Tom van Wezel

Chromosomal instability (CIN), characterised by recurrent chromosome mis-segregation, fuels intratumour heterogeneity and tumour evolution. Yet, its proximal molecular causes remain ill-defined. Tumour-scale genomic and transcriptomic analyses associate MPS1 overexpression with CIN in colon carcinomas. Consistently, CIN ⁺ patient-derived colon cancer cells (PCCCs) display elevated MPS1, frequent merotelic kinetochore-microtubule attachments and lagging chromosomes that are suppressed by partial MPS1 inhibition. Conversely, ectopic MPS1 overexpression in otherwise stable near-diploid cells phenocopies these defects, inducing micronuclei formation and karyotypic divergence. Mechanistically, MPS1 overactivity maintains ROD phosphorylation at Thr13/Ser15, continuously sustaining fibrous corona assembly despite mature end-on attachments. 3D-STED microscopy reveals split-interface configurations in which microtubules from opposing poles engage the canonical outer-kinetochore surface and a spatially distinct corona domain, explaining how merotely forms and persists into anaphase. Disrupting corona assembly restores chromosome segregation fidelity in MPS1-overexpressing RPE-1 cells and in CIN ⁺ PCCCs. Together, our findings establish MPS1 overexpression as a driver of CIN and uncover how oncogenic transcriptional rewiring of mitotic signalling converts a transient microtubule-capture structure into a pathological source of merotely and chromosome mis-segregation in colon cancer.

Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent lesions to aggressive systemic disease. Over recent decades, advances in genomic profiling have transformed the biological understanding of these conditions. The discovery of recurrent oncogenic mutations has reframed histiocytoses from primary inflammatory disorders to myeloid neoplasms, with a notable dependence on aberrant mitogen‐activated protein kinase (MAPK) signalling. Novel genetic drivers continue to be uncovered, with many alterations correlating with distinct clinical and pathological phenotypes. Parallel studies have refined the understanding of disease ontogeny, demonstrating that diverse histiocytoses originate from haematopoietic stem/progenitor cells. In Langerhans cell histiocytosis, the differentiation stage of the mutated precursor cell is considered an important — but not the sole — determinant of disease extent and severity. Additional evidence suggests that specific clinical manifestations, such as neurodegenerative disease, may result from somatic mosaicism affecting tissue‐resident macrophages derived from yolk sac progenitors. Collectively, these findings refine histiocytosis diagnosis, risk stratification, disease monitoring and treatment, with robust activity of kinase inhibitors in patients with severe or refractory disease. In this review, we synthesise recent genomic insights into histiocytosis development and variation, while addressing remaining questions and future directions. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Homologous Recombination Factor With OB‐Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8‐MCM9 helicase complex activity. Recent findings link biallelic germline HROB variants to primary gonadal insufficiency (hypergonadotropic hypogonadism), a phenotype also associated with MCM8/MCM9 deficiency. Here, we describe a family where two individuals with biallelic HROB variants presented with hypergonadotropic hypogonadism and colonic polyposis. Exome sequencing identified three unique HROB variants: a likely pathogenic nonsense variant (c.1267C>T [p.(Gln423*)]) in exon four, and two missense variants (c.1363C>G [p.(Leu455Val)] and c.1318A>G [p.(Ser440Gly)]) in exon five. RNA analysis and protein mapping indicate that the nonsense variant is likely pathogenic, whereas the missense variants remain of uncertain significance. Mutational signature analysis of polyposis tissue did not reveal signatures directly linked to HROB deficiency, yet a review of published cases and analyses of cohorts with unexplained polyposis/cancer identified additional individuals with HROB variants exhibiting hypergonadotropic hypogonadism or colonic polyposis. These findings reinforce the association between biallelic germline HROB variants and hypergonadotropic hypogonadism and suggest a potential role in colonic polyposis predisposition. We recommend incorporating HROB into diagnostic gene panels for hypergonadotropic hypogonadism, especially in cases where colonic polyposis is also present. Furthermore, we emphasize the importance of additional studies to comprehensively characterize HROB 's phenotypic impact and assess its contribution to disease risk.

Purpose: Gastric cancer (GC) is the fifth most lethal form of cancer. Because of its late diagnosis, high intratumor heterogeneity, and the presence of a dense stromal compartment, GC is less susceptible to systemic treatments compared to other tumor types. Many systemic therapies, developed to support curative and palliative treatment for GC and other cancers, did not reach the clinic, which might be due to the fact that preclinical data, obtained from simple cell-based models, does not translate to the complex GC tumor structure and the occurrence of drug resistance. Therefore, this study is aimed to establish fibroblast-rich, close-to-patient models for GC and evaluate their robustness by comparison with the primary GC tissue from the respective patients. Material and Methods: Five different GC models were established: I) a subcutaneous and II) orthotopic patient-derived xenograft (PDX) model, III) an in vitro patient-derived organoid (PDO) model, which was IV) subcutaneously engrafted in vivo, and V) co-cultured with GC fibroblasts to form a novel multicellular fibroblast-rich GC model. Histology, immunohistochemistry, mutational status and tumor/stroma composition were compared between the parental tissues and the various models. Results: Both PDX models reflected the histological structure of the parental tissue, consisting of distinct parenchymal and stromal compartments. Primary tumor mutations were maintained in the PDX, as well as markers of clinical interest, like HER2. Orthotopic GC-PDX models showed high growth rates, accompanied by significant stromal accumulation. GC-PDOs showed histological similarities with parental tissues, maintaining the various histological phenotypes. Engrafted subcutaneously in mice, these organoids generated stroma-rich tumors. To mimic these features in vitro, we established a multicellular model composed of GC-associated fibroblasts and GC organoids, aggregating into complex multicellular structures with high similarity to parental GC tumor tissues. Conclusion: We generated five close-to-patient GC models, which can potentially facilitate preclinical evaluations of novel therapies.

Background: Lynch syndrome (LS) predisposes carriers to the accelerated development of colorectal cancer (CRC). Pathogenic PMS2 variant (PV) carriers are believed to have the lowest CRC risk and develop MMR deficiency (dMMR) at a later stage of CRC progression. In addition, the PMS2 adenoma incidence rate is considered lowest among all MMR PV carriers. However, neither the exact adenoma incidence nor the prevalence of dMMR among PMS2 PV carriers is known. Method: We established a cohort of 171 confirmed PMS2 PV carriers in the Netherlands and collected clinical excerpts to establish adenoma incidence. We also collected 123 paraffin blocks from PMS2 PV carriers and investigated PMS2 and MLH1 expression with immunohistochemistry (IHC). Results: We collected 123 paraffin blocks containing adenomatous lesions from PMS2 PV carriers removed who underwent surveillance colonoscopy between 2018-2023. Of the 123 IHC-stained lesions 109 were tubular adenomas, 86.2% of which (n=94/109) retained PMS2 protein expression. All specimens showed intact MLH1 staining. Conclusion: Adenomas are frequent in PMS2 PV carriers, although the majority of PMS2-associated adenomas retained MMR-proficiency. The result of our study corroborates the late involvement of PMS2 deficiency in the evolution of to PMS2 associated CRC.

Background Because breast cancer (BC) is molecularly heterogeneous, diagnosis and treatment will likely benefit from comprehensive genetic profiling. However, routine, high-resolution sequencing is not feasible yet, due to implementation challenges associated with whole-genome sequencing of formalin-fixed paraffin embedded (FFPE) BC samples. Therefore, we explored the potential of an alternative low-resolution, genome-wide testing approach that is able to capture the copy number (CN) landscape, including actionable alterations, in FFPE derived DNA. Methods The performance of the genome-wide CN testing approach, including CN signatures/focal CN alterations, was evaluated in two phases: (i) exploration and (ii) feasibility phase. First, high-resolution sequencing data of a previously published triple-negative BC cohort (n = 237) was leveraged to benchmark the homologous recombination deficiency (HRD)-related CN signature using a comprehensive, multimodal approach incorporating both genetic and functional HRD tests. Secondly, the low-resolution testing strategy’s feasibility was prospectively evaluated in a BC cohort of patients referred to clinical genetic services (n = 147). Results Applying the HRD threshold that was established using both genomic and functional HRD data, we identified a 100% sensitivity for BC with BRCA1/BRCA2/PALB2 pathogenic variants in the prospective cohort. Moreover, the success rate of the low-resolution testing approach proved high, regardless of input material. Finally, additional CN alterations were enriched in the HR-proficient BC population, indicating potential actionable CN-alterations beyond HRD. Conclusions In conclusion, low-resolution, genome-wide sequencing has shown high potential in capturing the CN landscape, including features associated with HRD, in BC patients. This preselection testing approach is likely to maximize potential for personalized medicine and genetic counseling.

Primary cutaneous follicle center lymphoma (PCFCL) is a type of cutaneous B-cell lymphoma with an indolent behavior and a 5-year disease-specific survival of 95%. Given the difficulty of identifying patients at risk for developing extracutaneous dissemination (ECD), this study aimed to identify predictors in the clinical presentation, histopathology, immune phenotype, and genetic profile of PCFCL patients by comparing those who developed ECD with those whose disease remained skin limited (SL) during follow-up. After review of clinical data and histopathology, a total of 13 ECD-PCFCL patients and 15 SL-PCFCL patients with varying treatments were included from the Dutch Cutaneous Lymphomas Registry. At diagnosis, all patients presented with classic PCFCL lesions on the trunk or head-and-neck region, and histology indicated a predominance of centrocytes admixed with centroblasts. IgM expression was significantly more frequent in ECD-PCFCL (54%) than in SL-PCFCL (7%; P=0.006). Targeted next-generation sequencing (NGS) with a 200 B-cell lymphoma-related gene panel demonstrated known PCFCL-like mutations in both groups. In addition, ECD-PCFCL demonstrated an enrichment of mutations associated with the activated B-cell genotype, including MYD88 (n=2), and some unique mutations, such as in ERBB4 (n=4). In conclusion, this study identified IgM expression at diagnosis as a potential biomarker for extracutaneous spread in PCFCL. In IgM-positive cases, genetic testing may be warranted. Patients with uncommon mutational profiles, such as those resembling the ABC-DLBCL genotype, may particularly benefit from closer follow-up and consideration of more aggressive treatment, including immuno-polychemotherapy. As these observations were made in a limited number of patients, our results require validation in an independent cohort.