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1.
J Pathol ; 264(3): 305-317, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39344423

RESUMEN

CREB gene family (ATF1, CREB1, CREM) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2::CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2::CREM and one with a novel SMARCA4::CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel-based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to FET::CREB entities, but not with SMARCA4/SMARCB1-deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence (n = 2), locoregional lymph node metastases (n = 2), and an isolated visceral metastasis (n = 1). Overall, our study suggests that SMARCA2/4::CREM fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the FET::CREB family of tumors. © 2024 The Pathological Society of Great Britain and Ireland.


Asunto(s)
Modulador del Elemento de Respuesta al AMP Cíclico , ADN Helicasas , Proteínas Nucleares , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Masculino , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Femenino , Adulto Joven , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Adolescente , Niño , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Adulto , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Metilación de ADN , Neoplasias/genética , Neoplasias/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología
2.
BMC Biol ; 22(1): 43, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38378561

RESUMEN

BACKGROUND: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. RESULTS: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001). CONCLUSIONS: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.


Asunto(s)
Neoplasias , Humanos , Mutación , Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos
3.
Genes Chromosomes Cancer ; 63(4): e23232, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38607246

RESUMEN

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.


Asunto(s)
Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Masculino , Humanos , Adulto , Niño , Rabdomiosarcoma/genética , Rabdomiosarcoma Embrionario/genética , Epigenómica , Genómica , Ribonucleasa III , ARN Helicasas DEAD-box , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética
4.
Mod Pathol ; 37(10): 100570, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39025406

RESUMEN

Invasive lobular carcinomas (ILC) are characterized by the loss of E-cadherin expression and CDH1 gene inactivation. Diagnostic reproducibility for this tumor type is currently suboptimal and could be improved by a better understanding of its histomolecular and clinical heterogeneity. We have analyzed the relationship between the presence, type, or position of CDH1 mutations, E-cadherin expression, and clinicopathological features (including outcome) in a retrospective series of 251 primary ILC with a long follow-up (median: 9.5 years). The mutational status of E-cadherin gene (CDH1) was determined by RNA sequencing from frozen tumor samples. E-cadherin immunohistochemistry (IHC) was performed with antibodies directed against the intracellular domain (clone 4A2C7) and the extracellular domain (clone NCH38). IHC expression of p120 and ß-catenin was also assessed in E-cadherin diffusely positive cases. Three major patterns of E-cadherin membrane expression were identified by IHC, with good agreement between the 2 clones (overall concordance: 83.8%, Kappa 0.67): null/focal expression (≤10%) (72.8% of cases for 4A2C7 and 83.8% for NCH38), heterogeneous expression (11%-89%) (19.2% of cases for 4A2C7 and 6.9% for NCH38), and diffuse expression (≥90%) (8% of cases for 4A2C7 and 9.3% for NCH38). E-cadherin membranous expression, when present, was abnormal (incomplete labeling and/or reduced intensity). ILC with diffuse E-cadherin expression showed abnormal ß-catenin or p120-catenin staining in 21% of cases. Interestingly, these cases with diffusely expressed E-cadherin had a CDH1 mutation rate as high as the E-cadherin null/focal cases (∼70%) but were enriched in nontruncating mutations. Regarding CDH1 mutation location, intracytoplasmic domain mutations correlated with a divergent E-cadherin IHC phenotype between the 2 antibodies (4A2C7 ≤ 10%/NCH38 ≥ 10%). Clinico-pathological correlation analyses found that stromal amount (inversely correlated with tumor cellularity) and tumor-infiltrating lymphocytes were less abundant in ILC with E-cadherin null/focal cases. In addition, CDH1 truncating mutations were associated with radiohistologic size discordance and were identified in multivariate survival analysis as an independent poor prognosis factor in terms of metastasis risk and breast cancer-related mortality. Overall, our study highlights the importance of the precise mutational status of CDH1 in the clinical, radiological, histologic, and phenotypic expression of lobular carcinomas. These findings should be taken into account in future attempts to improve diagnostic criteria or methods for ILC, as well as for clinicobiological studies dedicated to this tumor type.


Asunto(s)
Antígenos CD , Biomarcadores de Tumor , Neoplasias de la Mama , Cadherinas , Carcinoma Lobular , Mutación , Humanos , Cadherinas/genética , Cadherinas/análisis , Carcinoma Lobular/genética , Carcinoma Lobular/patología , Carcinoma Lobular/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Femenino , Persona de Mediana Edad , Antígenos CD/genética , Anciano , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Adulto , Anciano de 80 o más Años , Inmunohistoquímica
5.
Histopathology ; 82(1): 162-169, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36482269

RESUMEN

The diagnosis, histomolecular classes of breast cancers (luminal A, luminal B, HER2-enriched, and basal-like), and accurate prediction of prognosis are commonly determined using morphological and phenotypical analyses in clinical practice worldwide. Therapeutic strategies are mostly based on the disease stage and molecular subclasses of breast cancer. Targeted therapies, such as anti-HER2s, poly-ADP ribose polymerase inhibitors or, to a lesser extent, phosphatidylinositol 3 kinase inhibitors, have substantially improved breast cancer patient prognosis over the past decades. Human epidermal growth factor receptor 2 (HER2) overexpression is widely determined based on immunohistochemistry, while next-generation sequencing (NGS) is currently employed to assess the presence of molecular alterations, including breast cancer gene 1 (BRCA1) and 2 or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, which are targets of these new approved therapies. In addition, next-generation sequencing (NGS) can aid the pathologist in challenging situations, such as a diagnostic workup for a metastatic carcinoma in lymph nodes of unknown origin, differential diagnosis of spindle cell tumourtumor in the breast between metaplastic carcinoma, malignant PT and sarcoma, o, as well as determining relatedness between primary breast cancers and recurrences. NGS offers a powerful tool that enables the pathologist to combine morphological analyses together with molecular alterations in challenging diagnostic situations.


Asunto(s)
Neoplasias de la Mama , Carcinoma , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética
6.
Histopathology ; 83(6): 925-935, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37706251

RESUMEN

AIMS: Malignant tumours of the lacrimal apparatus are rare and frequently show a poor prognosis, with no clear therapeutic standards. Characterisation of the genetic landscape of these rare tumours is sparse, and therefore therapeutics generally follow those of their common salivary gland counterparts. To further clarify the pathophysiology and discover potential therapeutic targets, we investigated the genetic landscape of eight tumours of the lacrimal apparatus. METHODS AND RESULTS: DNA and RNA sequencing were performed to identify genetic mutations and gene fusions. Immunohistochemistry, fluorescence in-situ hybridisation and reverse transcription-polymerase chain reaction followed by Sanger sequencing were performed to confirm the identified molecular alterations. Genetic alterations were detected in six tumours. Among five adenoid cystic carcinomas (ACC), four had confirmed alterations of MYB or MYBL1 genes, including a MYB::NFIB fusion, a MYBL1::NFIB fusion, a MYB amplification and a novel NFIB::THSD7B fusion. Mutations in genes encoding epigenetic modifiers, as well as NOTCH1, FGFR2 and ATM mutations, were also identified in ACCs. A carcinoma ex pleomorphic adenoma showed TP53 and CIC mutations and an amplification of ERBB2. A transitional cell carcinoma was associated with HPV16 infection. No genetic alteration was found for one adenocarcinoma, not otherwise specified. CONCLUSIONS: Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.


Asunto(s)
Adenoma Pleomórfico , Carcinoma Adenoide Quístico , Aparato Lagrimal , Neoplasias de las Glándulas Salivales , Humanos , Aparato Lagrimal/patología , Proteínas de Fusión Oncogénica/genética , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/patología , Fusión Génica , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología
7.
J Pathol ; 257(3): 274-284, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35220606

RESUMEN

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for the heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole-exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intratumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (eight patients). Activating AR alterations were seen in nine (75%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the 'index' primary PCa area. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Genómica , Humanos , Masculino , Proteínas Nucleares/genética , Filogenia , Proyectos Piloto , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Represoras/genética
8.
Radiology ; 305(3): 565-574, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35880977

RESUMEN

Background Ultrafast dynamic contrast-enhanced (DCE) MRI parameters are associated with breast cancer aggressiveness. However, the role of these parameters as predictive biomarkers for pathologic response after neoadjuvant chemotherapy (NAC) has been poorly investigated. Purpose To assess whether semiquantitative perfusion parameters calculated at initial ultrafast DCE MRI are associated with early prediction for pathologic response after NAC in participants with breast cancer. Materials and Methods This prospective single-center study included consecutive women with nonmetastatic invasive breast cancer treated with NAC followed by surgery who underwent initial ultrafast DCE MRI between December 2020 and August 2021. Six semiquantitative ultrafast DCE MRI parameters were calculated for each participant from the fitted time-signal intensity curve. Multivariable logistic regression was used to identify independent predictors of pathologic complete response (pCR) and residual cancer burden (RCB). Results Fifty women (mean age, 49 years ± 12 [SD]) were included in the study; 20 achieved pCR and 25 achieved low RCB (RCB-0 and I). A wash-in slope (WIS) cutoff value of 1.6% per second had a sensitivity of 94% (17 of 18 participants) and a specificity of 59% (19 of 32 participants) for pCR. A WIS of more than 1.6% per second (odds ratio [OR], 8.4 [95% CI: 1.5, 48.2]; P = .02), human epidermal growth factor receptor 2 (HER2) positivity (OR, 6.3 [95% CI: 1.5, 27.4]; P = .01), and tumor-infiltrating lymphocytes of more than 10% (OR, 6.9 [95% CI: 1.3, 37.7]; P = .03) were independent predictive factors of pCR. The area under the receiver operating characteristic curve of the three-component model, which included WIS, tumor-infiltrating lymphocytes, and HER2 positivity, was 0.92 (95% CI: 0.84, 0.99). A WIS of more than 1.6% per second was associated with higher pCR rates in the HER2-positive (OR, 21.7 [95% CI: 1.8, 260.6]; P = .02) breast cancer subgroup. For luminal HER2-negative and triple-negative breast cancers, a WIS of more than 1.6% per second was associated with low RCB (OR, 11.0 [95% CI: 1.1, 106.4]; P = .04). Conclusion The wash-in slope (WIS) assessment at initial ultrafast dynamic contrast-enhanced MRI may be used to predict pathologic complete response (pCR) in participants with breast cancer. The WIS value was used to identify two subsets of human epidermal growth factor receptor 2-positive cancers with distinct pCR rates. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Moy in this issue.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Mama/diagnóstico por imagen , Mama/patología , Imagen por Resonancia Magnética/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/patología , Estudios Prospectivos , Resultado del Tratamiento
9.
Mod Pathol ; 35(11): 1624-1635, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35697931

RESUMEN

Breast carcinomas (BC) with osteoclast-like giant cells (OGC) are rare. Despite their distinct stromal features, their molecular characteristics remain unknown. Here, we report comprehensive clinico-pathological and molecular findings for 27 patients diagnosed with BC-OGC at Institut Curie between 2000 and 2021. Seventeen (63%) cases were invasive carcinomas of no special type (IC NST) with OGC (OGC-IC NST), four (15%) were mixed or multifocal cases with and without OGC (OGC-Mixed), and six (22%) were metaplastic carcinomas with OGC (OGC-MC). All OGC-IC NST and OGC-Mixed cases were ER+ HER2- tumors (most being luminal A based on transcriptomic subtyping, when available), while all OGC-MC were triple-negative. The median age at diagnosis was 46, 45 and 62 years for OGC-IC NST, OGC-Mixed and OGC-MC, respectively. Three patients developed distant metastases (one OGC-IC NST, two OGC-Mixed), one of whom died of metastatic disease (OGC-Mixed), and one other patient died of locally advanced disease (OGC-MC). Histopathological evaluation comparing 13 OGC-IC NST and 19 control IC NST without OGC confirmed that OGC-IC NST showed significantly higher density of vessels (by CD34 immunohistochemistry (IHC)), iron deposits (Perls stain), and CD68 and CD163-positive cell infiltrates. Genomic findings for nine OGC-IC NST and four OGC-MC were consistent with the underlying histologic subtype, including activating alterations of the PI3K/AKT/mTOR pathway in 7/13 cases. Using RNA-seq data, differential gene expression analysis between OGC-IC NST (n = 7) and control IC NST without OGC (n = 7) revealed significant overexpression of TNFSF11 (RANK-L), TNFRSF11A (RANK), CSF1 (M-CSF), CSF1R, and genes encoding osteoclastic enzymes (MMP9, ACP5, CTSK, CTSB) in OGC-IC NST, while OPG (osteoprotegerin) was underexpressed. We also confirmed for the first time RANK-L expression in BC with OGC by IHC (seen in 15 out of 16 cases, and only in 2 of 16 controls without OGC). These findings could offer a rationale for further investigating RANK-L as a therapeutic target in BC with OGC.


Asunto(s)
Neoplasias de la Mama , Carcinoma , Ligando RANK , Femenino , Humanos , Neoplasias de la Mama/patología , Carcinoma/patología , Células Gigantes/patología , Hierro , Factor Estimulante de Colonias de Macrófagos , Metaloproteinasa 9 de la Matriz , Osteoclastos/patología , Osteoprotegerina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Ligando RANK/genética
10.
Clin Chem ; 68(2): 322-331, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34928333

RESUMEN

BACKGROUND: DICER1 syndrome is an autosomal dominant inherited syndrome predisposing to various benign and malignant tumors, mainly occurring in children and young adults, requiring broad surveillance starting at birth with repeated irradiating imaging exams and sedations for young patients. It is caused by monoallelic germline pathogenic variants in the DICER1 gene. More than 90% of tumors bear an additional somatic DICER1 missense hotspot mutation, as a second hit, involving 1 of 6 codons clustered in exons 24 and 25. We designed and in vitro validated a drop-off droplet digital PCR (ddPCR) system to scan all DICER1 hotspot codons, allowing for a liquid biopsy test, an alternative to sedation and radiation exposure. METHODS: Three drop-off ddPCR assays were designed, with 2 TaqMan probes per assay, 1 complementary to the wild-type sequence of the region containing hotspots and another 1 used as a reference. Eight tumor-derived DNAs and 5 synthetic oligonucleotides bearing DICER1 hotspot mutations were tested. RESULTS: All tested mutations were detected, with a limit of detection ranging from 0.07% to 0.31% for codons p. E1705, p. D1709, and p. D1713 in exon 24 and from 0.06% to 0.15% for codons p. G1809, p. D1810, and p. E1813 in exon 25. CONCLUSIONS: The high sensitivity of this method is compatible with its use for plasma circulating tumor DNA (ctDNA) analysis for early tumor detection in DICER1 syndrome patients. It may reduce the need for radiation exposure and sedation in surveillance protocols and may also improve patient prognosis. Clinical trials are needed to evaluate ctDNA analysis in these patients.


Asunto(s)
ADN Tumoral Circulante , Neoplasias , Niño , Codón , ARN Helicasas DEAD-box/genética , Humanos , Recién Nacido , Mutación , Neoplasias/genética , Reacción en Cadena de la Polimerasa/métodos , Ribonucleasa III/genética , Adulto Joven
11.
J Pathol ; 255(1): 1-15, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33999421

RESUMEN

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
ADN Helicasas/deficiencia , Proteínas Nucleares/deficiencia , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Factores de Transcripción/deficiencia , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Preescolar , ADN Helicasas/genética , Femenino , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína SMARCB1/deficiencia , Proteína SMARCB1/genética , Factores de Transcripción/genética
12.
Proc Natl Acad Sci U S A ; 116(23): 11428-11436, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-31061129

RESUMEN

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/genética , Anciano , Androstenos/uso terapéutico , Benzamidas , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/genética , Resultado del Tratamiento
13.
Cancer ; 124(5): 1008-1015, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29266381

RESUMEN

BACKGROUND: Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging. METHODS: Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed. RESULTS: Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/µL and 16.2 ng/µL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes. CONCLUSIONS: This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.


Asunto(s)
Neoplasias Óseas/secundario , Huesos/patología , Próstata/patología , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/genética , Huesos/diagnóstico por imagen , Huesos/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Biopsia Guiada por Imagen , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Medicina de Precisión/métodos , Estudios Prospectivos , Próstata/diagnóstico por imagen , Próstata/metabolismo , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/genética
14.
J Pathol ; 237(2): 179-89, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26095796

RESUMEN

Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Adenoide Quístico/genética , Genómica , Mutación , Neoplasias de la Mama Triple Negativas/genética , Biomarcadores de Tumor/análisis , Carcinoma Adenoide Quístico/química , Carcinoma Adenoide Quístico/patología , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genes myb , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Hibridación Fluorescente in Situ , Proteínas de Fusión Oncogénica/genética , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Mama Triple Negativas/química , Neoplasias de la Mama Triple Negativas/patología
15.
Radiology ; 272(3): 875-84, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24761836

RESUMEN

PURPOSE: To study whether volume-based indices of fluorine 18 fluorodeoxyglucose positron emission tomographic (PET)/computed tomographic (CT) imaging is an accurate tool to predict the amount of residual viable tumor after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed consent. Twenty-two patients with locally advanced NSCLC underwent surgery after induction chemotherapy. All had pre- and posttreatment FDG PET/CT scans. CT largest diameter, CT volume, maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (TV), and total lesion glycolysis of primary tumor were calculated. Changes in tumor measurements were determined by dividing follow-up by baseline measurement (ratio index). Amounts of residual viable tumor, necrosis, fibrous tissue, inflammatory infiltrate, and Ki-67 proliferative index were estimated on resected tumor. Correlations between imaging indices and histologic parameters were estimated by using Spearman correlation coefficients or Mann-Whitney tests. RESULTS: No baseline or posttreatment indices correlated with percentage of residual viable tumor. TV ratio was the only index that correlated with percentage of residual viable tumor (r = 0.61 [95% confidence interval: 0.24, 0.81]; P = .003). Conversely, SUVmax and SUVmean ratios were only indices correlated with Ki-67 (r = 0.62 [95% confidence interval: 0.24, 0.82]; P = .003; and r = 0.60 [95% confidence interval: 0.21, 0.81]; P = .004, respectively). Total lesion glycolysis ratio was moderately correlated with residual viable tumor (r = 0.53 [95% confidence interval: 0.13, 0.78]; P = .01) and with Ki-67 (r = 0.57 [95% confidence interval: 0.18, 0.80]; P = .006). No ratios were correlated with presence of inflammatory infiltrate or foamy macrophages. CONCLUSION: TV and total lesion glycolysis ratios were the only indices correlated with residual viable tumor after induction chemotherapy in locally advanced NSCLC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Humanos , Imagenología Tridimensional/métodos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Neoplasia Residual , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del Tratamiento , Carga Tumoral
16.
J Exp Med ; 221(6)2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38563818

RESUMEN

Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.


Asunto(s)
Melanoma , Neoplasias de la Úvea , Humanos , Melanoma/terapia , Linfocitos T CD8-positivos , Drenaje
17.
Eur J Surg Oncol ; 50(9): 108483, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38897095

RESUMEN

BACKGROUND AND AIMS: Alveolar soft part sarcoma (ASPS) is an ultra-rare chemo-resistant sarcoma in children, occurring preferentially in young adults. We aimed to describe and compare its clinical presentation and behaviour in children and young adults to determine whether the same therapeutic strategy should be addressed for both populations. METHODS: National retrospective multicentre study of children (0-18 years) vs. young adults (19-30 years) included in the "ConticaBase" sarcoma database, treated for ASPS between 2010 and 2019 with pathology reviewed via the NETSARC + network. RESULTS: Overall, 45 patients were identified, 19 children (42%) and 26 young adults (58%). All ASPS diagnoses were confirmed with TFE3 rearrangement by immunohistochemistry or FISH. All clinical characteristics were balanced between both populations with frequent metastases at diagnosis (8/19 vs. 10/26). The therapeutic strategy was based on surgery (17/19 vs. 21/26), radiotherapy (8/19 vs. 12/26) ± systemic treatment (8/19 vs. 9/26). In patients with initially localized disease, metastatic relapse occurred only in adults (8/16), whereas metastatic progression was present in both metastatic groups (5/8 vs. 8/10). After a median follow-up of 5.2 years (range, 0.2-12.2), 5-year EFS was 74% [95%CI, 56-96] vs. 47% [30-74] (p = 0.071) respectively, and 5-year OS was 95% [85-100] vs. 85% [70-100] (p = 0.84). For localized tumours, 5-year MFS was 100% [100-100] vs. 60% [39-91] (p = 0.005). The 5-year OS of all patients with metastasis at diagnosis was 80.2% (62.2%-100%). CONCLUSIONS: ASPS appears to have the overall same clinical characteristics, but a more aggressive behaviour in young adults than in children. However, despite frequent metastases at diagnosis, long-term survival is high in both groups. Overall, the same therapeutic strategies may be considered for both populations.


Asunto(s)
Sarcoma de Parte Blanda Alveolar , Humanos , Sarcoma de Parte Blanda Alveolar/terapia , Sarcoma de Parte Blanda Alveolar/patología , Adolescente , Masculino , Femenino , Adulto , Niño , Adulto Joven , Estudios Retrospectivos , Preescolar , Francia/epidemiología , Lactante , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Recién Nacido
18.
Cancers (Basel) ; 15(12)2023 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-37370837

RESUMEN

PURPOSE: To confirm the overall benignity of fat-containing soft tissue tumors (STT) on a pediatric cohort and to define the clinical and imaging features that warrant a biopsy. METHODS: A retrospective monocentric study was conducted on patients aged less than 25 years consecutively referred for fat-containing STT to our Comprehensive Cancer Center between 1998 and 2022. Tumor imaging characteristics at diagnosis (US, CT, or MRI) were correlated with pathology. RESULTS: The database extraction identified 63 fat-containing tumors with clinical, histologic, and imaging data available for review. In total, 58 (92%) were benign tumors: 36 lipoblastomas and lipomas, 12 fibrous hamartomas of infancy (FHI), 5 lipofibromatosis, 2 lipomas arborescens, 2 lipomatosis and 1 spindle-cell lipoma. Five patients (8%) were diagnosed with liposarcoma. Factors significantly correlated with malignancy were age >10 years old (p < 0.001), having a cancer-predisposing condition (p < 0.001), a percentage of fat <25% (p = 0.002), and a presence of myxoid zones (p < 0.001) on imaging. CONCLUSION: Most fat-containing STT in children may be classified as benign tumors based on clinics and imaging. The indication for biopsy could be limited to patients aged 10 years or more with either a cancer-predisposing condition or imaging features demonstrating either a low-fat component (<25%) or the presence of myxoid zones.

19.
Eur J Cancer ; 191: 112981, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37506588

RESUMEN

PURPOSE: To evaluate tipapkinogene sovacivec (TG4001), a viral immunotherapeutic vaccine expressing human papillomavirus (HPV)16 E6/E7 non-oncogenic proteins and IL-2, in combination with avelumab in HPV16+ cancer patients. PATIENTS AND METHODS: In this open-label, phase Ib/II, multicenter study, HPV16+ advanced cancer patients received subcutaneous TG4001 at two dose levels (DL) in phase Ib and at the recommended phase II dose (RP2D) in phase II weekly for 6 weeks, then every 2 weeks (q2Wk) until 6 months, thereafter every 12 weeks, in combination with avelumab q2Wk starting from day 8. Exploratory end-points included immunomonitoring from sequential tumour and blood samples. RESULTS: Forty-three patients, mainly heavily pretreated (88% ≥ 1 previous line), were included in the safety analysis, with a majority of anal cancer (44%). No dose-limiting toxicities were reported, and DL2 (5 × 107 Plaque forming units (PFU)) was selected as the RP2D. Treatment-related adverse events to TG4001 occurred in 93% of patients, mostly grade 1/2, with grade 3 anaemia in one patient and no grade 4/5. Overall response rate (ORR) was 22% (8/36) and 32% (8/25) in all and patients without liver metastases, respectively. Median progression-free survival (PFS) and Overall Survival (OS) were 2.8 months (95% CI: 1.4-5.6) and 11.0 months (95% CI:7.5-16.7) in the total population and 5.6 months (95% CI:1.6-9.6) and 13.3 months (95% CI:8.7-32.7) in patients without liver metastases. Antigen-specific T-cell response was identified in 7/11 patients by IFNγ ELISpot. CONCLUSIONS: TG4001 in combination with avelumab is safe, demonstrated antitumour activity in heavily pre-treated HPV16+ cancer patients, and is currently being evaluated in a randomised phase II trial in patients with incurable anogenital cancer and limited hepatic involvement. GOV IDENTIFIER: NCT03260023.


Asunto(s)
Neoplasias Hepáticas , Vacunas Virales , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico
20.
Cell Rep ; 42(1): 112013, 2023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36656711

RESUMEN

Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity.


Asunto(s)
Rabdomiosarcoma , Sarcoma , Niño , Adulto , Humanos , Animales , Ratones , Pez Cebra/metabolismo , Factores de Transcripción/genética , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Fusión Génica , Coactivador 2 del Receptor Nuclear/genética , Proteínas Musculares/genética
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