Hongseok Yun

Aims: Triple‐positive diffuse large B‐cell lymphoma ( TP ‐ DLBCL ), co‐expressing CD10 , BCL6 and MUM1 , represents a rare subset with potential associations with IRF4 rearrangements. This study investigated the clinicopathological spectrum and frequency of IRF4 rearrangements in TP ‐ DLBCL and characterised large B‐cell lymphoma with IRF4 rearrangement ( LBCL ‐ IRF4 ‐R) in a Korean population. Methods and results: We retrospectively analysed 977 DLBCL cases diagnosed between 2003 and 2022. TP‐DLBCL accounted for 4.9% (48/977) of all cases. Among 40 eligible TP‐DLBCL cases, 17.5% (7/40) harboured IRF4 rearrangements by fluorescence in situ hybridization. Including two double‐positive cases, nine LBCL‐ IRF4 ‐R cases were characterized. TP‐DLBCL showed a significant predilection for low‐stage disease (stage I–II: 30/40, 75.0%) compared to non‐TP‐DLBCL (67/143, 46.9%; P = 0.002). LBCL‐ IRF4 ‐R patients were significantly younger than TP‐DLBCL without IRF4 rearrangement (mean age 40.6 versus 59.8 years, P = 0.049) with distinct features including preferential involvement of lymph nodes, tonsils and spleen (6/9, 66.7%), less frequent multiple extranodal involvement ( P = 0.041) and conglomerated mass presentation. Most LBCL‐ IRF4 ‐R cases achieved complete remission, though one adult case with MYD88 mutation showed aggressive behaviour. Genetic profiling revealed heterogeneous patterns with IRF4 mutations in all sequenced cases, and recurrent PIM1 , HIST1H1E and CARD11 mutations. Conclusions: LBCL‐ IRF4 ‐R represents a clinically and molecularly heterogeneous entity extending beyond paediatric populations and head‐and‐neck locations. IRF4 fluorescence in situ hybridization testing should be considered in TP‐DLBCL cases, particularly in younger patients with localized disease.

Several molecular subclassifications of diffuse large B-cell lymphoma (DLBCL) with prognostic and therapeutic potential have been proposed; however, validation in diverse populations and real-world clinical settings remains limited. We investigated the genetic subtypes of Korean DLBCL using the LymphGen classifier and an institutionally developed 121-gene targeted next-generation sequencing (NGS) panel. We also assessed quality control metrics, copy number reliability, and benchmarking performance against an external reference data set (Memorial Sloan Kettering Cancer Center–Integrated Mutation Profiling Actionable Cancer Targets). LymphGen subtypes differed by entity. Patients with DLBCL, not otherwise specified (DLBCL-NOS; n = 123) were classified as MCD (25.2%), A53 (14.6%), ST2 (7.3%), BN2 (5.7%), EZB (3.3%), composite EZB/ST2 (1.6%), and unclassified (“other”; 42.3%). Patients with primary DLBCLs of the central nervous system (n = 77) were classified as MCD (70.1%), composite MCD/A53 (2.6%), A53 (3.9%), BN2 (2.6%), ST2 (1.3%), EZB (1.3%), and “other” (18.2%). Compared with Western cohorts, the LymphGen subtype distribution in our Korean DLBCL-NOS cohort differed notably, with MCD being significantly more prevalent. The MCD subtype tended to be associated with non–germinal center B-cell–like DLBCL and DLBCL with MYC/BCL2 double expression (DE). In R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone)-treated DLBCL-NOS, patients with MCD, BN2, and A53 subtypes had poorer overall survival than those with EZB and ST2, particularly among patients with concurrent MYC/BCL2 DE. Using a clinically applicable NGS panel, we successfully implemented the LymphGen classification system. This study underscores the distinct genetic landscape of Korean DLBCL and highlights the utility of LymphGen in identifying high-risk subgroups, providing a basis for prognostic stratification and therapeutic optimization.

Purpose: Targeting aberrant metabolism in tumors with alterations in genes encoding Krebs cycle enzymes, a central component of glucose metabolism, is a promising therapeutic strategy. These tumors rely on aerobic glycolysis and promote VEGF-dependent angiogenesis; furthermore, EGFR signaling enhances aerobic glycolysis. This phase II trial evaluated bevacizumab and erlotinib in patients with solid tumors harboring Krebs cycle gene mutations. Patients and Methods: Eligible patients had solid tumors bearing pathogenic mutations in fumarate hydratase (FH), isocitrate dehydrogenase 1/2, succinate dehydrogenase, or maleate dehydrogenase 2 and measurable disease per RECIST version 1.1 or Response Assessment in Neuro-Oncology 2.0 criteria. Participants received bevacizumab (10 mg/kg IV on day 1) and erlotinib (150 mg orally once daily) every 14 days until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Results: From February to November 2023, 35 participants were enrolled: 19 with biliary tract cancer (54.3%), seven with brain tumors (20.0%), and five with FH-deficient renal cell carcinomas (FH-deficient RCC, 17.1%). ORR was 37.1% (one complete and 12 partial responses). The disease control rate was 85.7%. Subgroup ORR were 80.0% in FH-deficient RCC, 36.8% in biliary tract cancer, and 28.6% in brain tumors. At a median follow-up of 11.7 months, the median PFS was 8.3 months; median overall survival was not reached. No new safety signals were observed. Exploratory transcriptomic analyses revealed VEGF and immune pathway enrichment in patients with favorable PFS, whereas amino acid, fatty acid metabolism, and oxidative phosphorylation–related pathways were enriched in those with poor PFS. Conclusions: Bevacizumab plus erlotinib demonstrated promising efficacy in tumors with Krebs cycle gene mutations, warranting further investigation beyond FH-deficient RCC.

Background: The 2021 WHO Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS5), introduced revised diagnostic criteria for pediatric brain tumors (BTs), redefining pediatric-type diffuse high-grade gliomas (pHGGs) into 4 subtypes: diffuse midline glioma, H3 K27-altered (DMG-H3K27), diffuse hemispheric glioma, H3 G34-mutant (DHG-H3G34), diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (DpHGG-H3wt/IDHwt), and infant-type hemispheric glioma (IHG). This study revisits prior diagnoses of HGGs and primitive neuroectodermal tumors (PNETs) in children and incorporates next-generation sequencing (NGS) to classify tumors according to the revised criteria and analyze their clinicogenomic characteristics and outcomes. Methods: A retrospective review of pediatric patients diagnosed with glioblastoma (GBM), anaplastic astrocytoma, anaplastic oligoastrocytoma (AOA), gliomatosis cerebri, or PNET between 1997 and 2023 was conducted. Cases underwent pathology review, immunohistochemistry (IHC), and BT-targeted NGS for reclassification per WHO CNS5. An additional 20 patients diagnosed with pHGG via genetics-integrated diagnosis since 2020 were included. Clinical characteristics, genomic alterations, and outcomes were analyzed. Results: Among the 78 reviewed cases, 41 were reclassified as pHGGs. TP53 mutations were the most prevalent, particularly in DpHGG-H3wt/IDHwt, which showed associations with cancer predisposition syndrome (CPS). Two patients with Li-Fraumeni syndrome (LFS) developed DpHGG-H3wt/IDHwt adjacent to prior radiation fields. The 2-year overall survival (OS) rates were lowest in DpHGG-H3wt/IDHwt (23.2%) and highest in IHG (92.3%). Long-term survival was observed in IHG patients, with a 5-year OS rate of 73.8%, indicating the need for different adjuvant treatment strategies compared to other pHGGs. Conclusions: BT-targeted NGS facilitates the reclassification of pHGGs, revealing associations with CPS. Routine germline sequencing is warranted, and accurate molecular diagnosis enables a shift in treatment strategies tailored to specific pHGG subtypes.

Kim TK, et al. J Korean Med Sci. 2025 Jan;40:e62. https://doi.org/10.3346/jkms.2025.40.e62

In recent years, next-generation sequencing (NGS)–based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Jiwon Yun, M.D., Ph.D., Dong Soon Lee, M.D., Ph.D., Sungyoung Lee, Ph.D., and Hongseok Yun, Ph.D.. Ann Lab Med -0001;0:. https://doi.org/10.3343/alm.2023.0444

We present the clinicopathological and molecular genetic characteristics of a neuroepithelial tumor (NET), EWSR1::PATZ1 fusion-positive with a literature review. This fusion has recently been discovered in rare central nervous system tumors and soft tissue sarcomas and was not included in the fifth edition of the WHO classifications. We identified this fusion in 2 NETs. The first case involved a 7-year-old girl and the second case occurred in a 53-year-old man; both presented with headaches and vomiting. The pediatric case initially showed an intermediate grade of the tumor, but upon recurrences, it transformed into a high-grade tumor with 2 relapses in 8.3 years. This case exhibited high mitotic activity (20/10 high-power fields), and a high Ki-67 index (21%). The TERT promoter (TERTp) mutation was present in both initial and recurrent tumors. In contrast, the adult case was a low-grade tumor with no mitotic activity or recurrence over 13.5 months after subtotal resection and gamma knife surgery. Interestingly, the pediatric case demonstrated a longer survival time compared to conventional glioblastoma. The TERTp mutation, similar to being a molecular signature in adult-type glioblastoma, could also be an indicator of high-grade behavior in PATZ1 fusion NET.