Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome.

UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis. CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome. WHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.

Dysregulation of microRNAs in angioimmunoblastic T-cell lymphoma.

BACKGROUND: Angioimmunoblastic T-cell lymphomas (AITLs) are the second most frequent peripheral T-cell lymphomas in humans worldwide and histomorphologically well characterized. MicroRNAs are a group of small non-coding RNAs that can negatively regulate gene expression on a posttranscriptional level. Their dysregulation has been shown to be of importance in numerous tumour entities. MATERIALS AND METHODS: As a first step towards understanding the possible influence of microRNA-dysregulation in AITL, we analyzed the expression signatures of 760 microRNAs in 30 nodal AITLs in comparison to reactive lymphadenitis with T-zone hyperplasia. RESULTS: We found miR-34a, miR-146a and miR-193b to be up-regulated, as well as miR-140-3p, let-7g, miR-30b and miR-664 to be down-regulated in AITL to a significant level. CONCLUSION: The microRNA-signatures of AITL reveal some overlap to autoimmune diseases, virus-triggered lymphomas and angiogenic factors that, coupled with future studies, will potentially provide better understanding of this disease.

Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.

CONTEXT: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. OBJECTIVE: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. DESIGN: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. RESULTS: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively. CONCLUSIONS: Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors.

Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, and CD44-CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+CD24- human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.