Sahyadri Hospitals is a chain of hospitals in Maharashtra, India.
e14060 Background: Gliomas have few approved targeted therapies. Given frequent blood-brain-barrier disruption in gliomas, molecular targets with FDA-approved therapies in other solid tumors represent relevant precision-oncology opportunity. Methods: A total of 235 glioma tumor tissue samples underwent targeted next-generation sequencing at Datar Cancer Genetics. Clinical actionability was assessed using ESCAT. Subgroup analyses were performed based on IDH status. Results: Of 235 samples, 6 were grade I (2.6%), 17 grade II (7.2%), 38 grade III (16.2%), and 159 grade IV (67.8%); grade was unavailable in 15 (6.4%). Overall, 43.8% (103/235) harbored ≥1 tumor-agnostic or cross-indication actionable alteration with an FDA-approved therapy in solid tumors. Tumor-agnostic biomarkers included TMB-H (11.6%; 16/138), dMMR (1.7%; 2/116), BRAF V600E (4.9%; 11/225), and NTRK fusions (0.6%; 1/178); HER2 amplifications and RET fusions were not detected. Canonical CNS alterations included IDH1/2 (24.0%; 54/225), TERT promoter (36.1%; 73/202), TP53 (42.4%; 95/224), H3F3A (3.8%; 7/185), ATRX (8.2%; 18/219), EGFR amplification (21.2%; 43/203), CDKN2A/2B loss (18.8%; 38/202), EGFRvIII (12.9%; 23/178), and EGFR mutations (10.7%; 24/225). Cross-indication alterations involved PI3K-AKT-mTOR ( PIK3CA 8.4% [19/225], PTEN 18.3% [41/224]) and FGFR (4.3%; 10/235); KIAA1549-BRAF and PTPRZ1-MET fusions were each detected in 1.1% (2/178). ESCAT Tier I alterations were present in 29% (69/235) and Tier II–III in 56% (132/235). Though incidence of tumor-agnostic biomarkers was similar in IDH -mutant and IDH -wildtype ( IDH -WT) gliomas (13.0% [7/54] vs 11.6% [21/181]), the cross-indication biomarkers were enriched in IDH -WT gliomas (40.9% [74/181] vs 20.4% [11/54]). In grade IV gliomas, cross-indication biomarkers were more frequent in IDH -WT than IDH -mutant tumors (45.3% [62/137] vs 18.2% [4/22]), with similar findings in combined grade III–IV gliomas (42.9% [66/154] vs 25.6% [11/43]). Conclusions: Despite poorer prognosis, IDH -WT gliomas are enriched for cross-indication actionable alterations, reflecting biological actionability without established clinical benefit, and supporting comprehensive molecular profiling to guide indication-expanded therapies, clinical trial enrolment, and prospective interventional basket trials. Tumor-agnostic and cross-indication actionable alterations in gliomas. Biomarker Overall % (n/N) IDH -WT (%) IDH -Mutant (%) Approved Indication PTEN mutations 18.3 (41/224) 21.8 7.4 Breast FGFR1/2/3 alterations 4.3 (10/235) 5.5 0.0 Multiple ERBB2 mutations 0.0 (0/179) 0.0 0.0 Multiple BRCA1/2 mutations 0.6 (1/156) 0.8 0.0 Multiple PIK3CA mutations 8.4 (19/225) 7.6 11.1 Breast TMB-H 11.6 (16/138) 8.9 23.1 Tumor-agnostic dMMR/MSI-H 1.7 (2/116) 2.0 0.0 Tumor-agnostic NTRK fusions 0.6 (1/178) 0.7 0.0 Tumor-agnostic
To evaluate how the updated steatotic liver disease (SLD) nomenclature—metabolic dysfunction–associated steatotic liver disease (MASLD), metabolic–alcohol associated liver disease (MetALD), and alcohol-associated liver disease (ALD)—influences the diagnostic performance and clinical applicability of non-invasive tests (NITs) for fibrosis assessment, and to determine the need for phenotype-specific risk-stratification strategies. Across studies published between 2023 and 2025, serum-based NITs such as FIB-4 and NAFLD Fibrosis Score (NFS) retain robust rule-out performance for advanced fibrosis (≥ F3) in MASLD (AUROC 0.75–0.85) and MetALD (AUROC 0.72–0.83), with high negative predictive values (> 95
e22636 Background: Germline BRCA1/2 pathogenic variation is structurally heterogeneous, comprising small sequence variants and large genomic rearrangements that differ in their genomic architecture and biological consequences. Real-world data defining the contribution of these variant classes across BRCA genes and tumor types remain limited. Methods: We analyzed germline BRCA1/2 findings from 3,248 individuals undergoing comprehensive hereditary cancer testing for small sequence variants (single nucleotide variants and short insertions/deletions) and large genomic rearrangements (deletions and duplications) using a multigene panel. Pathogenic and likely pathogenic variants were classified using standard criteria and evaluated by gene, variant class, tumor type, and clinical actionability. Results: Overall, pathogenic or likely pathogenic BRCA variants were identified in 8.9% (288/3,248) of individuals. Small sequence variants were identified in 258 individuals, while large genomic rearrangements were identified in 39 individuals, with 9 individuals harboring both variant types. At the cohort level, this corresponds to approximately one pathogenic BRCA large genomic rearrangement per 83 individuals analyzed. Among BRCA -positive cases, 58% (167/288) involved BRCA1 and 42% (122/288) involved BRCA2 , with one individual carrying pathogenic variants in both BRCA1 and BRCA2 . Variant-level analysis revealed that large genomic rearrangements were more frequent in BRCA1 than BRCA2 (15.2% vs 10.2%), with deletions predominating over duplications (82.1% vs 17.9%). BRCA pathogenic variants demonstrated marked enrichment in ovarian cancer (16.1%, 77/477), compared with breast (7.7%, 118/1,541), prostate (4.4%, 11/250), and pancreatic cancers (4.1%, 15/362).Large genomic rearrangements were also most prevalent in ovarian cancer (2.1%), compared with breast (1.0%), prostate (0.8%), pancreatic (0.6%), indicating relative enrichment of rearrangements in ovarian tumors. Pathogenic variants in cancer predisposition genes were identified in 14.6% (475/3248) of individuals, with non- BRCA genes accounting for 41.7% of findings. Overall, 12.1% of individuals harbored germline alterations with direct therapeutic relevance including eligibility for PARP inhibitor therapy. Conclusions: Large genomic rearrangements constitute a non-trivial component of germline BRCA pathogenic variation, show preferential involvement of BRCA1 , and demonstrate enrichment in ovarian cancer, consistent with HRD-driven tumor biology. Together, these findings provide population-level insight into pathogenic germline alterations across BRCA and other therapeutically relevant hereditary predisposition genes, underscoring the broader relevance of inherited cancer susceptibility in informing targeted and immunotherapy strategies within precision oncology.
BackgroundNiemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal disorder caused by pathogenic variants in NPC1 or NPC2, resulting in impaired intracellular cholesterol trafficking and progressive neurovisceral disease. Although the clinical and molecular spectrum of NPC has been well characterized in several populations, data from India remain limited. The present study aimed to describe the clinical and molecular characteristics of NPC in Indian patients and to expand the mutational spectrum of the disease.MethodsWe conducted a retrospective multicentre study of 28 patients with NPC diagnosed between 2010 and 2026 based on clinical, biochemical, and molecular investigations. Filipin staining was done in two patients. Plasma chitotriosidase activity (n = 21), β-glucosidase (n = 16) and sphingomyelinase activities (n = 21) were measured in plasma sample and leukocytes respectively using fluorometric enzyme assays. Molecular testing included clinical exome sequencing and Sanger sequencing in 2 patients and 1 patient, respectively while single-molecule molecular inversion probes (smMIP)-based targeted sequencing assay was performed in 25 patients. In-silico tools were used to predict the effect of novel variants on protein function and structure.ResultsHepatosplenomegaly was the most common presenting feature, followed by developmental delay, neuroregression, ataxia, seizures, and vertical supranuclear gaze palsy. Importantly, nearly one-third of patients presented with isolated visceral manifestations in the absence of neurological involvement. Molecular analysis identified 32 variants (27 in NPC1 and 5 in NPC2), including 11 novel variants and two exon-level deletions. More than 60% of diagnoses were established during the final four years of the study following implementation of the FRIGE–Sanofi DISHA Program, highlighting the impact of improved access to affordable biochemical and molecular testing for lysosomal storage disorders. The indigenous smMIP assay enabled simultaneous detection of single nucleotide variants, small insertions/deletions, and exon-level copy number variants within a single cost-effective workflow. Structural analysis predicted that novel missense variants affect functionally critical domains of NPC1, resulting in disruption of protein stability, cholesterol trafficking, and lysosomal function.ConclusionThe present study provides a comprehensive characterization of the clinical spectrum and molecular heterogeneity of NPC in a large cohort of patients of Indian origin.
