BRCA1-associated Protein Research Articles

BAP1 mutations inhibit the NF-κB signaling pathway to induce an immunosuppressive microenvironment in uveal melanoma

BackgroundTumor immune microenvironment regulates the growth and metastasis of uveal melanoma (UM). This study aims to reveal the possible molecular mechanism of BRCA1-associated protein 1 (BAP1) mutations in affecting the tumor immune microenvironment in UM through mediating the nuclear factor-κB (NF-κB) signaling pathway.MethodsTCGA and cBioPortal databases jointly analyzed the genes with high mutation frequency in UM samples. Following survival analysis of UM patients, UM samples with BAP1 mutations were subjected to immune cell infiltration analysis. The signaling pathways associated with the mutated genes were screened by GSEA. Subsequently, the differential BAP1 expression was analyzed in the selected UM cell lines with wild type (WT) or mutant type (MUT) BAP1.ResultsBioinformatics analysis identified 12 genes mutated in the UM samples, while only BAP1 mutations were related to the prognosis of UM patients. UM patients with BAP1 mutations had higher immune cell infiltration. BAP1 mutations inhibited the NF-κB signaling pathway, suppressing the cytokine secretion and antigen presentation by macrophages. Rescue experiments confirmed that overexpressed NF-κB could reverse the effect of BAP1 mutations on the immunosuppressive microenvironment, thus suppressing the malignant phenotypes of UM cells.ConclusionBAP1 mutations may inhibit the NF-κB signaling pathway, repressing the cytokine secretion and antigen presentation by macrophages, which induces the immunosuppressive microenvironment, enhances the malignant phenotypes of UM cells and ultimately promotes the growth and metastasis of UM.

BRCA Associated Protein-1 Immuno-Histochemical Stain in Diagnosis of Malignant Mesothelioma

Objective: To differentiate malignant mesothelioma from benign mesothelial proliferations and other histological mimickers such as adenocarcinoma and squamous cell carcinoma, utilizing BRCA Associated protein1 (BAP1) immune-histochemical stain.
 Study Design: Retrospective longitudinal study.
 Place and Duration of Study: Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore Pakistan, from 2015 to 2020.
 Methodology: We examined BAP1 IHC expression in 82 cases, including 56 malignant mesotheliomas, 12 Adenocarcinomas, and 14 Squamous cell carcinomas. Fifty-six malignant mesotheliomas included 49 epithelioid, 6 Biphasic and one sarcomatoid subtype. Loss of expression was established for cases showing complete loss of nuclear staining.
 Results: Of 56 malignant mesotheliomas, 38(67.85%) showed loss of BAP1 expression, whereas 18(32.14%) showed retained expression. Of 12 adenocarcinoma cases, 10(83.33%) showed retained expression. Similarly, out of 14 squamous cell carcinomas, 12(85.71%) showed retained expression.
 Conclusion: Loss of nuclear expression of BAP1 IHC serves as a valuable diagnostic ancillary tool in distinguishing malignant mesothelioma from its histological mimickers.Keywords: BAP1, Immunohistochemistry, Malignant mesothelioma.

BRAP silencing protects against neuronal inflammation, oxidative stress and apoptosis in cerebral ischemia-reperfusion injury by promoting PON1 expression.

BRCA1 associated protein (BRAP) participates in the regulation of myocardial infarction and atherosclerosis. But the function of BRAP in cerebral ischemia-reperfusion (CIR) injury has not been elucidated yet. BRAP expression in PC12 cells in response to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment was examined with Western blot assay. PC12 cells underwent OGD/R-treatment and were subsequently transfected with pcDNA-BRAP or sh-BRAP, followed by determination of viability, lactate dehydrogenase (LDH) production, apoptosis, inflammatory cytokine secretion, and oxidative stress marker protein levels. Paraoxonase 1 (PON1) promoter methylation was evaluated with methylation-specific PCR assay. the effect of BRAP/PON1 axis on CIR injury was investigated by rescue experiments. Additionally, sh-BRAP was injected into a middle cerebral artery occlusion (MCAO) rat model, and the changes of neurological damage were evaluated. BRAP overexpression exacerbated OGD/R-induced viability reduction, LDH production, apoptosis, inflammatory cytokine secretion and oxidative stress in PC12 neuronal cells. In contrast, BRAP silencing showed the opposite results. Mechanistically, BRAP reduced PON1 expression by promoting DNA methyl transferase1 (DNMT1)-mediated PON1 promoter methylation. PON1 silencing reversed BRAP-mediated neuroprotection. Additionally, BRAP silencing alleviated CIR-induced neurological damage in MCAO rats. BRAP silencing suppressed OGD/R-induced neuronal apoptosis, inflammation, and oxidative stress, and alleviated CIR-induced neurological damage in MCAO rats through facilitating PON1 expression.

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

Malignant mesothelioma cells with characteristic intracytoplasmic vacuolization and lipids.

In this brief report, we described some uncommon cytomorphological features of malignant mesothelioma (MM) cells in pleural effusions. The tumor cells exhibited abundant cytoplasmic vacuolization, with presence of single or multiple eccentric nuclei in several cells. In the Giemsa-stained smear, we observed a glossy spherical material in some cells, which tested positive in Sudan III stain. In immunocytochemical analysis, tumor cells were positive for calretinin, podoplanin, epithelial membrane antigen, and methylthioadenosine phosphorylase; tumor cells were negative for BRCA1-associated protein 1, CD68, and desmin. The intracytoplasmic vacuoles were positive for adipophilin expression.

Deficiency of BAP1 inhibits neuroblastoma tumorigenesis through destabilization of MYCN

The transcription factor MYCN is frequently amplified and overexpressed in a variety of cancers including high-risk neuroblastoma (NB) and promotes tumor cell proliferation, survival, and migration. Therefore, MYCN is being pursued as an attractive therapeutic target for selective inhibition of its upstream regulators because MYCN is considered a “undruggable” target. Thus, it is important to explore the upstream regulators for the transcription and post-translational modification of MYCN. Here, we report that BRCA1-associated protein-1 (BAP1) promotes deubiquitination and subsequent stabilization of MYCN by directly binding to MYCN protein. Furthermore, BAP1 knockdown inhibits NB tumor cells growth and migration in vitro and in vivo, which can be rescued partially by ectopic expression of MYCN. Importantly, depletion of BAP1 confers cellular resistance to bromodomain and extraterminal (BET) protein inhibitor JQ1 and Aurora A kinase inhibitor Alisertib. Furthermore, IHC results of NB tissue array confirmed the positive correlation between BAP1 and MYCN protein. Altogether, our work not only uncovers an oncogenic function of BAP1 by stabilizing MYCN, but also reveals a critical mechanism for the post-translational regulation of MYCN in NB. Our findings further indicate that BAP1 could be a potential therapeutic target for MYCN-amplified neuroblastoma.

CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma

Malignant mesothelioma (MMe) is a rare but aggressive malignancy. Although the molecular genetics of MMe is known, including BRCA1-associated protein-1 (BAP1) gene alterations, the prognosis of MMe patients remains poor. Here, we generated BAP1 knockout (BAP1-KO) human mesothelial cell clones to develop molecular-targeted therapeutics based on genetic alterations in MMe. cDNA microarray and quantitative RT-PCR (qRT-PCR) analyses revealed high expression of a calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D) gene in the BAP1-KO cells. CAMK2D was highly expressed in 70% of the human MMe tissues (56/80) and correlated with the loss of BAP1 expression, making it a potential diagnostic and therapeutic target for BAP1-deficient MMe. We screened an anticancer drugs library using BAP1-KO cells and successfully identified a CaMKII inhibitor, KN-93, which displayed a more potent and selective antiproliferative effect against BAP1-deficient cells than cisplatin or pemetrexed. KN-93 significantly suppressed the tumor growth in mice xenografted with BAP1-deficient MMe cells. This study is the first to provide a potential molecular-targeted therapeutic approach for BAP1-deficient MMe.

Research Progress of BAP1 in Structure, Function, and Cancer.

Cancer is an important chronic non-communicable disease that endangers human health and has become the main cause of death of residents around the world in the 21st century. At present, most of the mature treatment methods stay at the level of cell and tissue, which is difficult to fundamentally solve the problem of cancer. Therefore, explaining the pathogenesis of cancer at the molecular level becomes the answer to the key problem of cancer regulation. BRCA-associated protein 1 (brca1- associated protein 1) is a kind of ubiquitination enzyme encoded by the BAP1 gene and composed of 729 amino acids. As a carcinogenic protein, BAP1 can affect the cancer cell cycle and proliferation capacity, mutation, and deletion. For example, depending on catalytic activity, it participates in the regulation of intracellular function through transcription, epigenetic, and DNA damage repair. This article mainly reviews the basic structure and function of BAP1 in cells, its role in cancer development, and cancer-related mutants.

Tumores renales múltiples y hereditarios. Revisión por y para radiólogos

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of “sporadic” multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended.Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition.The concept of “non-hereditary” familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

CDKN2A/p16 evaluation in cytology specimens.

CDKN2A/p16 evaluation in cytology specimens.

Surgical phenotype of patients with peritoneal mesothelioma and a germline mutation.

This study aimed to investigate if peritoneal mesothelioma (PM) patients with germline mutations (GM) have distinct surgical characteristics when compared to those without GM. PM patients were selected from an ongoing prospective study that conducts germline testing of 82 susceptibility genes. Germline status was correlated with surgical data obtained from a prospectively collected database using univariate, multivariate, and receiver operating characteristic (ROC) analyses. Out of 88 PM patients enrolled between 2009 and 2019, 18GMs (20.5%) were identified in BRCA1-associated protein 1 (BAP1) (n=11, 12.5% of all patients), SDHA (n=2) and WT1, CDKN2A, CHEK2, ATM, and BRCA2 (n=1 patient each). Surgical procedures were performed in 71 patients, the most common of which were cytoreductive surgeries with hyperthermic intraperitoneal chemotherapy (n=61). Patients with GM presented with a higher prevalence of other prior cancers (61.1% vs. 31.4%, p=.02) and lower platelet count (251 [160-413] vs. 367 [196-780] K/µL, p=.005) compared to those without GM (n=70). Survival outcomes did not differ significantly between the groups. Patients with BAP1 GMs were more likely to develop bicavitary disease and to present with lower platelet count and mitotic count score, and higher peritoneal cancer index (PCI, all p≤.04) compared with those without GM. On ROC analysis, the combination of PCI, platelet count and mitotic score yielded an area under the curve of 0.96 (95% CI, 0.91-1.0) for BAP1 GM detection among operated PM patients. Higher intraoperative tumor burden and lower platelet count and mitotic score are suggestive of BAP1 GMs in surgical PM patients and should prompt germline testing.

Abstract 2610: GNAQ/GNA11 and BAP1 mutant isogenic cell lines engineered by CRISPR/Cas9 gene editing to model ocular melanoma

Abstract Uveal melanoma (UM) is the most frequent intraocular cancer in adults and 50% of patients develop liver metastases for which no treatment is effective. According to The Cancer Genome Atlas, 92% of cases are characterized by early mutations in two genes coding for alpha subunits of G protein coupled receptors (GPCR): G protein subunit alpha q (GNAQ) or 11 (GNA11). These mutations are mostly found in the codon Q209 causing a constitutive activation of different signaling pathways linked to cellular proliferation such as MAPK and PKC. Furthermore, a bi-allelic inactivation of the BRCA1 associated protein-1 (BAP1) is found in 83% of metastatic UM and causes a loss of function of this protein. Our hypothesis is that the genes essential for the survival of mutant UM cells will be ideal therapeutic targets. Using CRISPR/Cas9 technology, we engineered GNAQ/11 and BAP1 mutant isogenic cell lines derived from wildtype UM cells or choroidal melanocytes (CM) to better understand the molecular mechanisms involved in UM development. We have designed three ribonucleoprotein complexes (RNPs) composed of single-guide RNA (sgRNA) and Streptococcus pyogenes Cas9 (spCas9) specific to the GNAQ/11 and BAP1 genes. This allowed to target the DNA sequence on the exon 5 of these proteins to induce a double-strand break. To introduce the desired mutations Q209L in GNAQ/11 or C91G in BAP1, we have also designed DNA templates called single-strand oligo DNA nucleotides (ssODNs) that were co-transfected with respective RNPs by electroporation into UM cells (Mel285) or CM and favorized the homologous recombination (HR) during DNA repair to knock-in these mutations. After a few days, we genotyped the clones by Sanger sequencing and expanded those of interest into cell lines. We obtained an electroporation efficiency of 50% for CM and 70% for Mel285 using an eGFP plasmid. The first CRISPR transfections showed a mean edition of 20-60% of targeted regions with 4% HR. To increase our percentage of HR, we have also used the Prime Editing method; nine plasmids per mutation have been designed and constructed. The first transfection tests in HEK293T cells are currently underway. We obtained three KO cell lines: Mel285GNAQ-KO, Mel285GNA11-KO and Mel285BAP1-KO. We saw no morphologic changes. A decrease in the proliferation and metabolic activity was observed in Mel285GNAQ-KO and Mel285BAP1-KO cell lines in comparison to the wildtype cells. Furthermore, an increase of phosphorylated ATF2/7 was noted in Mel285GNAQ-KO and Mel285GNA11-KO cell lines by western blotting. A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically metastatic UM cells. Citation Format: Aurélie Fuentes-Rodriguez, Andrew Mitchell, Joël Rousseau, Jacques P. Tremblay, Solange Landreville. GNAQ/GNA11 and BAP1 mutant isogenic cell lines engineered by CRISPR/Cas9 gene editing to model ocular melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2610.

BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13.

The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with BAP1 tumor predisposition syndrome (TPDS). BAP1 is a tumor suppressor gene whose alterations in cancer are commonly caused by gene mutations leading to protein loss of function. By CRISPR-Cas, we have generated mutations in ubh-4, the BAP1 ortholog in Caenorhabditis elegans, to model the functional impact of BAP1 mutations. We have found that a mimicked BAP1 cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of ubh-4 deletion mutants. Despite ubh-4 being ubiquitously expressed, the gene is not essential for viability and its deletion causes only mild phenotypes without affecting 20S proteasome levels. Such viability facilitated an RNAi screen for ubh-4 genetic interactors that identified rpn-9, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. ubh-4[A87D], similarly to ubh-4 deletion, cause a synthetic genetic interaction with rpn-9 inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how ubh-4 inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study BAP1 cancer-related mutations in C. elegans, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of BAP1 tumors.

The cytologic diagnosis of mesothelioma: are we there yet?

Mesothelioma is a rare but highly aggressive malignancy with poor prognosis that frequently present with recurrent effusions. Establishing the diagnosis by cytology can lead to early diagnosis and treatment and consequently improve prognosis. This review examines the cytological diagnosis of mesothelioma in the context of its historical and morphologic evolution and provides an update of the current reporting systems. Clues to identify the mesothelial and malignant nature of the sample are detailed as well as the supporting ancillary tests. Cytologically, the samples are overwhelmingly cellular and malignancy is recognized by both architectural and cytological atypia. Numerous variably sized clusters and enlarged cells are easily identified, some with papillary architecture and collagen cores. Recognizing the mesothelial nature of the cells and supportive immunostains are essential to rule out the differential diagnosis of metastatic carcinomas and reactive mesothelium. Current ancillary tests such as homozygous deletion of CDKN2A, loss of BRCA1-associated protein, and methylthioadenosine phosphorylase expression can provide further support of malignancy. At this time with the aid of current ancillary tests and in the hands of cytopathologists with adequate experience with the interpretation of effusions, the diagnosis of mesothelioma can be established with accuracy in most cases.

Highlighting the immunohistochemical differences of malignant mesothelioma subtypes via case presentations.

Malignant mesothelioma (MM) is a rare tumor of mesothelial cells, with an increasing incidence both in developed and developing countries. MM has three major histological subtypes, in order of frequency, according to the World Health Organization (WHO) Classification of 2021: epithelioid, biphasic, and sarcomatoid MM. Distinction may be a challenging task for the pathologist, due to the unspecific morphology. Here, we present two cases of diffuse MM subtypes to emphasize the immunohistochemical (IHC) differences, and to facilitate diagnostic difficulties. In our first case of epithelioid mesothelioma, the neoplastic cells showed cytokeratin 5/6 (CK5/6), calretinin, and Wilms-tumor-1 (WT1) expression, while remaining negative with thyroid transcription factor-1 (TTF-1). BRCA1 associated protein-1 (BAP1) negativity was seen in the neoplastic cells' nucleus, reflecting loss of the tumor suppressor gene. In the second case of biphasic mesothelioma, expression of epithelial membrane antigen (EMA), CKAE1/AE3, and mesothelin was observed, while WT1, BerEP4, CD141, TTF1, p63, CD31, calretinin, and BAP1 expressions were not detected. Due to the absence of specific histological features, the differentiation between MM subtypes could be a challenging task. In routine diagnostic work, IHC may be the proper method in distinction. According to our results and literature data, CK5/6, mesothelin, calretinin, and Ki-67 should be applied in subclassification.

Difficult to Diagnose Cutaneous Melanoma in a Patient with BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein 1 (BAP1)-inactivated melanomas can occur sporadically or in germline contexts, particularly in recently recognized BAP1-tumor predisposition syndrome. Diagnosis represents a clinical and histopathological challenge, requiring comprehensive analysis of morphology and sometimes molecular analysis in addition to immunohistochemistry. We report a BAP1-inactivated cutaneous melanoma initially diagnosed as an atypical Spitz tumor on the auricle in a patient with BAP1-tumor predisposition syndrome. Immunohistochemistry, fluorescence in situ hybridization, and comparative genomic hybridization allowed diagnosis. Cutaneous BAP1-inactivated melanocytic tumors, previously classified as atypical Spitz Nevi, may have a dermal mitotic activity that can resemble melanoma and on the other hand, atypical Spitz tumors are sometimes difficult to differentiate from BAP1-inactivated melanoma. Specific criteria, requiring molecular diagnosis have been proposed in order to support melanoma diagnosis.

Modulation of Schwann cell homeostasis by the BAP1 deubiquitinase.

Schwann cell programming during myelination involves transcriptional networks that activate gene expression but also repress genes that are active in neural crest/embryonic differentiation of Schwann cells. We previously found that a Schwann cell-specific deletion of the EED subunit of the Polycomb Repressive Complex (PRC2) led to inappropriate activation of many such genes. Moreover, some of these genes become re-activated in the pro-regenerative response of Schwann cells to nerve injury, and we found premature activation of the nerve injury program in a Schwann cell-specific knockout of Eed. Polycomb-associated histone modifications include H3K27 trimethylation formed by PRC2 and H2AK119 monoubiquitination (H2AK119ub1), deposited by Polycomb repressive complex 1 (PRC1). We recently found dynamic regulation of H2AK119ub1 in Schwann cell genes after injury. Therefore, we hypothesized that H2AK119 deubiquitination modulates the dynamic polycomb repression of genes involved in Schwann cell maturation. To determine the role of H2AK119 deubiquitination, we generated a Schwann cell-specific knockout of the H2AK119 deubiquitinase Bap1 (BRCA1-associated protein). We found that loss of Bap1 causes tomacula formation, decreased axon diameters and eventual loss of myelinated axons. The gene expression changes are accompanied by redistribution of H2AK119ub1 and H3K27me3 modifications to extragenic sites throughout the genome. BAP1 interacts with OGT in the PR-DUB complex, and our data suggest that the PR-DUB complex plays a multifunctional role in repression of the injury program. Overall, our results indicate Bap1 is required to restrict the spread of polycomb-associated histone modifications in Schwann cells and to promote myelin homeostasis in peripheral nerve.

Targeting BAP1 with small compound inhibitor for colon cancer treatment

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 μM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC).

Diffuse malignant peritoneal mesothelioma: A review.

Diffuse malignant peritoneal mesothelioma (DMPM) is an unusual and life-threatening locally invasive tumor. The morbidity and mortality of the disease are associated with progressive local effects in the abdominal cavity, such as abdominal distention, painful sensations, and early saturation with reduced oral intake, which eventually lead to intestinal obstruction and cachexia. Computed tomography (CT) has been widely used as a first-line diagnostic tool for DMPM. In addition, the most sensitive immunohistochemical markers of DMPM include WT 1, D2-40, and calmodulin. This paradigm has altered with the advancements in the immunohistochemical analysis of BRCA1-Associated Protein 1 (BAP1) the lack of BAP1 expression shows the diagnosis of malignancy. DMPM is resistant to conventional chemotherapies. Therefore, the gold standard for the treatment of DMPM is the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The overexpression of the phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) signaling pathway drives the malignant phenotype of DMPM, thereby showing promising potential for the treatment of DMPM. The coordinated activities among multiple RTKs are directly involved in the biological processes of DMPM, suggesting that the combined inhibition of the PI3K and mTOR signaling pathways might be an effective measure. This treatment strategy can be easily implemented in clinical practice. However, the combined inhibition of ERBB1(HER1)/ERBB2 (HER2) and ERBB3 (HER3) requires further investigations. Thus, based on these, the discovery of novel targeted therapies might be crucial to improving the prognosis of DMPM patients.