ATRX mutation

The clinical value of IDH and ATRX mutations in prognostic assessment was confirmed (p ≤0.05). The overexpression of p53 had no significant impact on OS (p = 0.726). Therefore, p53 alone cannot predict survival in glioblastoma patients. Based on the results, these biomarkers may be a potential therapeutic target to prolong patient survival, hence the need for further investigations.

In summary, this is an excellent example of tumor heterogeneity both histologically and by molecular analysis. It is probable, given the clinical history of presentation 2 years prior, that this tumor originated as a low-grade glioma and subsequently evolved.

Compared to traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

P1, N=49, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: May 2024 --> May 2025

P1, N=42, Recruiting, Nader Sanai | Trial completion date: Oct 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Aug 2024

The AUC value of the D parameter model was 0.97 (95% CI: 0.93-1.00) in the training set and 0.91 (95% CI: 0.79-1.00) in the validation set, which was significantly higher than that of the D* parameter model (0.90, 0.82) and the f parameter model (0.89, 0.91). The imaging genomics nomogram based on IVIM-DWI can effectively predict the ATRX gene status of patients with brain gliomas, with the D parameter showing the highest efficacy.

While exceedingly rarely, FH mutations may be found in uLMS. Confirmation of FH deficiency should not preclude the diagnosis of sarcoma in smooth muscle neoplasms that meet histologic criteria for malignancy.

Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

Implementation of combined phenotypic-genotypic diagnosis with the use of histomorphology and immunohistochemical surrogates for molecular genetic alterations will yield more homogeneous and narrowly defined diagnostic entities which will provide better prognostication and definitive treatment. It also is cost-effective in a resource-limited setup.

Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

265 patients within the cohort completed postoperative radiotherapy, while 141 patients underwent chemotherapy (procarbazine, lomustine, and vincristine, or temozolomide). Of particular importance, molecular sub-classification significantly predicted survival outcomes for IDH, ATRX, and 1p19 co-deletion mutations. Expanding brain tumor epidemiology will benefit assessing the efficacy of regional oncological centers and establishing standards of care.

The fusion model showed the best prediction performance with an area under curve of 0.969 in the training set, 0.956 in the validation set, and 0.949 in the test set as compared to the optimal imaging model (0.966, 0.916, and 0.936, respectively) and clinical model (0.677, 0.641, 0.772, respectively). The clinical trait-imaging fusion model based on preoperative MRI could effectively predict the ATRX mutation status of individuals with IDH-mutant high-grade astrocytoma and has the potential to help patients through the development of a more effective treatment strategy before treatment.

Three first-line drug (paclitaxel, doxorubicin and tamoxifen) resistance datasets in BC from GEO were merged to obtain 1,461 differentially expressed genes for weighted correlation network analysis, resulting in identifying ATRX as the hub gene. Importantly, overexpression of ATRX significantly inhibited the IC of the three first-line drugs on MCF-7 cell. Thus, ATRX is an efficient predictive biomarker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ BC and acts by suppressing the AR, GLI3 and GATA2 transcriptional network.

The T2/FLAIR mismatch sign detected diffuse astrocytomas with 100% specificity. When combined with high Cho/Cr and raised rCBV, this predicted histological grading with high accuracy. The future direction for imaging should explore a similar integrated layered approach of 2021 classification of central nervous system (CNS) tumours combining radio-phenotyping and grading from structural and multiparametric imaging.

In this study, we described the most common clinico-pathological characteristics and IHC marker expression profiles, highlighting a variety of percentage ranges in primary and secondary glioblastomas. Given the small number of studied cases, further prospective studies on larger cohorts are needed in the future to evaluate the role of these immunohistochemical markers as prognostic factors for survival or recurrence.

These mutations were not previously associated with ovarian cancer and are considered novel candidate markers for ovarian cancer susceptibility. Confirmation of these results through larger cohort studies or functional investigations will contribute to a better understanding of the molecular mechanisms underlying ovarian cancer.

Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.

HGG_F separate into two groups dictated by brain location, and despite the presence of TERT promoter mutations, appear distinct from GBMs. Overall, our work represents an initial effort to understand the morphologic, genomic and clinical characteristics of these previously uncharacterized subtypes of gliomas.

IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.

In an orthotopic model of ALT-positive glioma, doxycycline-inducible RNAi targeting SMARCAL1 extended the median survival of tumor-bearing animals to 155 days compared to 111 days in the non-targeting control condition. These data validate the therapeutic targetability of SMARCAL1 in ALT-positive gliomas and support the development of small molecule SMARCAL1 inhibitors for treatment of ALT-positive tumors.

LFS patients may have glioma with higher incidence of non-canonical IDH1 mutations, lower likelihood of ATRX and IDH1 co-mutations, and less likely to be treated upfront after initial diagnosis despite having high risk profile for low grade glioma.

Multiplex immunohistochemistry of CX-5461 alone and the combinational treatment tumors shows enhanced induction of G4s, replication stress, and DNA damage, recapitulating in vitro findings. Taken together, our work defines mechanisms of action and efficacy for a novel therapeutic strategy for pre-clinical ATRX-deficient HGG, with strong implications for clinical translation.

In an orthotopic model of ALT-positive glioma, doxycycline-inducible RNAi targeting SMARCAL1 extended the median survival of tumor-bearing animals to 155 days compared to 111 days in the non-targeting control condition. These data validate the therapeutic targetability of SMARCAL1 in ALT-positive gliomas and support the development of small molecule SMARCAL1 inhibitors for treatment of ALT-positive tumors.

One of these contained a novel fusion involving the NTRK2 and LRRFIP2 genes, while the other showed loss of MSH2 and MSH6 without genetic alterations in the encoding genes suggesting an epigenetic background. Genetic characteristics of ATRX-deficient IDH-wildtype adult high-grade gliomas suggest that these tumors are particularly intriguing targets of potential future therapeutic interventions including immunotherapies combined with MAPK pathway inhibition and DNA repair inhibitors.

In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.

High-risk gliomas were predicted to be more sensitive to rapamycin, dasatinib, 5-fluorouracil and gemcitabine. Thus, our model can be used for the diagnosis, prognostic prediction and treatment planning of ATRX-wt glioma patients.

Metabolomic profiling of lEV is able to differentiate between healthy controls and GBM. Metabolomic profiling reveals that changes in metabolite concentrations are associated with proliferation rate as well as mutational status of patients. Higher concentrations of specific sphingomyelins are observed in GBM with IDH2 wild type, loss of p53 and ATRX expression.

Skin primary glomus tumors show frequent mutations in NOTCH2 and NOTCH3 , including gene fusions and novel truncating mutations. The presence of occasional BRAF and PDGFRB alterations raise the possibility of targeted therapies in clinically-advanced cases of this tumor type.

These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.

However, a set of PSGs display a decrease of chromatin accessibility after ATRX depletion, indicating that ATRX promote the transcription of these genes through chromatin remodeling. Thus, we highlight that ATRX mutation plays critical roles in blocking Type I IFN signaling in sarcoma cells and point out the clinical importance of this effect on sarcoma treatment.

Owing to the rarity of the condition, its prognosis is still unclear. Hence, more cases with such unusual features along with long-term follow-up should be reported to assess the clinical profile of this rare neoplasm.

In conclusion ATRX loss and TERT promoter mutations are only found in (pre)malignant conjunctival melanocytic lesions, with most metastatic cases harboring one of these alterations, suggesting that both alterations are associated with adverse behavior. Similar to TERT promoter mutations, ATRX loss may be used as a diagnostic tool in determining whether a conjunctival melanocytic lesion is prone to having an adverse course.

Methylation analysis improved diagnostic accuracy in 50% of cases, demonstrating its utility as complementary tool to refine diagnosis in a subset of highly selected patients. Importantly, methylome diagnostic refinement did not modify the final WHO tumor grade.

The frequent mutations in TP53, ATRX, and CDKN2A/p16 identified in our cohort support their potential as biomarkers for ULMS diagnosis and prognosis. Further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings and explore the clinical utility of these biomarkers.

This series represents the largest cohort of multi-omic characterization of ESS. Our data confirmed the characteristic presence of JAZF1:SUZ12 fusions in LG-ESS. However, this fusion was also found in HG-ESS cases with retention of ER and PR expression.

Prognosis of advanced STS appears to be histologic subtype and co-mutation-dependent. TP53 mutations appear to attenuate the adverse OS effect by mutPTEN and mutCDKN2A. Our results provide new insight that could be helpful for prognostic stratification in clinical practice and clinical trials and for understanding further the molecular mechanisms of STS.

Our study is the first to connect AA exposure to the etiology of liver AS. The high mutation rate and distinct telomere maintenance mechanism of liver AS provides insights into future treatments.

However, there is reaffirmation that prognostic molecular biomarkers of small bowel NETs should be sought in copy number variations (CNVs) rather than in single nucleotide variations (SNVs). This review also reveals how little is known about the prognostic significance of epigenetics in NETs.