expansion, proliferation and even inhibition. Other biomarkers may be useful in determining variations in the type of mesothelioma and differences between mesothelioma and other cancers of the lung.
An important factor of mesothelioma and other cancer types is the modification or increase/decrease of gene expression. BAP1 plays a pivotal role in regulating gene expression in malignant mesothelioma.7 ,17,18 In a study aiming to seek novel biomarkers for distinguishing malignancies,7 researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas. Out of 70 malignant mesothelioma (MM) biopsies (embedded tissue slides) in this research, BAP1 was mutated in 60% of the specimens.18 Not surprisingly, there is a loss of BAP1 expression in 50% of biphasic mesotheliomas and 25% of sarcomatoid mesotheliomas.17 In addition, BAP1 can be utilized in order to distinguish between non-small lung carcinoma and MM.7 Given about 10-20% immunohistochemical (IHC), a routine method differentiating MM and lung cancer, results to be unreliable in differentiation, scholars proposed to investigate BAP1 immunostaining as an potential accurate diagnosis predictor between the two cancer forms. The results shows that there was a greater lack of BAP1 nuclear staining in MM as compared to non-small lung carcinomas (in which the lack was extremely rare).
Merkel cell polyomavirus (MCPyV) is regarded as the first human polyomavirus with clear oncogenic potential, and it affects cell transformation relying on its large T antigen, like SV40. As SV40 have been suggested to be associated with MM, presence of MCPyV in mesothelioma was examined.19 Out of the 45 independent mesothelioma samples from the NMVB, 42 tissues were observed to have high level of cellular control gene RNaseP, while MCPyV was either never seen or detected at extremely low levels in all tissues. In 2020, researchers have studied the Bloom Syndrome (BLM) gene through multiple experiments in mesothelioma patients’ samples and animal models.20 BLM is a helicase enzyme that aids in DNA replication and the repair of DNA damage. There are two BLM mutations: biallelic BLM mutations and inactivating germline BLM heterozygous mutations. Biallelic mutations of the Bloom Syndrome gene cause Bloom Syndrome, leading to the risk of developing cancer because of chromosomal instability, the disruption of cell-cycle processes, and decreased p53-mediated apoptosis. Heterozygous BLM mutations lead to a truncated BLM protein. In a few experiments, the researchers found that some mesothelioma patients contained harmful BLM mutations. Another experiment regarding BLM-silencing human mesothelial cells found reduced caspase-3 levels, and therefore, reduced apoptosis in human mesothelial (HM) cells and reduced levels of phosphorylated histone γ-H2A.X involved in DNA repair. The researchers further conducted a mice experiment and observed an increase in M1 macrophages and levels of TNF-α, IL-1β, IL-3, IL-10, and IL-12(p70) for BLM heterozygous mutated mice compared to wide-type mice. These cytokines are linked to carcinogenesis.
A gene expression test study21 developed a molecular algorithm on gene ratio, that could improve the current MPM staging system, which has issues from small-scale, incapability with clinical staging. In this examination, samples would take assessed of gene expressions through clinical tests by combining lymph node status and histologic subtype. Utilizing MPM-matched frozen and formalin-fixed, paraffin-embedded (FFPE) samples, a gene expression score (GES) was confirmed to provide prognostic information about different patient conditions. GES evaluates the expression of four genes (TM4SF1, PKM2, ARHGDIA, and COBLL1) and three ratios (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA). This methodology has shown the robustness in evaluating patients’ survival and the high-tach assay performance.
Cells contain complicated interactions between cell surface receptors and transcriptional factors, leading to gene expressions that dictate the cell’s specific and wide-ranging functions. A SPaRTAN model is utilized to decipher the connections between cell surface receptors and transcriptional factors, which are then used as predictions for future transcriptional factor (TF) activity.22 The model includes a bilinear regression algorithm that learns an interaction matrix. SPaRTAN was applied to malignant peritoneal (MPeM) and pleural mesothelioma (MPM) tumors to obtain and analyze the regulatory states of CD8+ T cells. A portion of the MPeM CD8+ T cell population that was tested had high PD-1, TIM3, and TOGIT (checkpoint inhibitors) expression. A portion of the MPM CD8+ T cell population had the same results, indicating exhausted CD8+ T cells in these tumors. BCL3 activity was found in MPeM CD8+ T cells when PD-1 was present, but not in MPM CD8+ T cells.
In MM studies, BAP1 plays an essential role in malignant mesothelioma, showing a reduction in gene expression in malignant mesothelioma; similarly, abnormal expression levels of certain genes (e.g., BLM gene) may be indicators of mesothelioma. Utilizing algorithms such as the SPaRTAN and GES scores to understand cell activities.
Researchers have determined numerous therapeutic targets and potential inhibitory substances or molecules that could aid in the treatment of mesothelioma. There are two therapeutic targets, Forkhead box M1 (FOXM1) protein and CD30, that can decrease cell growth. Researchers observed that FOXM1 was present in the majority of human malignant mesothelioma cells (>50%).23 The protein FOXM1, controls gene expression in the cell cycle (specifically the S phase entry to mitosis), which assists in cell progression. CD30 is a cytokine receptor that aids in the regulation of apoptosis.24 To counter tumor progression, researchers utilized thiostrepton (TS) to inhibit this specific protein. TS disables peroxiredoxin 3 (PRX3) by increasing mitochondrial oxidant production, leading to the decrease of the FOXM1 protein and CD30 that cause cell death.23 As a result, FOXM1 and CD30 have the capability of being a therapeutic targets, and TS could be a therapeutic strategy. Researchers in 2015 observed the intensity of immunostaining using tissue microarray slides from the NMVB and applied brentuximab vedotin to target CD30 antigens.24 After subsequent analyses, CD30 mRNA expression was abnormally high in mesothelioma tissues, giving further evidence that the receptor could be a therapeutic target in the future. Additionally, brentuximab Vedotin does impact the activity of CD30, leading to decreased cell growth and survivability.
There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study25 has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for testing various treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay) by incubating the tissue sections with antibodies. As presumed, the expression of human IFN-β largely decreases of VSV-mediated cell lysis activity. And a preclinical mice study also confirm the delivery of IFNs would realize the addition in antitumor immune responses.
These studies have established FOXM1 and CD30 as therapeutic targets, and thiostrepton and brentuximab vedotin as therapeutic strategies that decrease cell stability. Additionally, the treatment of VSV vectors containing the Interferon-β gene serves as a cell progression inhibitor, as well.
Cases in which the usage of tumor samples aided in the determination of potential biomarkers, gene expression, and therapeutic factors for general mesothelioma and/or differentiating mesothelioma subtypes are summarized in Table 1.
Category | Platform | Research samples used in the study (not limited to samples from NMVB, may include samples from other resources) | Research findings | Publication |
---|---|---|---|---|
Biomarkers in tumor samples | Tissue and liquid biopsy tools for cancer detection | 497 normal and cancer-associated human and murine-derived samples | Extracellular vesicle and particle biomarkers are able to distinguish various cancer types through two main proteins (HSPA8 and CD63) and other less expressed proteins (such as THBS1 and VCAN). | 15 |
Targeted proteomics in serum sample | 402 serum sample from 213 MPM patients and 189 Asbestos-exposed patients | Intercellular adhesion molecule 1, basement membrane-specific heparan sulfate proteoglycan core protein, serum paraoxonase/arylesterase 1, mesothelin, hypoxia up-regulated protein 1, and thrombospondin-1 are biomarkers that can detect MPM. | 16 | |
Humoral immune response to cancer proteins | 5 tissue and 215 serum samples (NMVB) | 9 autoantibody biomarkers (PDIA6, MEG3, SDCCAG3, IGHG3, NADH dehydrogenase 1, BACRP11-484D18, CH507-528H12, RP11-413M2) in tissue and serum samples within the phage library (T7 MM) could provide accurate recognition of malignant mesothelioma | 12 | |
RT–PCR based assays | 28 nonmalignant biopsies, 20 pleural biopsies from lung adenocarcinoma patients and 94 mesothelioma tumor samples (made up of 42 epithelioid, 18 biphasic, 10 sarcomatoid, and 24 non-histologically defined mesothelioma patients) | SV40 is not a useful biomarker of mesothelioma. | 11 | |
Quantitative RT-PCR | 100 mesothelioma tumor samples: 77 mesothelioma tumor samples (NMVB) and 23 (Brigham and Women’s hospital) 32 adenocarcinoma tumor samples (National Disease Research Interchange) | Specifically, these 7 major types of microRNA, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, miR-429, can lead to the reduction of MYC, JUN, VANGL1, RHOA, ROCK2, WNT5A, or PLCB1 expression that is commonly found in mesothelioma. | 8 | |
Immunohistochemical stains | 32 primary lung adenocarcinomas, 13 primary lung SCC and 35 MM biopsies (20 epithelial, 8 biphasic, and 7 sarcomatoid) | MM has a lack of nuclear staining for BAP1 and non-small lung carcinoma has a positive BAP1 staining. The most specific marker for MM, adenocarcinoma, and SCC was WT1 nuclear positivity, TTF-1 & Napsin A, and p63 and p40, respectively. | 7 | |
Autophagy marker in sera | 29 serum samples from individuals with 4+ years of continuous exposure to asbestos fibers and mesothelial HMGB1-cKO mice | HMGB1 and ATG5 are biomarkers likely to cause carcinogenesis. | 14 | |
MicroRNA microarray transcriptional profiling studies | (unknown number) tumor samples from NMVB, 28 tumors (University of Minnesota Cancer Center), 6 patient’s normal parietal pleura without malignancies of any kind (Tissue Bank at Stanford Center), MPM cell lines (epithelial and sarcomatoid) (National Caner Institute) | miR-1 acts as an active MPM tumor suppressor. | 9 | |
Diagnosis and therapy history review | 1 sarcomatoid mesothelioma patient | There was positivity for pancytokeratin and GATA3. Additionally, there was a loss of CDKN2A and negativity for calretinin, D2-40, HBME and WT-1. | 17 | |
Protein expression in mesothelioma tumors | NMVB tissue microarray slides (does not state the exact amount) | Low PIAS3 expression in MM cells. PIAS3 prevents mesothelioma growth through the inhibition of STAT3 activity. | 13 | |
Changes of gene expression | Germline DNA sequencing | 122 pleural and peritoneal mesothelioma patients and germline DNA of 10 patients with mesothelioma | The cytokines, TNF-α, IL-1β, IL-3, IL-10, and IL-12(p70) are linked to carcinogenesis. BLM mutations can impact processes of the cell and proteins leading to cell death. | 20 |
Molecular test using fresh-frozen tissue | 73 patients with FFPE biopsy specimens and clinically documented evidence of surgical resection of the tumor with diagnosis of histologic subtype | As part of the GES system, the expression of four genes (TM4SF1, PKM2, ARHGDIA, and COBLL1) and three-ratios (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) are used for a more accurate patient condition reading. | 21 | |
Genomic and immunohistochemical analyses | 70 MM biopsies (embedded tissues slides) | BAP1 is mutated in 60% of the specimens, playing a pivotal role in regulating gene expression. | 18 | |
DNA extraction and PCR assay | 45 independent mesothelioma samples | 42 tissues were observed to have high levels of the human control gene. In contrast, merkel cell polyomavirus was either never seen or detected at extremely low levels in all tissues. | 19 | |
A computational method | Tumor samples | High PD-1, TIM3, and TIGIT checkpoint inhibitors expression in some populations of MPeM and MPM CD8+ T cells. | 22 | |
Therapeutic targets and potential inhibitory substances | Immunohistochemistry | 83 mesothelioma specimens | CD30 levels are high in mesothelioma cells. Brentuximab vedotin targets CD30 antigens. | 24 |
Test human mesothelial lines in vitro; animal studies | 48 mesothelioma tumors | Interferon- β prevent the lysis of mesothelioma cells when incorporate into a VSV vector, which is a virus that is normally an oncolytic agent. | 25 | |
Human tumor specimens analysis | Tissue microarrays (included duplicate paraffin-embedded sections for 46 tumors) | FOXM1 allows for cell progression. In turn, thiostrepton can be used to interfere with PRX3 in FOXM1 protein and cause cell death. | 23 | |
Biomedical informatics research | / | 888 pleural and peritoneal mesothelioma cases | Combined surgical and chemotherapy treatment in peritoneal mesothelioma is associated with improved survival compared to local therapy alone. | 30 |
/ | 508 history and physical reports | Both Dynamic-Window and ConText information extraction methods were dependant on the domain-specific lexicon and negation extraction. Although Dynamic- Window could be modified to retrieve other concepts, ConText is more robust and performs better on inconclusive concepts. | 29 | |
/ | 62 MPM-associated genes | The novel interactors KRT78, NDUFV2, PRMT1, RAN and RNH1—predicted to interact with the MPM genes KRT72, TYMS, PDPN, POLE and RRM1, respectively—had higher abundance in epithelioid samples, whereas IGHA2—predicted to interact with HSP90AA1—had higher abundance in sarcomatoid samples. | 31 | |
/ | 59 genes associated with malignant peritoneal mesothelioma | More than 75% of the interactome as a whole, and more than 60% of the novel interactors that were predicted to interact with MPeM-associated genes had MPeM-related transcriptomic aberrations in rodent and human cell line models. More than 70% of the repurposable drugs that researchers identified using comparative transcriptome analysis has been shown to be effective against peritoneal mesothelioma, pleural mesothelioma, peritoneal metastasis and/or primary peritoneal cancer in clinical trials, animal models or cell lines. | 32 | |
/ | 40 cases (36 were malignant mesothelioma) | Automated image analysis provides similar results to manual scoring by pathologist, and provides a reproducible, objective, and accurate platform for immunohistochemical assessment of biomarker expression. | 28 |
Through the process of continuously enriching the research cohort of mesothelioma patients and providing samples and research data to external institutions, the NMVB team has also been upgrading NMVB infrastructure using state-of-the-art informatics techniques and sharing our experience in peer-reviewed articles.26,27 We developed a multidisciplinary approach to conducting honest broker service efficiently and effectively, sharing our practical experience in Ref. 26. Using mesothelioma as an example, we have developed and deployed common data elements for tissue banks for translational research in cancer. These data elements are generalizable to other types of cancers.27
Furthermore, the NMVB team has been using NMVB data to conduct internal scientific research. We explored the potential of using automated image analysis in the evaluation of mesothelioma tissue microarray, matching the performance of manual scoring by pathologists.28 This result indicates that an automated image analysis approach may be a reproducible, objective, and accurate way for the immunohistochemical assessment of biomarker expression. In a cancer history classification study,29 we applied Natural Language Processing (NLP), a modern Artificial Intelligence technique, to automatically classify personal and family history from free-text medical reports of mesothelioma patients, with a high accuracy. In another study,30 we conducted a retrospective review of the NMVB cohort, and identified factors influencing malignant mesothelioma survival, including age (younger than 45), gender (female), epithelioid histological subtype, staging (I), peritoneal occurrence, and having the combined treatment of surgical therapy with chemotherapy. Moreover, for malignant pleural mesothelioma, we developed a novel computational algorithm that automatically discovered 364 potential protein-protein interactions, of which five interactions (BAP1-PARP3, KDR-ALB, PDGFRA-ALB, CUTA-HMGB1, and CUTA-CLPS) were validated experimentally; our comparative transcriptiome analysis identified five potentially repurposable drugs targeting the interactome proteins (cabazitaxel, primaquine, pyrimethamine, trimethroprim, and gliclazide).31 To share our findings with the whole research community, we make the discovered interactions publicly available through Wiki-MPM (https://hagrid.dbmi.pitt.edu/wiki-MPM/, last accessed on July 31st, 2022). Realizing the computational approach may be more needed with rare types, we further applied similar techniques on malignant peritoneal mesothelioma and identified 417 novel protein-protein interactions.32
Worldwide, many countries have established the specific mesothelioma registries, while others have cancer registries that include mesothelioma cases.33 As a country with large asbestos production and import in the past, Italy has one of the most comprehensive mesothelioma registries, the Italian National Mesothelioma Registry (ReNaM), founded in 1993. ReNaM identifies the mesothelioma cases by querying hospitals, clinics and pathology services and reviewing death certificates; obtains the lifestyle information, like residence and work history by questionaries; then evaluates the exposure level by working with hygienists.33 France has been collecting mesothelioma cases through National Program for Mesothelioma Surveillance (PNSM), utilizing similar questionnaire and exposure evaluation processes like ReNaM, but has several steps for different groups of expertise to confirm the mesothelioma diagnosis. For the Australia Mesothelioma Registry, it obtains mesothelioma case notifications from cancer registries in Australia nationwide and collects residential and occupational history from postal questionnaires first, then interviews patients via phone to assess their potential asbestos exposure. In the United Kingdom, the National Lung Cancer Audit and the National Mesothelioma Audit are the two audits that mainly collect mesothelioma patients information, while MesoBanK serves as a bio-source of pleural mesothelioma tissues.
In the United States, cancer data is reported by states and territories. The National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER) Program serve as the two federal cancer incidence surveillance systems, which together cover the entire US; and the National Vital Statistics System (NVSS) serves as a registry for cancer mortality.34 Though mesothelioma incidence and mortality data are provided in NPCR, SEER and NVSS, they are still limited in terms of information on exposure, biomarkers and treatment information in mesothelioma cases. NMVB, founded in 2006 by National Institute for Occupational Safety and Health (NIOSH), provides more detailed information, like work and exposure history, biospecimens, treatments and follow-ups, than the three surveillance systems. However, the NMVB is not population-based and has a relatively small number of participating centers.34
In the upcoming years, the NMVB plans to improve its system by expanding the reach of its database, and including specific specimen types and related annotation from mesothelioma researchers’ feedback. Currently, there are nine collaborating institutions that are a part of the NMVB, including New York University, University of Pittsburgh/UPMC, University of Pennsylvania, Roswell Park Cancer Institute, Mount Sinai School of Medicine (currently inactive), Baylor College of Medicine, Fox Chase Cancer Center, Temple University and University of Maryland (https://mesotissue.org/about/, last accessed on July 31th, 2022). Additionally, the NMVB hopes to make use of international networks like MesoNet (France), the United Kingdom Biobank and the Italian Mesothelioma Biobank to obtain far-reaching and increased data from mesothelioma patients that can be accessed by researchers.33
With regard to research findings using NMVB, there was a high number of publications that investigated and examined specific genes’ roles in mesothelioma, such as IFN-β, BAP1, and PIAS3, and pre-existing or current cancer/mesothelioma therapies, such as HDACi panobinostat, CRS, and HIPEC. In addition, there were publications related solely to the development and utilization of NMVB as a significant resource. Many publications had some positive scientific findings that allowed for possible therapies to aid in mesothelioma or cancer treatment including (but not limited to) delivery of type I IFNs, carcumin, brentuximab vedotin, panobinostat, and CRS/HIPEC. There were also gene markers that were not related to or did not provide enough information for lung inflammation, cancer, or mesothelioma, such as MCPyV DNA and CRP. When comparing mesothelioma and lung adenocarcinoma, there were certain miRNA expression that may be potential biomarkers. The NMVB has been shown to be a robust biobanking resource to support the fundamental domain of biomedical science, including molecular and genetic epidemiology, molecular pathology and pharmacogenomics.
The NMVB was cited in 879 publications in 2021 compared to 676 publications in 2020 (a nearly 30% increase). NMVB is on track for over 1000 citations in CY2022, establishing that the bank is important in sharing genomic data and specimens. There are many NMVB publications from the users of the resource that focus on biomarker development, of which some are previously discussed in this publication.
The NMVB is making efforts with the CDC and MedMorph to create advanced infrastructure and refined tools that can enhance data extraction of asbestos exposure and occupational health data. With so many years of practical experience, the team leaders of NMVB actively joined a nationwide workshop discussing the potential usefulness and feasibility of national mesothelioma registry.34 Moving forward, the NMVB is working with an epidemiology and occupational health expert and to gain knowledge through the CDC NIOSH to enhance the investigation of occupational history and the exposure that may contribute to mesothelioma.
Lastly, the NMVB utilizes a communications plan involving the NMVB website, mass mailings to users, and presentations at national meetings. The NMVB website contains links to the CTSA, NIH, NCI, Office of Biospecimen and Biorepository Research, National Center for Biotechnology Information, the Cancer Genome Atlas Project, as well as dozens of other biorepository and relevant organizational websites. These supply information about mesothelioma, biospecimens, and other specimens via a searchable database. Letters and/or e-mails are sent to investigators and their cancer research coordinators that have published articles in mesothelioma research in the recent past as well as investigators that have received or applied for Mesothelioma Foundation research grant funding. NMVB is always present and markets the resource especially at the Mesothelioma Applied Research Foundation’s annual symposium, the International Mesothelioma Interest Group’s biennial meeting, the AACR meeting and other research meetings. The NMVB will have outreach efforts, such as increasing the awareness of the NMVB resource, increasing education about the function NMVB and how it is operated, providing information about scientific advances facilitated by NMVB, and learning from the affected communities about the disease especially through active participation at the International Symposium on Malignant Mesothelioma (Mesothelioma Foundation sponsored annual meeting).
The NMVB has aided in biomarker, gene expression, and therapeutic target studies. NMVB plans to improve its resources and system allowing for future researchers to make widespread use of the data and specimens within the database. It is essential that the NMVB dataset continues to expand and play a pivotal role in cancer research, especially for possible treatments/phenomena that target NMVB specimens and aid in inhibiting tumor growth in certain cells.
We thank Schwenk, Melissa Dawn for setting up the NMVB research paper Google scholar webpage: https://scholar.google.com/.
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Is the topic of the review discussed comprehensively in the context of the current literature?
Yes
Are all factual statements correct and adequately supported by citations?
Yes
Is the review written in accessible language?
Partly
Are the conclusions drawn appropriate in the context of the current research literature?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Cytopathology, immunostaining, mesothelioma
Competing Interests: Am a member of the review team for NMVB
Reviewer Expertise: Mechanisms of mesothelioma development and therapy.
Is the topic of the review discussed comprehensively in the context of the current literature?
Yes
Are all factual statements correct and adequately supported by citations?
Partly
Is the review written in accessible language?
Yes
Are the conclusions drawn appropriate in the context of the current research literature?
Yes
References
1. MacCorkle RA, Slattery SD, Nash DR, Brinkley BR: Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts.Cell Motil Cytoskeleton. 2006; 63 (10): 646-57 PubMed Abstract | Publisher Full TextCompeting Interests: Dr. Mossman has used materials from the NMVB in her NIH-funded research and has reviewed research requests by others for materials from the NMVB.
Reviewer Expertise: Mechanisms of mesothelioma development and therapy.
Is the topic of the review discussed comprehensively in the context of the current literature?
Partly
Are all factual statements correct and adequately supported by citations?
Partly
Is the review written in accessible language?
Partly
Are the conclusions drawn appropriate in the context of the current research literature?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: fundamental and translational research in mesothelioma
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Version 2 (revision) 11 Sep 23 |
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Version 1 18 Nov 22 |
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Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
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