RESUMEN
ABSTRACT: Idiopathic multicentric Castleman disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within the affected lymphoid organs and the host circulation using multiomic high-dimensional profiling. Using spatial enhanced resolution omics sequencing (Stereo-seq) transcriptomic profiling, we performed unsupervised spatially constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. After a cell segmentation approach, interleukin 6 (IL-6) pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10× Chromium). Furthermore, single-cell sequencing of peripheral blood mononuclear cells revealed an "inflammatory" peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model.
Asunto(s)
Enfermedad de Castleman , Interleucina-6 , Análisis de la Célula Individual , Gemelos Monocigóticos , Humanos , Enfermedad de Castleman/patología , Enfermedad de Castleman/genética , Gemelos Monocigóticos/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Femenino , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/patología , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.
Asunto(s)
Hemangiosarcoma , Humanos , Hemangiosarcoma/patología , Hemangiosarcoma/terapia , Mastocitos , Transducción de Señal , Apoptosis , PronósticoRESUMEN
BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape. METHODS: Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed. RESULTS: Notable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFß) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event. CONCLUSION: Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.