Mutations In Tumor Suppressor Gene Research Articles

Immune-inflammatory markers and clinical characteristics as predictors of the depth of response and prognosis of patients with PD-L1 ≥50% metastatic non-small cell lung cancer receiving first-line immunotherapy.

Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune-inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non-high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD-L1 ≥50% were further clarified. The clinical characteristics and immune-inflammatory markers of 17 patients with PD-L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. Among the 17 patients, seven (41.2%) patients achieved HDPR (range: -50%, -72%) and 10 (58.8%) patients achieved NHDPR (range: -13%, -45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow-up of 26.0 months (range: 17.2-34.8 months), the median progression-free survival (PFS) following first-line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0-13.0) and not reached (NR), respectively. The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent prognostic factor on first-line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2-80.2) than those with an NLR <4 following first-line immunotherapy. Among patients with PD-L1 ≥50% metastatic NSCLC who received first-line immunotherapy, a lower CD4/CD8 ratio and the presence of genes mutations showed a diminished tumor response and a higher NLR ratio exhibited a worse median PFS.

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.

Multiparametric whole-body MRI of patients with neurofibromatosis type I: spectrum of imaging findings.

Neurofibromatosis (NF) type I is a neuroectodermal and mesodermal dysplasia caused by a mutation of the neurofibromin tumor suppressor gene. Phenotypic features of NF1 vary, and patients develop benign peripheral nerve sheath tumors and malignant neoplasms, such as malignant peripheral nerve sheath tumor, malignant melanoma, and astrocytoma. Multiparametric whole-body MR imaging (WBMRI) plays a critical role in disease surveillance. Multiparametric MRI, typically used in prostate imaging, is a general term for a technique that includes multiple sequences, i.e. anatomic, diffusion, and Dixon-based pre- and post-contrast imaging. This article discusses the value of multiparametric WBMRI and illustrates the spectrum of whole-body lesions of NF1 in a single imaging setting. Examples of lesions include those in the skin (tumors and axillary freckling), soft tissues (benign and malignant peripheral nerve sheath tumors, visceral plexiform, and diffuse lesions), bone and joints (nutrient nerve lesions, non-ossifying fibromas, intra-articular neurofibroma, etc.), spine (acute-angled scoliosis, dural ectasia, intraspinal tumors, etc.), and brain/skull (optic nerve glioma, choroid plexus xanthogranuloma, sphenoid wing dysplasia, cerebral hamartomas, etc.). After reading this article, the reader will gain knowledge of the variety of lesions encountered with NF1 and their WBMRI appearances. Timely identification of such lesions can aid in accurate diagnosis and appropriate patient management.

A Novel CRISPR/Cas9-mediated Mouse Model of Colon Carcinogenesis

Background & AimsHuman sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC in vivo is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities. Aims: Generate a sporadic CRC model that more closely mimics this multi-step process and use this model to study the role of a novel Let7 target PLAGL2 in CRC pathogenesis. MethodsWe generated a CRISPR/Cas9 somatic mutagenesis mouse model that is inducible and multiplexed for simultaneous inactivation of multiple genes involved in CRC pathogenesis. We used both a doxycycline-inducible transcriptional activator and a dox-inactivated transcriptional repressor to achieve tight, non-leaky expression of the Cas9 nickase. This mouse has transgenic expression of multiple guide RNAs to induce sporadic inactivation in the gut epithelium of four tumor suppressor genes commonly mutated in CRC, Apc, Pten, Smad4 and Trp53. These were crossed to Vil-LCL-PLAGL2 mice which have Cre-inducible overexpression of PLAGL2 in the gut epithelium. ResultsThese mice exhibited random somatic mutations in all four targeted tumor suppressor genes, resulting in multiple adenomas and adenocarcinomas in the small bowel and colon. Crosses with Vil-LCL-PLAGL2 mice demonstrated that gut-specific PLAGL2 overexpression increased colon tumor growth. ConclusionsThis conditional model represents a new CRISPR/Cas9-mediated mouse model of colorectal carcinogenesis. These mice can be used to investigate the role of novel, previously uncharacterized genes in CRC, in the context of multiple commonly mutated tumor suppressor genes and thus more closely mimic human CRC pathogenesis.

TUSC3, p53 and p21 genetic association with development of oral submucous fibrosis and oral squamous cell carcinoma among addictive tobacco chewers of Pakistan

BackgroundThis study delves into the intricate landscape of oral cancer, a global concern with a high incidence in Asian countries. We focus on oral squamous cell carcinoma (OSCC), primarily driven by the consumption of betel nut and its derivatives. OSCC often arises from premalignant lesions like oral submucous fibrosis (OSF). In Pakistan, OSCC is prevalent among men due to various addictive substances, including smokeless tobacco and chewing materials. Mutations in tumor suppressor genes, such as TP53 and p21, play crucial roles in this malignancy’s development. We also explore the involvement of TUSC3 gene deletion in OSCC and OSF.MethodsIn this study we investigated demographics, TUSC3 gene expression, deletion analysis, and TP53 and p21 genetic alterations in OSCC and OSF patients (blood and tissue of 50 samples in each condition) who had tobacco derivates usage history. The association analysis was carried out mainly through PCR based genotyping.ResultsThe study’s patient cohort (OSCC and OSF) displayed a wide age range from 13 to 65 years (Mean = 32.96 years). Both conditions were more prevalent in males, with a male-female ratio of approximately 2.5:1. Chewing habits analysis revealed high frequencies of gutka use in both OSF and OSCC patients. TUSC3 expression analysis in OSCC cell lines indicated significant downregulation. Genotyping showed no TUSC3 deletion in OSF cases, but a deletion rate of over 22% in OSCC tissue samples. Analysis supported a significant association of TUSC3 deletion with OSCC development but not with OSF. Polymorphism in p53 exon 4 and p21 (rs1801270) were significantly associated with both OSCC and OSF, adding to their pathogenesis. Our findings further revealed a strong correlation between TUSC3 deletion and the excessive use of tobacco and related products, shedding light on the genetic underpinnings of OSCC development.ConclusionsNotably, our study provides a crucial insight into genetic aspects underlying OSCC and OSF in response of addictive consumption of areca nut, betel quid, and tobacco derivatives. A significant association between TUSC3 deletion and OSCC development, along with polymorphisms in TP53 and p21, underscores the importance of further research into the molecular mechanisms driving oral cancer progression for improved diagnosis and treatment outcomes.

TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion.

Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined transcriptome-wide changes in mRNA translation upon TSC2 loss. Our results reveal dysregulated translation in TSC2 -Null NPCs, which significantly overlaps with the translatome from TSC1 -Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD-and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in TSC2 -Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TSC, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.

Differences in merlin and p53 expression as a predisposing factor in orbital meningioma

Objectives: The behavior of orbital meningiomas is difficult to predict. The p53 tumor suppressor gene mutation and the neurofibromatosis 2 gene’s inactivation in the merlin formation are two of the several mechanisms that contribute to the development of tumors. This considers the comparison of merlin and p53 expression as an inclination to evaluate the orbital meningiomas. Materials and Methods: This investigation is an observational expository considered within the shape of cross-sectional (cross-sectional). The samples/objects of this study were 44 patients with orbital meningioma who had a clinical, radiological, and histopathological diagnosis at the anatomical pathology laboratory at Cicendo Eye Hospital and Hasan Sadikin Bandung in 2017–2020, then an immunohistochemical examination of merlin and p53 expression was performed. Results: The study indicated that there was no relationship between p53 expression and orbital meningioma grading, also there is no relationship between merlin expression and orbital meningioma grading. However, based on the analysis test results, grade 3 orbital meningiomas tended to have a positive p53 expression rather than a negative expression and tend to have a negative merlin expression instead of a positive. Conclusion: Meningiomas with negative merlin expression have a tendency to express positive p53. Likewise, the higher grade (grade 3) tends to express positive p53 and negative merlin, which may play a key role in tumorigenesis of orbital meningioma, hence, an added value for clinical information and behavioral descriptions of orbital meningioma itself.

DNA Mutational and Copy Number Variation Profiling of Primary Craniofacial Osteosarcomas by Next-Generation Sequencing.

Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes.

MiR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage.

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation.

Therapeutic targeting of TP53 nonsense mutations in cancer.

Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.

Role of Nutrition in the Management of Patients with Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome caused by inactivating mutations in the MEN1 tumor suppressor gene. The three main clinical manifestations of MEN1 are primary hyperparathyroidism (PHPT), duodenal-pancreatic neuroendocrine tumors (DP-NETs) and anterior pituitary tumors. Endocrine tumors in patients with MEN1 differ from sporadic tumors because of their younger age at onset, common multiple presentations and the different clinical course. MEN1 is characterized by a complex clinical phenotype; thus, patients should be followed by a multidisciplinary team of experts that includes an endocrinologist, a surgeon, a oncologist, a radiotherapist, and not least, a nutritionist. It is important to remember the fundamental role that diet plays as a primary prevention tool, together with a healthy and active lifestyle in preventing osteoporosis/osteopenia and reducing the risk of developing kidney stones due to hypercalciuria, two frequent clinical complications in MEN1 patients. Is very important for MEN1 patients to have an adequate intake of calcium, vitamin D, magnesium and phosphate to maintain good bone health. The intake of foods containing oxalates must also be kept under control because in combination with calcium they concur to form calcium oxalate crystals, increasing the risk of nephrolithiasis. Another aspect to consider is the management of patients with pancreatic neuroendocrine tumors undergoing major surgical resections of the pancreas that can lead to alterations in digestion and absorption mechanisms due to partial or total reduction in pancreatic enzymes such as amylase, lipase, and protease, resulting in malabsorption and malnutrition. Therefore, the nutritionist's aim should be to devise a dietary plan that takes into consideration each single patient, educating them about a healthy and active lifestyle, and accompanying them through various life stages by implementing strategies that can enhance their quality of life.

#2675 Role of ANXA4 as a modifier in VHL-dependent ccRRC

Abstract Background and Aims The von Hippel-Lindau (VHL) syndrome is a rare genetic disease caused by inactivating mutations of the VHL tumor suppressor gene. VHL syndrome patients frequently develop clear cell renal cell carcinomas (ccRCCs). pVHL acts as the substrate recognition subunit of an E3 ligase involved in the ubiquitinylation of HIFs. Consequently, aberrant HIF-signalling results in a pseudo-hypoxic state characterized by pronounced vascularization in respective tumours. Previous studies have indicated VHL-dependent alterations of the extracellular matrix (ECM). However, to date comprehensive description and understanding of VHL-dependent matrisome signatures is missing. Method Proteomics were used to reveal VHL-dependent protein expression in ccRCC cell lines (A498, 786-O) and CRISPR/Cas9-modified human proximal tubular epithelial cells (hRPTECs) as well as syndromic and sporadic ccRCC patient cohorts. For candidate proteins analysis of proteomic and histological datasets was performed. Further functional analysis was conducted using overexpression, CRISPR/Cas9-mediated knockout (KO) and shRNA-mediated knockdown (KD) approaches (assessment of proliferation, migration, invasion, ECM, cellular membrane-integrity, protein localisation studies and transcriptomics). Results Filtering of proteomic datasets (ccRCC tumors and cell lines) for matrisomal proteins highlighted an enrichment of the ANXA-protein family. Interestingly, functional genetic titration of ANXA4 employing knockdown, overexpression or complete ablation using CRISPR/Cas9 genome editing did not translate into major changes of cellular proliferation or migration in renal cancer or tubular cells. Detailed localization studies revealed that ANXA4 is detectable in distinct cellular compartments, namely the cell membrane and nucleus/nuclear lamina. Various cellular stressors (including cellular densities) initiated shuttling of ANXA4 between these different compartments. Remarkably, similar distribution patterns were detectable in situ in tumours tissue of ccRCC patients. Further transcriptomic analysis of ANXA4 knockout cells demonstrated a major impact on ECM- and cell-adhesion-associated gene sets, reflected by impaired invasive migratory capacity in conditions of reduced ANXA4-expression. Conclusion Loss of VHL distinctly alters the ECM composition in ccRCC. We have identified the ECM-associated ANXA4 as a prominently upregulated protein, although canonical hallmarks of cancer were not directly influenced. Based on RNA-sequencing studies and subcellular localization patterns we assume that ANXA4 (co-)regulates matrisome-related transcriptomic signatures in response to various external stressors. These observations highlight the intricate regulation of ECM-associated signalling pathways in the context of VHL-dependent renal cell carcinoma.

Environmental and Metabolic Risk Factors Linked to Gallbladder Dysplasia.

Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer (GBC) may be incidentally discovered during cholecystectomy for presumed benign conditions, underscoring the need for a thorough examination. However, the lack of clarity regarding the molecular mechanisms of GBC has impeded diagnostic and therapeutic advancements. Timely detection is crucial due to GBC's aggressive nature and poor prognosis. Chronic inflammation plays a central role in carcinogenesis, causing DNA damage and oncogenic alterations due to persistent insults. Inflammatory cytokines and microRNAs are among the various mediators contributing to this process. Gallbladder calcifications, particularly stippled ones, may signal malignancy and warrant preemptive removal. Molecular pathways involving mutations in oncogenes and tumor suppressor genes drive GBC pathogenesis, with proposed sequences such as gallstone-induced inflammation leading to carcinoma formation. Understanding these mechanisms, alongside evaluating mucin characteristics and gene mutations, can deepen comprehension of GBC's pathophysiology. This, in turn, facilitates the identification of high-risk individuals and the development of improved treatment strategies, ultimately enhancing patient outcomes. Thus, in this review, our aim has been to underscore the primary mechanisms underlying the development of gallbladder dysplasia and neoplasia.

Calcifying Odontogenic Cyst Demonstrates Recurrent WNT Pathway Mutations and So-Called Adenoid Ameloblastoma-Like Histology: Evidence Supporting Its Classification as a Neoplasm

Calcifying odontogenic cyst (COC), once called calcifying cystic odontogenic tumor, is classified under the category of odontogenic cysts. However, the proliferative capacity of the lesional epithelium and consistent nuclear β-catenin expression raise questions about its current classification. This study aimed to determine whether COC would be better classified as a neoplasm in the histologic and molecular context. Eleven odontogenic lesions diagnosed as COC or calcifying cystic odontogenic tumor were included in this study. The growth patterns of the lesional epithelium were analyzed histologically in all cases. β-catenin immunohistochemistry and molecular profiling using Sanger sequencing and whole-exome sequencing were performed in 10 cases. Of the 11 cases studied, histologic features reminiscent of so-called adenoid ameloblastoma were observed in 72.7% (8/11), and small islands of clear cells extended into the wall in 36.4% (4/11). Intraluminal and/or mural epithelial proliferation was found in 72.7% of the cases (8/11). Nuclear β-catenin expression was observed focally in all 10 cases studied, mainly highlighting epithelial cells forming morules and adjacent to dentinoid. CTNNB1 hotspot mutations were detected in 60.0% of the cases (6/10). All the remaining cases had frameshift mutations in tumor-suppressor genes involved in the WNT pathway, including APC and NEDD4L. Recurrent WNT pathway mutations leading to nuclear translocation of β-catenin and distinct epithelial growth patterns found in COC are the neoplastic features shared by its solid counterpart, dentinogenic ghost cell tumor, supporting its classification as a tumor rather than a cyst.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma

IntroductionMalignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. MethodsWe performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry. ResultsWe revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis). ConclusionOur results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.

Abstract 7361: The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma

Abstract Background: Temozolomide has been extensively utilized in the treatment of gliomas across various grades, offering significant therapeutic benefits. However, the impact of concurrent mutations in TP53 and other tumor suppressor genes (TSG) on treatment outcomes in patients with IDH1 mutant low-grade glioma (LGG) treated with temozolomide remains to be fully understood. This study aims to explore the influence of these genetic factors on the response to temozolomide therapy, focusing on identifying potential genetic markers that can predict therapeutic outcomes. Methods: Our study exclusively analyzed The Cancer Genome Atlas (TCGA) LGG PanCancer dataset from cBioPortal, focusing on IDH1 mutant cases treated with temozolomide. Data analysis was carried out using Python 3.11. The cohort was categorized based on genetic alterations: TP53 mutation with additional TSGs (ATRX, CIC, FUBP1, NOTCH1) mutations (TP53mut/TSGmut), TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and no TP53 mutations (TP53wt). Results: In our study, 178 LGG samples with IDH-1 mutation treated with temozolomide were selected. Of these, 113 samples had a mutation in TP53, and 88 had an additional mutation in a TSG. For TP53mut/TSGmut compared to TP53wt, the analysis revealed significant differences in clinical outcomes (PFS: HR 1.95, CI: 1.17-3.26, p=0.011; OS: HR 1.6, CI: 1.13-2.26, p=0.008). When comparing TP53mut/TSGwt with TP53mut/TSGmut, the findings were (PFS: HR 1.36, CI: 0.63-2.92, p=0.432; OS: HR 0.93, CI: 0.31-2.79, p=0.896). Finally, the comparison between TP53wt and TP53mut/TSGwt showed (PFS: HR 1.45, CI: 0.62-3.39, p=0.397; OS: HR 2.31, CI: 0.64-8.3, p=0.200). Conclusion: The presence of concurrent mutations in TP53 and other TSGs in IDH1 mutant LGG patients (TP53mut/TSGmut) is indicative of a more aggressive disease course and reduced response to temozolomide treatment, as evidenced by significantly worse clinical outcomes. In contrast, the TP53mut/TSGwt group did not exhibit significant differences in treatment outcomes. These findings underscore the importance of detailed genetic profiling in developing personalized treatment strategies for this patient population. Citation Format: Yahia E. Salem, Bayan O. Abu Alragheb. The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7361.

Abstract 5628: Aberrant 3'UTR processing regulates a tumor suppressor network in AML

Abstract Differentiation blockade is a hallmark of acute myeloid leukemia (AML). While inactivating mutations in tumor suppressor genes (TSGs) have been well-studied, non-genetic mechanisms that impair TSGs to promote myeloid differentiation and influence drug response remain poorly understood. In this study, we performed genome-wide loss-of-function CRISPR/Cas9 screens to identify suppressors of myeloid differentiation. These screens converged on the zinc finger transcriptional repressor, ZBTB7A whose ablation restricted myeloid maturation and promoted a dysregulated inflammatory state to protect leukemic cells from undergoing differentiation. Moreover, genetic deletion of ZBTB7A or its paralog, ZBTB7B impeded leukemia differentiation and conferred resistance to differentiation-inducing agents. Mechanistically, we found that leukemia cells hijack 3’UTR processes to reduce mRNA expression of the tumor suppressor gene paralogs ZBTB7A and ZBTB7B. These findings provide a molecular framework of altered 3’UTR regulation that orchestrate a tumor suppressive function and promote resistance to AML differentiation-based therapies. Citation Format: Eric Wang, Cuijuan Han, Alexander Calderon, Abimbo Lawal, Sakthi Harini Rajendran, Sadik Karma, Nidhi Hariramani, Iannis Aifantis, Aristotelis Tsirigos. Aberrant 3'UTR processing regulates a tumor suppressor network in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5628.

Abstract 1252: AI-derived predictions improve identification of real-world cancer driver mutations

Abstract AI-based variant effect predictors (VEPs), such as AlphaMissense, which is based on the protein structure prediction method AlphaFold, have gained significant attention for their potential to predict pathogenic effects of mutations. However, the utility of these methods for identifying pathogenic mutations in cancer remains unknown. We sought to quantify the prevalence of variants of unknown significance (VUSs) across the pan-cancer, multi-institution AACR GENIE cohort (N=160,965 samples) and test the utility of VEPs (SIFT, PolyPhen, MutationAssessor, REVEL, CADD, and AlphaMissense), using publicly available mutation annotations from each method, for 1) Annotating known pathogenic somatic cancer variants across the GENIE cohort, using known benign single nucleotide polymorphisms as negative controls 2) Identifying VUSs associated with overall survival (OS) in two cohorts of patients with non-small cell cancer (NSCLC), the MSK-IMPACT NCSLC (N=8,690) and non-MSK AACR GENIE Biopharma Collaborative NSCLC (N=977) cohorts, and 3) Identifying VUSs associated with known genomic patterns of mutual exclusivity in the MSK-IMPACT NSCLC cohort. In the GENIE cohort, 79% of mutations identified were VUSs according to an FDA-recognized molecular knowledge database, with a wide range of VUS frequencies across genes. Among VEPs trained without prior human-annotated knowledge, CADD and AlphaMissense had the highest AUROCs (0.940, 95%CI 0.937-0.943 and 0.917, 95%CI 0.913-0.922 respectively) for predicting known cancer drivers, demonstrating the power of protein structure modeling or functional genomic data for enhancing cancer drivers prediction. All VEPs identified known driver mutations in tumor suppressor genes more accurately than oncogenes, highlighting the challenge in identifying gain-of-function mutations. We tested whether VUSs reclassified as pathogenic by VEPs are associated with prognosis using inverse probability of treatment-weighted Cox’s propensity hazard models controlling for tumor mutational burden, treatment history, and other factors. VUSs reclassified as pathogenic by AlphaMissense and other VEPs in KEAP1 and SMARCA4 correlated with worse OS, comparable to that of known oncogenic mutations in those genes. Patients with tumors containing VUSs annotated as benign had similar OS to patients without analogous driver mutations. Finally, VUSs reclassified as oncogenic by AlphaMissense in genes within the RTK/RAS and NRF2 pathways followed expected patterns of mutual exclusivity, further suggesting biological validity. Despite not being trained to predict somatic effects in cancer, AI-derived mutation annotations can broaden the subset of annotated pathogenic variants in cancer and contribute to a more complete understanding of cancer genetics. Real-world outcomes and alteration patterns are additional benchmarks to consider when assessing the utility of VEPs in cancer. Citation Format: Thinh N. Tran, Chris Fong, Karl Pichotta, Anisha Luthra, Ronglai Shen, Yuan Chen, Michele Waters, Susie Kim, Gregory Riely, Debyani Chakravarty, Nikolaus Schultz, Justin Jee. AI-derived predictions improve identification of real-world cancer driver mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1252.

Abstract 5586: Hijacking mutant E3 ligase for targeted protein degradation: Discovery of cancer-specific PROTACs for the treatment of FBXW7 R465C driven cancers

Abstract Many cancers carry LOF mutations of tumor suppressor genes and drug discovery against these cancers are challenging. Fbxw7 is a major tumor suppressor E3 ligase and is frequently mutated (LOF) in cancer. Fbxw7 R465C mutation correlates with worse survival and resistance to both chemo- and targeted therapies. Blueray have discovered Fbxw7 R465C-selective ligands and developed PROTAC molecules selectively targeting cancers carrying Fbxw7 R465C mutation. The Fbxw7 R465C-based PROTACs show superior degradation activity for several target proteins and inhibit proliferation of cancer cells carrying Fbxw7 R465C mutations. These PROTACs show tumor growth inhibition in Fbxw7 R465C mutant cell derived xenograft models with clear PK/PD correlations. Development of bi-functional molecules such as PROTACs bring new options to target cancers with LOF mutations. Citation Format: Hailong Zhang. Hijacking mutant E3 ligase for targeted protein degradation: Discovery of cancer-specific PROTACs for the treatment of FBXW7 R465C driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5586.