Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3′ of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband’s mutation; of these, 24 developed cancer, with 41 remaining unaffected

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

Multiple myeloma is a malignancy of plasma cells initiated and driven by primary and secondary genetic events. However, myeloma plasma cell survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B-cell development in both human and murine cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma plasma cells, the interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the plasma cell lineage-defining transcription factor IRF4, thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a noncanonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology

Thyroid MALT lymphoma: self-harm to gain potential T-cell help.

Funder: CUH | Addenbrooke’s Charitable Trust, Cambridge University Hospitals (Addenbrooke’s Charitable Trust, Cambridge University Hospitals NHS Foundation Trust); doi: https://doi.org/10.13039/501100002927Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.Bloodwise the Kay Kendall Leukaemia Fund the Addenbrooke’s Charitable Trust Pathological Society of Great Britain and Irelan

Divergent evolution of metachronous follicular lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue from a common precursor

The translocation t(14;18)(q32:q21)/IGH::BCL2 occurs at the pre‐B stage of B‐cell development in the bone marrow and is insufficient for malignant transformation, although it leads to the formation of in situ follicular B‐cell neoplasia (ISFN). Despite that, the translocation is the genetic hallmark of follicular lymphoma (FL), it occurs infrequently in metachronous/synchronous lymphomas, including extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (EMZL), mantle cell lymphoma, and Hodgkin's lymphoma. In each of these scenarios, the two lymphomas often appear to be clonally related by analyses of IGH::BCL2 and/or rearranged IG genes. However, it remains largely unknown whether one lymphoma originates from the other or they develop independently. We studied five cases of metachronous EMZL and FL. In four cases, the two lymphomas were clonally related, as shown by identical IGH::BCL2 and/or rearranged IG genes or shared mutations. There were common and unique mutations between the paired EMZL and FL, indicating that they developed independently from a common premalignant cell population, harbouring IGH::BCL2 in three cases. Furthermore, case 1 presented with three metachronous FLs, and all of them originated from a common precursor cell population via divergent evolution. Our findings highlight the multi‐malignant potential of IGH::BCL2‐positive B‐cells. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Divergent evolution of metachronous follicular lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue from a common precursor.

The translocation t(14;18)(q32:q21)/IGH::BCL2 occurs at the pre-B stage of B-cell development in the bone marrow and is insufficient for malignant transformation, although it leads to the formation of in situ follicular B-cell neoplasia (ISFN). Despite that, the translocation is the genetic hallmark of follicular lymphoma (FL), it occurs infrequently in metachronous/synchronous lymphomas, including extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), mantle cell lymphoma, and Hodgkin's lymphoma. In each of these scenarios, the two lymphomas often appear to be clonally related by analyses of IGH::BCL2 and/or rearranged IG genes. However, it remains largely unknown whether one lymphoma originates from the other or they develop independently. We studied five cases of metachronous EMZL and FL. In four cases, the two lymphomas were clonally related, as shown by identical IGH::BCL2 and/or rearranged IG genes or shared mutations. There were common and unique mutations between the paired EMZL and FL, indicating that they developed independently from a common premalignant cell population, harbouring IGH::BCL2 in three cases. Furthermore, case 1 presented with three metachronous FLs, and all of them originated from a common precursor cell population via divergent evolution. Our findings highlight the multi-malignant potential of IGH::BCL2-positive B-cells. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Blood Cancer UK (19010) BBSRC DTP PhD studentshi

Progressive TP53 inactivation in an aggressive splenic diffuse red pulp small B-cell lymphoma.

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is a rare lymphoma with variable clinical outcomes, lacking molecular markers for prognostication and prediction of treatment response. We report a case of aggressive SDRPL showing progressive disease despite multimodality treatments. Next generation sequencing identified variants of BIRC3 (p.I427fs), CCND3 (p.H291fs), TP53 (p.V272L) and a deletion of RB1 (p.654_656del), together with the TP53 mutation progressing from heterozygous at diagnosis to homozygous during disease progression, hence, representing a possible marker of aggressive disease.Blood Cancer U

Relapses in early‐stage follicular lymphoma frequently develop via a divergent evolution from their clonally related precursor cells

Publication status: PublishedFunder: Cancer Research UK; doi: http://dx.doi.org/10.13039/501100000289; Grant(s): CRUK: C8333/A29707Funder: British Division of the International Academy of PathologyFollicular lymphoma (FL) develops through a stepwise acquisition of cooperative genetic changes with t(14;18)(q32;q21)/IGH::BCL2 occurring early at the pre‐B stage of B‐cell development. Patients with FL typically show an indolent clinical course, remitting and relapsing with the eventual development of resistance to treatments. Interestingly, the majority of transformed FL do not progress directly from FL but originate from their clonally related lymphoma precursor (CLP) cells. To examine whether such divergent tumour evolution also underpins the relapses in patients with early‐stage FL, we investigated by targeted next‐generation sequencing 13 cases (stage I = 9, stage II = 4), who showed complete remission (mean: 5 years; range: 1–11.5 years) following local radiotherapy but subsequently relapsed (≥2 in 5). A clonal relationship between the diagnostic FL and relapses was confirmed in 11 cases. In six cases, common and distinct variants were seen between the paired diagnostic and relapsed lymphomas, indicating their divergent evolution from a CLP. In two cases, different B‐cell clones were involved in the diagnostic and relapsed lymphomas, including one case involving two different BCL2 translocations. In the remaining five cases, the relapsed lymphoma developed via a linear progression (n = 4) or a mixed evolutionary path (n = 1). These findings may bear important implications in the routine diagnosis and management of relapsed FL. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

A wolf in sheep's clothing: enteropathy associated T‐cell lymphoma involving a nasal polyp masquerading as primary mucosal CD30 ‐positive T‐cell lymphoproliferative disorder

Publication status: PublishedFunder: BBSRC DTP PhD studentshipFunder: NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; doi: http://dx.doi.org/10.13039/100014461Funder: Cancer Research UK; doi: http://dx.doi.org/10.13039/501100000289Funder: Blood Cancer UK; doi: http://dx.doi.org/10.13039/50110001557

A wolf in sheep's clothing: enteropathy associated T-cell lymphoma involving a nasal polyp masquerading as primary mucosal CD30-positive T-cell lymphoproliferative disorder.

CASE SUMMARY An 81-year-old woman presented with nose bleeds and a left anterior nasal septal polyp. Excision biopsy revealed a mucosal lymphoid infiltrate with features of anaplastic large cell lymphoma (ALCL) (Figure 1A). The neoplastic cells were positive for CD45, CD30, EMA (focal), CD3 (variable), CD2, CD25, pSTAT3, TIA1 (focal) and granzyme-B (focal), but negative for ALK, CD5, CD7, CD4, CD8, TCR, CD103 and B-cell markers. Ki67 proliferation approached 100%. EBV encoded small RNA was negative by in situ hybridisation. Fluorescent in situ hybridisation analysis did not detect DUSP22 or TP63 rearrangements. In view of the clinically localised disease, the proffered diagnosis was mucosal CD30+ T-cell lymphoproliferative disorder (T-LPD) akin to primary cutaneous CD30+ T-LPD, with the caveat imaging should confirm localised disease, excluding systemic ALK-negative ALCL