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PubMed2026

Pan-cancer landscape of APEX1 expression and genomic alterations: Associations with clinical outcomes and functional validation in lung cancer.

This pan-cancer study systematically evaluated APEX1 expression, genomic alteration status, and prognostic value across 13,270 tumors and 2544 normal tissues from TCGA and GTEx. APEX1 overexpression was prominent in bladder, breast, and colon adenocarcinomas and correlated with advanced tumor stages and survival outcomes in a cancer-type-specific manner, with unfavorable associations in selected tumor contexts and an opposite favorable association in KIRC. Low-frequency APEX1 genomic alterations require cautious interpretation and may be associated with adverse outcomes in selected tumor contexts. Statistical methods including t-tests, ANOVA, Cox regression, Benjamini-Hochberg false-discovery rate correction for cohort-wise OS analyses, and log-rank tests were used to correlate APEX1 expression or alteration status with survival outcomes. The findings suggest that APEX1 expression and low-frequency genomic alterations are associated with tumor progression and worse patient outcomes in selected cancer contexts. This study supports APEX1 as a candidate prognostic indicator requiring further validation and suggests its potential value for future clinical stratification research. The pan-cancer approach improves contextual breadth, and the large sample size adds robustness. The observed relevance of APEX1 across malignancies supports further evaluation of its value for risk stratification and treatment planning. Future prospective studies are needed to validate its clinical utility. This work contributes to the growing field of DNA repair-related biomarkers and may inform future studies of APEX1-targeted therapeutic strategies.

Apurinic/Apyrimidinic Endonuclease 1↗

PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗

PubMed2026

Subclonal Complete Loss of CDKN1B as a Common Genomic Alteration in Prostate Cancer: Associations With Race and Prostate Cancer Outcomes.

Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer, including prostate cancer. In the present study, we report that the prevalence of subclonal genomic loss of CDKN1B, especially among self-reported African-American or Black (AA) individuals, has likely been underestimated in primary prostate cancer. Using immunohistochemistry (IHC) for p27 protein and a large cohort of whole tissue sections from radical prostatectomy (N = 412) from AA and European American (EA) individuals, we discovered an unexpectedly high frequency of regions of intratumoral complete p27 protein loss (IPPL) within larger tumor nodules that otherwise showed intact p27 staining that was more prevalent among prostate cancer in AA individuals (18.1%) than EA individuals (12.2%). Regions of IPPL were tightly associated with loss of CDKN1B messenger RNA by in situ hybridization. Furthermore, these focal regions of IPPL were closely linked to CDKN1B genomic loss as detected by next-generation sequencing panel sequencing of laser-captured regions. The detection of IPPL by IHC was associated with ≥pT3 pathologic stage (extraprostatic extension and seminal vesicle involvement) and pN1 (local lymph node involvement) disease; however, when stratified by race, these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available data sets as well as in our analysis of autopsy specimens via IHC. Overall, subclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer and could contribute to worse prostate cancer outcomes, specifically in AA individuals. Our findings warrant further exploration into the clinical utility of using IHC for p27 loss as a prognostic biomarker.

CDKN1B cancer disparities↗

PubMed2026

Subclonal Complete Loss of CDKN1B as a Common Genomic Alteration in Prostate Cancer: Associations with Race and Prostate Cancer Outcomes.

BACKGROUND: Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. EXPERIMENTAL DESIGN: We used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. RESULTS: IPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with ≥pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. CONCLUSIONS: Subclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.

Journal Article↗

PubMed2026

Antimicrobial susceptibility patterns of commensal fecal bacteria isolated from pigs with an intentional genomic alteration that included the selectable marker gene nptII.

INTRODUCTION: Animals with intentional genomic alterations (IGAs) hold promise for meeting increasing worldwide demand for animal-source proteins. As part of regulatory risk assessment for introducing animals with IGAs into the food chain, monitoring commensal bacterial microbiota is recommended due to concern that antimicrobial resistance genes used during IGA selection could be transferred, via horizontal gene transfer, to gastrointestinal or environmental bacterial populations, potentially contributing to antimicrobial resistance. The objective of this study was to assess the antimicrobial susceptibility patterns in commensal bacteria isolated from fecal samples of GalSafe™ pigs that have an IGA that includes the aminoglycoside resistance gene nptII. METHODS: Antimicrobial resistance rates observed in Escherichia coli, Salmonella, Campylobacter and Enterococcus isolated from GalSafe™ pigs were compared to resistance rates observed in conventional pigs at slaughter. Bacterial isolates were tested for antimicrobial resistance genes by PCR and one isolate underwent whole genome sequencing. RESULTS: In total, 137 bacterial isolates recovered from 55 fecal samples collected from 47 individual adult GalSafe™ pigs were evaluated. Prevalence of antimicrobial resistance in GalSafe™ pigs was generally similar to, or lower than, resistance prevalence reported from conventional pigs at slaughter, based on National Antimicrobial Resistance Monitoring System (NARMS) data. Higher resistance rates in GalSafe™ pigs were observed only for quinolones in Campylobacter coli (ciprofloxacin and nalidixic acid) and nitrofurantoin in Enterococcus spp. One isolate (E. coli) was positive for nptII neomycin resistance gene, the same gene used for IGA selection in GalSafe™ pigs, and the remaining 136 isolates were negative for nptII. However, the positive isolate did not appear to contain nptII derived from the GalSafe™ pig genome as the sequences flanking the gene did not match the IGA. DISCUSSION: We did not detect evidence of nptII gene transformation into bacterial species of potential human health importance in this population of GalSafe™ pigs.

NARMS↗

PubMed2026

Integrated expression profiling of trophoblast cell-surface antigen 2 (TROP2), folate receptor alpha (FRα), and human epidermal growth factor receptor 2 (HER2) in endometrial Cancer across molecular classes, genomic alterations, and histologic subtypes.

OBJECTIVE: Antibody-drug conjugates (ADCs) are expanding treatment options in endometrial carcinoma, but the distribution of actionable surface targets across histologic, molecular, and genomic subgroups remains incompletely defined. METHODS: This single-institution retrospective tissue microarray (TMA) study included 312 endometrial carcinomas: 158 endometrioid and 154 serous tumors. Trophoblast cell-surface antigen 2 (TROP2) was quantified by histochemical score (H-score); human epidermal growth factor receptor 2 (HER2) was assessed using endometrial carcinoma-specific and gastric/DESTINY-PanTumor02 criteria; and folate receptor alpha (FRα) positivity was defined as ≥75% viable tumor cells with ≥2+ membranous staining. Molecular class was assigned using a hierarchical DNA polymerase epsilon (POLE)-mutant, microsatellite instability/mismatch repair-deficient (MSI/MMRd), p53-abnormal, and no specific molecular profile (NSMP) classifier. Tumor mutational burden (TMB) and recurrent genomic alterations were analyzed in relation to biomarker expression. RESULTS: TROP2 was broadly expressed, with median H-scores of 280 in endometrioid and 200 in serous carcinomas. HER2 gastric-score 2+/3+ expression and FRα positivity were enriched in serous versus endometrioid carcinoma (22.5% vs 8.9% and 20.1% vs 4.4%), restricted to FIGO grade 3 tumors, and concentrated in p53-abnormal disease. FRα positivity was absent in POLE-mutant and MSI/MMRd tumors. HER2 2+/3+ expression correlated with erb-b2 receptor tyrosine kinase 2 (ERBB2) alterations, whereas FRα-positive tumors were enriched for TP53 alterations and showed lower frequencies of ARID1A and PTEN alterations. Triple-negative TROP2/HER2/FRα tumors were uncommon (6/308, 1.9%). CONCLUSIONS: TROP2 is broadly expressed in endometrial carcinoma, whereas HER2 and FRα define a more restricted high-grade, serous/serous-like, p53-abnormal compartment, supporting biomarker-informed ADC development.

Humans↗

PubMed2026

Comparative Analysis of Potential Clinical Actionability of Genomic Alterations in Early-Onset Versus Later-Onset GI Cancers.

PURPOSE: As biomarker-directed therapy increasingly shapes GI oncology, it remains unclear whether early-onset (EO) and later-onset (LO) GI cancers harbor comparable opportunities for clinically actionable targeting. We compared the landscape of potentially actionable genomic alterations in EO versus LO GI cancers using American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange v19.0. METHODS: GI tumor samples were assigned to 10 prespecified tumor groups using OncoTree codes. Samples were annotated with OncoKB therapeutic levels and classified as potentially actionable if they harbored at least one level 1-3B alteration. EO and LO disease were defined as age at sequencing <50 years and ≥50 years, respectively. Group-wise comparisons used Wilcoxon rank-sum, chi-square, or Fisher exact testing as appropriate and with false discovery rate correction. Multivariable logistic regression evaluated age group associations overall and within tumor groups. RESULTS: Among 53,945 GI tumor samples, 10,573 (19.6%) were EO and 43,372 (80.4%) were LO. EO tumors had lower prevalence of potentially actionable alterations in colorectal (71% v 78.1%, q < 0.001), esophagogastric (53.3% v 57.9%, q = 0.0097), GI stromal tumor (GIST) (75.1% v 90.9%, q < 0.001), liver (25.4% v 35.4%, q = 0.0021), and pancreatic tumors (82.9% v 90.7%, q < 0.001). In the overall model, LO status was associated with higher odds of potential actionability (odds ratio, 1.39 [95% CI, 1.33 to 1.47]; P < .001). Tumor group-specific associations persisted in colorectal, GIST, liver, and pancreatic tumors after multivariable adjustment. CONCLUSION: Potential clinical actionability differs between EO and LO GI cancers in a tumor lineage-specific manner. Several major EO GI tumor groups appear relatively depleted of potentially actionable alterations, suggesting that the expanding therapeutic reach of precision oncology may not be distributed evenly across age-defined GI cancer populations and underscoring the need for EO-focused biomarker discovery and therapeutic development.

Humans↗

PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

ESCAT↗

PubMed2026

Associations of TILs and genomic alterations in HER2+ early breast cancer.

This study investigated the associations between tumor-infiltrating lymphocytes (TILs), genomic features, and prognosis in HER2+ early breast cancer (EBC) patients receiving adjuvant trastuzumab. We retrospectively analyzed 864 HER2+ EBC patients from Shanghai Ruijin Hospital (2009-2017). The optimal threshold of TILs for predicting disease-free survival (DFS) and overall survival (OS) was explored. Whole-exome sequencing (WES) on 261 tumors assessed the mutational profiles, tumor mutational burden (TMB), and copy number alteration (CNA). Associations between these genomic features, TIL levels, and prognosis were further evaluated. TILs showed a right-skewed distribution (median: 15%, IQR: 1-30%), and higher TIL levels were significantly associated with hormone receptor negativity and high histologic grade (P < 0.001). A 15% TIL threshold optimally predicted prognosis, with low-TIL (≤15%, 63.0%) patients showing inferior DFS (HR: 1.63, P = 0.009) and OS (HR: 2.12, P = 0.037). WES identified frequent mutations in TP53 (62.8%), PIK3CA (34.5%), and BRCA2 (9.6%). A higher TIL density was observed in TP53-wild-type, low-TMB or low-CNA tumors (P < 0.05). PIK3CA mutations conferred a significant DFS advantage. Integrating TIL level with PIK3CA or BRCA2 mutational status yielded distinct DFS trajectories (log-rank P = 0.023 and 0.040, respectively); patients with both high TIL levels and either PIK3CA or BRCA2 mutations had the most favorable outcomes. Stromal TILs at a 15% cutoff provide robust prognostic information in trastuzumab-treated HER2+ EBC. Integrating TIL levels with PIK3CA or BRCA2 mutational status enables refined risk stratification, offering a practical framework for personalized treatment decisions.

Humans↗

PubMed2026

In silico analysis of SH3BP2 genomic alterations and expression profiles in CRC.

AIM: Colorectal cancer (CRC) is a widespread health issue that attains high mortality. The adaptor protein SH3BP2 amplification results in metabolic changes, oxidative stress, NK cell activity, and inflammation. The NK cells are capable of destroying tumor cells without prior activation, help prevent metastasis, and have prognostic value. Targeting SH3BP2 to regulate NK cell activity in the TME could enhance CRC-based immunotherapy. MATERIALS AND METHODS: The cancer hallmark tool helps in understanding SH3BP2 hallmark annotation. Utilizing the STRING tool and the KEGG pathway, protein functional enrichment and PPI networking were analyzed. TIMER 2.0 was used for immune cell infiltration correlation analysis, and UALCAN was used for CPTAC-based protein expression profiling. RESULTS AND CONCLUSIONS: The GEO (GSE9348) dataset showed SH3BP2 is upregulated in CRC (log2 fold change = 1.18). GEO, TCGA, and cBioPortal revealed SH3BP2 alterations in CRC cases, potentially aiding immune evasion. Mutations in SH3BP2 influence cancer growth, suppressing tumors or promoting them by activating NF-κB and affecting immune responses through WNT/β-catenin, PI3K, MAPK, and JAK-STAT pathways. Overall, SH3BP2 plays a key role in cancer growth and immune regulation, making it a promising target for CRC therapy. Further experimental validation is needed to demonstrate its diagnostic and therapeutic potency.

Humans↗

PubMed2026

Molecular characterization of salivary cancers: Patterns of genomic alterations and potential for impact on therapeutic choices.

BACKGROUND: Salivary cancers are rare malignancies with diverse histologies, molecular landscape, and limited effective systemic therapy options. Recent tumour genomics research has identified driver alterations in salivary gland cancers that have led to personalized therapy approaches. The primary objective was to perform molecular characterization using next generation sequencing (NGS) panel and evaluate the potential impact of results on clinical decision-making and treatment outcomes. METHODS: Patients with locally advanced or incurable metastatic salivary cancers suitable for systemic therapy underwent NGS tumour testing with an amplicon-based DNA/RNA NGS panel. Patient demographics, baseline characteristics, treatment and treatment outcomes were retrospectively collected. RESULTS: From 2021 to 2024, 58 advanced salivary cancer patients underwent molecular characterization of their tumour. Baseline characteristics at diagnosis: male 60%, median age 67, most common histologies; adenoid cystic 27%, salivary duct 19% and mucoepidermoid 12%. PIK3CA alterations were the most common molecular finding across all subtypes 22% (13/58) and were enriched in salivary duct carcinoma 73% (8/11). Other alterations identified were: ERBB2 (4), EGFR (2), HRAS (3), NTRK3 (2), BRAF p.V600E (1), and RET (1). Immunohistochemistry identified androgen receptor positivity across salivary cancer subtypes in 8/19 and HER2 positivity in 2/20 tested. Twenty-two patients received systemic therapy prior to NGS results for incurable/metastatic disease, first line treatments included 69% chemotherapy, 18% anti-androgen, 9% lenvatinib, 4% trial. CONCLUSION: Molecular characterization of salivary cancers identified targetable alterations in 37% of patients. The identification of potential therapeutic targets offers the opportunity for expanded treatment options to benefit salivary gland cancer patients.

Metastatic salivary gland cancer↗

PubMed2026

Genomic introgressions from wild relatives in the wheat genome alter meiotic dynamics in inter-varietal hybrids.

The use of wild relatives to introduce original diversity in the genome of bread wheat (Triticum aestivum L.) is an interesting approach to face the challenges of sustainable agriculture and the impact of climate change on wheat production. However, the influence of these wild-species introgressions on meiosis in inter-varietal wheat hybrids remains poorly understood. We analyzed the French wheat variety Renan (Re) carrying Aegilops ventricosa (Aev)-derived 2AS/2NS and 7DL/7DvL introgressions, the reference cultivar Chinese Spring (CS), which lacks these introgressions, and their inter-varietal hybrid Chinese Spring × Renan (CSRe). This analysis combined cytogenetic approaches with the assessment of reproductive performance. Furthermore, we generated a cytological atlas of meiosis in wild tetraploid Aev, quantifying bivalent configurations and chiasma frequency. We observed a reduced pollen viability and a slight decrease in floret fertility in the hybrid CSRe. Exploration of the meiotic behavior showed that CSRe exhibited increased numbers of rod bivalents and univalents, leading to a reduced average chiasma number and frequent chromosome bridges and fragmentations, whereas the parental lines maintained stable chromosome pairing. These rearrangements indicate that homologous chromosome pairing and recombination are affected in CSRe. We applied introgression-specific oligo-Fluorescent In Situ Hybridization to localize alien segments in CSRe, providing a novel strategy to investigate the meiotic behavior of introgressed regions. The 2AS/2NS introgressed segments in CSRe were frequently located on rod bivalents or univalents, while 7DL/7DvL segments consistently formed ring bivalents. Our results provide a foundation for guiding alien gene introgression and for understanding the behavior of chromosomes with introgressions in the wheat genome.

Meiosis↗

PubMed2025

Genomic Alterations in Multiple Myeloma: A Comprehensive Landscape.

UNLABELLED: Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy in which cytogenetic abnormalities play a key role in disease prognosis. This study evaluates the spectrum of genomic aberrations in newly diagnosed multiple myeloma (NDMM) patients, with a focus on high-risk cytogenetic profiles, including double-hit (DHMM), and triple-hit multiple myeloma (THMM). This is a retrospective analysis of NDMM patients, reviewing clinical and laboratory data for baseline characteristics, cytogenetics, therapy, and outcomes. Patients were categorized based on the cytogenetic abnormalities. Double-hit MM was defined by the coexistence of two high-risk abnormalities and triple-hit MM was defined by coexistence of three or more high-risk abnormalities. Survival outcomes were assessed using Kaplan-Meier analysis and Cox regression models using SigmaPlot (version 15). A total of 314 NDMM cases (205 Male: 109 Female; median age 58 years) enrolled between 2014 and 2021 were evaluated. Using the Revised International Staging System (R2-ISS), most patients were in stage 2 (41.1%) and stage 3 (38.2%). Cytogenetic analysis revealed one or more high-risk abnormalities in 43% of cases. Among the high-risk group, one, two and three or more high-risk abnormalities were observed in 89 (28%), 35 (11%), and 11 (4%) patients, respectively. THMM cases exhibited the poorest outcomes [median overall survival (OS):7 months], in comparison to DHMM (OS: 33 months), SHMM (OS: 40 months), and patients without high-risk features (OS: 60 months). Cox regression analysis confirmed that THMM patients had a 3.6-fold increased risk of death (HR: 3.677; 95% CI: 2.219-7.915; p < 0.001) and 4-fold increased risk of progression (HR: 4.191; 95% CI: 1.897-7.126; p < 0.001) compared to patients without any high-risk abnormalities. Among 67 patients undergoing autologous stem cell transplant (ASCT), high risk abnormalities were significantly associated with shorter OS (HR: 2.409; 95% CI: 1.094-5.291; p = 0.029, 111 months for ASCT without high-risk vs. 78 months for ASCT with high- risk abnormalities) and shortened PFS (HR: 2.379; 95% CI: 1.285-4.403; p = 0.006, 85 months for ASCT without high-risk vs. 34 months with high-risk abnormalities). Double and triple-hit MM constitute 14.6% of NDMM cases, indicating poor survival and early disease progression. Comprehensive cytogenetic profiling at diagnosis and post-ASCT has the potential to improve risk stratification and guide individualized treatment strategies for high-risk MM patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02284-5.

Cytogenetic↗

PubMed2026

Molecular profiling of pediatric medulloblastoma in Kazakhstan: Genomic alterations, subgroup distribution, and survival.

Medulloblastoma is the most common malignant pediatric brain tumor and comprises biologically distinct molecular subgroups with different clinicopathologic and prognostic characteristics. Molecular data from Kazakhstan and other underrepresented regions remain limited, and practical approaches for molecular subgroup assignment using formalin-fixed, paraffin-embedded (FFPE) material are needed in settings where advanced molecular classification is not routinely available. We retrospectively analyzed 40 pediatric medulloblastomas diagnosed between 2015 and 2024 at the Corporate Fund "University Medical Center," Kazakhstan. Archived FFPE tumor material underwent histologic review, immunohistochemical evaluation (β-catenin, YAP1, and GAB1), and whole-exome sequencing. Tumors were assigned to WNT, SHH, or non-WNT/non-SHH categories using a combined morphologic, immunophenotypic, and genomic framework, and clinicopathologic variables and overall survival were evaluated across subgroups. WNT medulloblastomas (n = 7, 17.5%) showed the most canonical profile, characterized by classic histology, uniform β-catenin nuclear positivity, recurrent CTNNB1/APC alterations, and frequent chromosome 6 loss. SHH medulloblastomas (n = 10, 25.0%) were enriched for desmoplastic/nodular morphology, frequent YAP1/GAB1 expression, pathogenic PTCH1/SUFU alterations, and additional events involving TP53, TERT, and focal amplifications in a subset. Non-WNT/non-SHH medulloblastomas (n = 23, 57.5%) showed the greatest genomic heterogeneity, including frequent i17q and broader structural complexity. Clinically, WNT tumors occurred predominantly in older children and had the most favorable survival, whereas non-WNT/non-SHH tumors were the only subgroup associated with metastatic disease at presentation and showed the poorest long-term survival. Overall, pediatric medulloblastoma in this cohort demonstrated subgroup-specific patterns consistent with established biology. The integration of pathology, immunohistochemistry, and sequencing enabled clinically meaningful molecular stratification. These findings expand evidence from an underrepresented setting and support pragmatic, resource-adapted profiling in routine practice.

Kazakhstan↗

PubMed2026

Mast cell leukemia with complex genomic alterations in an elderly patient with prior hematologic and solid malignancies: a case report.

INTRODUCTION: Mast cell leukemia (MCL) is the rarest and most aggressive variant of systemic mastocytosis (approximately 1% of cases), with a median survival of under 2 years. Diagnosis requires ≥20% atypical mast cells in the marrow aspirate, and the disease frequently overlaps with myeloid neoplasms. CASE PRESENTATION: An 86-year-old man with paranasal sinus diffuse large B-cell lymphoma in remission since 2017 after R-CHOP and methotrexate, and prostate adenocarcinoma treated in 2019, presented with acute pancytopenia, presumed to represent lymphoma relapse. Serum tryptase exceeded 11 999 ng/mL; the aspirate showed 20% pleomorphic mast cells (CD117+, weak CD25, CD2-), confirming aleukemic MCL. Formal CMML criteria could not be confirmed due to the unavailability of monocyte differential data; however, the findings raised suspicion for an associated myeloid neoplasm, with SM with an associated hematological neoplasm remaining an alternative classification. Karyotyping was normal; next-generation sequencing revealed pathogenic variants in TP53, RB1, DAXX, ASXL1, TET2, and SRSF2, and a rare extracellular-domain KIT p.D419del. He declined inpatient midostaurin, deteriorated rapidly, and died 2 weeks later. CLINICAL DISCUSSION: This case illustrates a therapy-related MCL (plausible but unconfirmed given the non-leukemogenic profile of methotrexate and the focal nature of prostate stereotactic body radiation therapy) with a suspected associated myeloid neoplasm and complex pathogenic mutations. The KIT p.D419del extracellular domain variant is a rare non-D816V mutation; the canonical D816V was not detected on NGS, though the presence of a low-variant allele fraction D816V cannot be fully excluded due to assay sensitivity. Despite midostaurin, the disease remained aggressive. CONCLUSION: Persistent unexplained cytopenias warrant heightened suspicion of MCL, and comprehensive genomic profiling clarifies diagnosis, distinguishes overlapping myeloid disease, and informs prognosis in this aggressive, refractory neoplasm.

case report↗

PubMed2026

Protein arginine methyltransferase (PRMT8) in cancer: Genomic alterations, subcellular dynamics, and clinical implications.

PRMT8 encodes a protein arginine methyltransferase, which is primarily expressed in the brain and nervous system. Several studies have reported its alterations, which have been implicated in various cancers. However, the existing information remains unsystematic and fragmented due to inconsistency in methodology. This review aims to explore PRMT8 gene alterations in humans, their effects on cellular function and physiology, and their clinical implications. We conducted a narrative literature review covering all publications on PRMT8 alterations across different cancer types, their effect on tumour cell characteristics, and their impact on patient prognosis. Reported PRMT8 alterations include mutations, copy number amplifications, and single-nucleotide polymorphisms, which lead to overexpression or downregulation of PRMT8 protein in tumour cells. PRMT8 alterations compromise the efficacy of both chemotherapy and immune checkpoint inhibitor treatment. These alterations enable tumour cells to maintain pluripotency via activation of the PI3K/AKT/SOX2 signalling pathway, thereby promoting cellular proliferation, invasion, and colony formation. Clinically, these PRMT8 alterations drive disease progression and therapy resistance, resulting in poor prognosis and reduced patient survival. These findings underscore the need to incorporate PRMT8 alterations assessment in clinical practice to guide therapeutic decision-making and improve treatment outcomes in affected patient populations.

Humans↗

PubMed2025

A Genomic Alteration in GATA3 Affects Treatment Responses With a CDK4/6 Inhibitor Collaborating With p18INK4C Expression in Advanced Breast Carcinoma.

Cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with endocrine therapy benefits patients with hormone receptor-positive, human epidermal growth receptor 2-negative breast carcinomas. However, most tumors develop resistance to CDK4/6i during the course of therapy. Although preclinical studies have proposed molecular mechanisms for the resistance, predictive markers are yet to be discovered. We investigated the tumor molecular profiling in 42 patients with advanced-stage breast carcinoma who received CDK4/6i therapy. The tumors carrying a GATA-binding protein 3 (GATA3) gene mutation, mainly a frameshift variant, showed a better treatment response compared with other tumors. Furthermore, we explored the potential underlying mechanism of this association. To that end, nuclear expression of p18, one of the INK family proteins, was found to be positively associated with the GATA3 mutation, as well as a CDK4/6i treatment response. Therefore, our study suggests that a GATA3 gene mutation, collaborating with p18 protein expression in tumor nuclei, may have a predictive value for CDK4/6i therapy in breast carcinoma.

Humans↗

PubMed2025

Pathway-specific genomic alterations in pancreatic cancer across diverse cohorts.

BACKGROUND/OBJECTIVES: Pancreatic cancer (PC) is an aggressive malignancy with rising incidence and poor survival rates. While Hispanic/Latino (H/L) patients have a lower overall incidence compared to Non-Hispanic White (NHW) patients, they are diagnosed at younger ages, often present with more advanced disease, and experience worse survival outcomes. The molecular drivers underlying these disparities remain poorly understood. Key oncogenic pathways, including TP53, WNT, PI3K, TGF-Beta, and RTK/RAS, play crucial roles in tumor progression, therapy resistance, and response to targeted treatments. However, their ethnicity-specific alterations and prognostic implications in PC remain largely unexplored. This study aims to characterize pathway-specific mutations in PC among H/L and NHW patients, assess tumor mutation burden, and identify ethnicity-specific oncogenic drivers using publicly available datasets. The findings may provide critical insights to optimize precision medicine strategies and enhance targeted therapies for underrepresented populations. METHODS: A bioinformatics analysis was performed using publicly available PC datasets to evaluate mutation frequencies in genes associated with the TGF-Beta, RTK/RAS, WNT, PI3K, and TP53 pathways. The study included 4,248 patients, with 407 identified as H/L and 3,841 as NHW. Patients were stratified by ethnicity to assess differences in mutation prevalence. Chi-squared tests were conducted to compare mutation rates between groups, while Kaplan-Meier survival analysis was performed to evaluate overall survival differences based on pathway-specific alterations. RESULTS: Significant differences were observed in the TGF-Beta pathway between H/L and NHW patients. TGF-Beta mutations were less prevalent in H/L patients (18.4% vs. 24.4%, p = 8.6e-3). Additionally, genes related to the TGF-Beta pathway showed significant alterations, with SMAD2 (1.5% vs. 0.4%, p = 6.3e-3) and SMAD4 (15% vs. 19.9%, p = 0.02) exhibiting notable differences. Although RTK/RAS, WNT, PI3K, and TP53 pathway mutations were not statistically significant overall, borderline significance was observed in genes associated with these pathways, including ERBB4 (3.4% vs. 1.8%, p = 0.03), ALK (2.7% vs. 1.1%, p = 0.01), HRAS (1.2% vs. 0.1%, p = 1.3e-4), and RIT1 (0.7% vs. 0.1%, p = 0.03) in the RTK/RAS pathway, as well as CTNNB1 (2.9% vs. 1.3%, p = 0.01) in the WNT pathway. Survival analysis revealed no significant differences in overall survival among H/L patients. However, NHW patients with TP53 pathway alterations exhibited borderline significant differences in survival outcomes.

PI3K pathway↗