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Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene ( TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1’s brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.

Lymphoplasmacytic lymphoma (LPL) is an indolent mature B-cell-neoplasm with involvement of the bone marrow. At least 90% of LPLs carry MYD88-L265P mutation and some of them (~10%) transform into diffuse large B-cell-lymphoma (DLBCL). Over the past 15 years we have collected 7 cases where the both LPL and DLBCL were diagnosed in the same patient. Clinical records, analytical data and histopathological specimens were reviewed. FISH studies on paraffin-embedded tissue for MYC, BCL2 and BCL6 genes were performed, as well as MYD88-L265P mutation and IGH rearrangement analysis by PCR. A mutational study was done by massive next generation sequencing (NGS). There were 4 women and 3 men between 36-91 years of age. Diagnoses were made simultaneously in 4 patients. In two cases the LPL appeared before the DLBCL and in the remaining case the high-grade component was discovered 5 years before the LPL. In 6 cases both samples shared the MYD88-L265P mutation. IGH rearrangement analysis showed overlapping features in two of 6 cases tested. Mutational study was evaluable in three cases for both samples showing shared and divergent mutations. These data suggest different mechanisms of DLBCL development in LPL patients.

NK/T-cell lymphoma (NKTCL) is the most frequent EBV-related NK/T-cell disease. Its clinical manifestations overlap with those of familial haemophagocytic lymphohistiocytosis (FHLH). Since PERFORIN (PRF1) mutations are present in FHLH, we analysed its role in a series of 12 nasal and 12 extranasal-NKTCLs. 12.5% of the tumours and 25% of the nasal-origin cases had the well-known g.272C>T(p.Ala91Val) pathogenic SNP, which confers a poor prognosis. Two of these cases had a double-CD4/CD8-positive immunophenotype, although no correlation was found with perforin protein expression. p53 was overexpressed in 20% of the tumoral samples, 80% of which were of extranasal origin, while none showed PRF1 SNVs. These results suggest that nasal and extranasal NKTCLs have different biological backgrounds, although this requires validation.

Activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) has worse outcomes than the germinal center B-cell (GCB) subtype, but underlying molecular mechanisms remain poorly understood. Transcriptomic analysis on 43 DLBCL samples (23 GCB and 20 ABC) was performed using NanoString PanCancer Immune Profiling Panel with 30 cell-of-origin genes. Tumor microenvironment characterization was performed using CIBERSORTx and gene set enrichment analysis (GSEA) deconvolution. Based on our previous findings of MAPK10 downregulation in ABC lymphomas, MAPK10 promoter methylation was studied via pyrosequencing. Prognostic biomarkers were identified using the Cox regression and least absolute shrinkage and selection operator (LASSO) regularization. Therapeutic candidates were identified through connectivity mapping. ABC lymphomas showed distinct profiles with the overexpression of , , and and the downregulation of and . GSEA revealed enrichment of inflammatory pathways with immunosuppressive signals in ABC cases. Confirming our prior observations, downregulation in ABC tumors was associated with promoter hypermethylation and inferior overall survival ( < 0.01). Immune deconvolution revealed greater microenvironmental diversity in ABC cases with significant eosinophil enrichment. High CD8 T-cell abundance was associated with improved survival, particularly in ABC patients ( < 0.01). Multivariate analysis identified as an independent adverse prognostic factor (HR: 1.87, 95% CI: 1.25-2.79, < 0.01). Connectivity mapping identified proteasome inhibitors and CDK4/6 inhibitors as promising therapeutic candidates. We validated promoter hypermethylation and overexpression as prognostic biomarkers in ABC DLBCL. These findings, derived from integrative transcriptomic and immunogenomic profiling, provide clinically relevant insights into disease biology and support biomarker-guided strategies for precision treatment in aggressive B-cell lymphomas.

We report a patient initially diagnosed with a triple hit high‐grade B cell lymphoma (HGBL‐TH), in which further morphologic, immunohistochemical, and next‐generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC‐DLBCL) with BCL2/BCL6 gene translocations, PVT1‐deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break‐apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH‐lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double‐hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas.

Spontaneous remissions (SRs) in acute myeloid leukemia (AML) are infrequent, poorly documented and transient. Similarly, morphological and cytogenetic complete remissions (CR) under azacitidine treatment are scarce. We report a 71-year-old man with a secondary AML arising from essential thrombocythemia (ET), who developed an SR after discontinuation of azacitidine following a respiratory infection (four courses were administered). The distinctive feature of our case is the depth of the achieved CR, documented by next-generation sequencing (NGS) techniques. We also detected persistence of molecular lesions that might already have been present in the previous ET clone. Our patient relapsed 5 months after achieving CR. We conclude that our patient showed a spontaneous remission of his AML rather than an exquisite response to azacitidine. We hypothesize that the concurrent respiratory infection, or any other unknown trigger, might have activated his immune system forcing the leukemic stem cell to enter a quiescent state through a yet unexplained mechanism.

Anaplastic large cell lymphoma (ALCL) with leukaemic presentation (either ab initio or along the course of the disease) has been rarely reported. Irrespective of ALK expression in the neoplastic cells, it features a dismal prognosis. We report a rare case of leukaemic, small cell variant ALK-positive ALCL with 9-year survival in a young woman who was treated upfront with corticosteroids and standard chemotherapy, and review thoroughly the previously published cases. Such an unexpected, good outcome hints at the existence of different clinical subgroups in the leukaemic variant of ALK-positive ALCL.

Next-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform. We describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others. The panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the (28%), (16%), (10%) and (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C). Prior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting.

Aims: To determine whether basal-like phenotype and vimentin and/or laminin are related in both sporadic/familial (BRCA1 or BRCA2 mutated) tumours. Methods: 230 non-familial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analysed for oestrogen receptors (ER), progesterone receptors (PR), cytokeratin 5/6 (CK5/6), epidermal growth factor receptors (EGFR), Ki67, p53, vimentin and laminin, using tissue microarrays. Tumours were considered to have basal-like phenotype if they were ER negative and HER2 negative, but positive for CK5/6 and/or EGFR. Results: In sporadic tumours, vimentin expression was found in 77.8% cases with basal-like phenotype and 15.5% of non-basal cases (p<0.001). In familial cases, vimentin was expressed in 83.3% basal-like cancers and 16.7% of non-basal tumours (p<0.001). Vimentin expression was more frequent in BRCA1 than BRCA2 mutation carriers. Vimentin expressing tumours were associated with poor prognosis (p = 0.012) among patients not receiving adjuvant chemotherapy and showed a trend for local recurrence or visceral but not bone metastasis (p = 0.021). Laminin expression was also related to basal-like phenotype in both sporadic/familial cases (p<0.001 and p = 0.007, respectively), but neither with prognosis nor recurrence pattern in sporadic cancers. Conclusions: Vimentin and laminin expression is associated with basal-like phenotype in breast cancer. Expression of vimentin and laminin is characteristic of BRCA1 associated tumours. Since vimentin and laminin staining is widely used by pathologists for diagnostic purposes, thus demonstrating the robustness of their specific antibodies, the immunohistochemical evaluation of these two molecules could be used in identification of basal-like breast tumours in both sporadic/familial cases.

HER2 (human epidermal growth factor receptor 2) is overexpressed in approximately 15–20% of breast cancers, leading to aggressive tumour growth and poor prognosis. Anti-HER2 therapies, such as trastuzumab and pertuzumab, have significantly improved the outcomes for patients with HER2-positive breast cancer by blocking HER2 signalling. However, intrinsic and acquired resistance remains a major clinical challenge, limiting the long-term effectiveness of these therapies. Understanding the mechanisms of resistance is essential for developing strategies to overcome it and improve the therapeutic outcomes. We generated multiple HER2-positive breast cancer cell line models resistant to trastuzumab and pertuzumab combination therapy. Using mass spectrometry-based proteomics, we conducted a comprehensive analysis to identify the mechanisms underlying resistance. Proteomic analysis identified 618 differentially expressed proteins, with a core of 83 overexpressed and 118 downregulated proteins. Through a series of advanced bioinformatics analyses, we identified significant protein alterations and signalling pathways potentially responsible for the development of resistance, revealing key alterations in the protein metabolism, mitochondrial function, and signalling pathways, such as MAPK, TNF, and TGFβ. These findings identify mitochondrial activity and detoxification processes as pivotal mechanisms underlying the resistance to anti-HER2 therapy. Additionally, we identified key proteins, including ANXA1, SLC2A1, and PPIG, which contribute to the tumour progression and resistance phenotype. Our study suggests that targeting these pathways and proteins could form the basis of novel therapeutic strategies to overcome resistance in HER2-positive breast cancer.