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doi: 10.1002/gcc.23100pmid: 36326821
Tumor mutational burden (TMB), measured by exome or panel sequencing of tumor tissue or blood (bTMB), is a potential predictive biomarker for treatment benefit in patients with various cancer types receiving immunotherapy targeting checkpoint pathways. However, significant variability in TMB measurement has been observed. We developed contrived bTMB reference materials using DNA from tumor cell lines and donor‐matched lymphoblastoid cell lines to support calibration and alignment across laboratories and platforms. Contrived bTMB reference materials were developed using genomic DNA from lung tumor cell lines blended into donor‐matched lymphoblastoid cell lines at 0.5% and 2% tumor content, fragmented and size‐selected to mirror the size profile of circulating cell‐free tumor DNA with TMB scores of 7, 9, 20, and 26 mut/Mb. Variant allele frequency (VAF) and bTMB scores were assessed using PredicineATLAS and GuardantOMNI next‐generation sequencing assays. DNA fragment sizes in the contrived reference samples were similar to those found within patient plasma‐derived cell‐free DNA, and mutational patterns aligned with those in the parental tumor lines. For the 7, 20, and 26 mut/Mb contrived reference samples with 2% tumor content, bTMB scores estimated using either assay aligned with expected scores from the parental tumor cell lines and showed good reproducibility. A bioinformatic filtration step was required to account for low‐VAF artifact variants. We demonstrate the feasibility and challenges of producing and using bTMB reference standards across a range of bTMB levels, and how such standards could support the calibration and validation of bTMB platforms and help harmonization between panels and laboratories.
Agaram, Narasimhan P.; Wexler, Leonard H.; Chi, Ping; Antonescu, Cristina R.
doi: 10.1002/gcc.23106pmid: 36414547
Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults and their pathogenesis is driven by the loss of function mutations in the PRC2 complex, regardless of their clinical presentation. In contrast, pediatric MPNST are rare and their pathogenesis has not been elucidated. In this study, we investigate a large cohort of 64 MPNSTs arising in children and young adults (younger than the age of 20 years) to better define their clinicopathologic and molecular features. Sixteen (25%) cases were investigated by MSK‐IMPACT, a targeted NGS panel of 505 cancer genes. Most patients (80%) were aged 11–20 years. A history of NF1 was established in half of the cases. Mean tumor size was 8.5 cm. The most common locations included the extremities (34%) and abdomen/pelvis (27%). Histologically, 89% of high‐grade MPNST showed conventional features, while the remaining three cases showed a predominant epithelioid phenotype. Heterologous differentiation occurred in 25% of high grade cases, with half showing rhabdomyoblastic differentiation. Tumors arose in a background of a plexiform neurofibroma (16%), neurofibroma (13%), and schwannoma in two cases (3%). Immunohistochemically, H3K27me3 expression was lost in 82% of conventional high‐grade MPNST analyzed, while loss of SMARCB1 expression was seen in one epithelioid MPNST. Genomically, all cases showed more than one genetic abnormality, with 53% showing mutations in EED / SUZ12 genes, and 47% of cases harboring alterations in NF1 and CDKN2A/CDKN2B genes. At the last follow‐up, 30% patients died of disease, 28% were alive with disease and 42% had no evidence of disease. NF1 status did not correlate with overall survival. In conclusion, half of pediatric and young adult MPNST were NF1‐related and showed loss of function alterations in PRC2 complex, NF1, and CDKN2A, similar to the adult counterpart. Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.
Brett, Victor‐Emmanuel; Lechevalier, Nicolas; Trimoreau, Franck; Dussiau, Charles; Dimicoli‐Salazar, Sophie; Coster, Lucie; Luquet, Isabelle; Nadal, Nathalie; Ribourtout, Bénédicte; Chapiro, Elise; Lefebvre, Christine; Tondeur, Sylvie; Balducci, Estelle; Nguyen‐Khac, Florence; Borie, Claire; Radford‐Weiss, Isabelle; Barin, Carole; Eclache, Virginie; Mansier, Olivier; Bidet, Audrey; ,
doi: 10.1002/gcc.23107pmid: 36412977
Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre‐malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico‐biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high‐risk (HR) MDS were similar between CACtUS patients and low‐risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR‐CCUS and should receive the follow‐up regimen recommended for MDS patients.
Dermawan, Josephine K.; Dashti, Nooshin; Chiang, Sarah; Turashvili, Gulisa; Dickson, Brendan C.; Ellenson, Lora H.; Kirchner, Martina; Stenzinger, Albrecht; Mechtersheimer, Gunhild; Agaimy, Abbas; Antonescu, Cristina R.
doi: 10.1002/gcc.23109pmid: 36445224
Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1‐fusion positive ESS presented in a 58‐year‐old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid‐to‐epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27–62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow‐up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow‐up. The EPC1::EZH2‐fusion positive ESS presented in a 52‐year‐old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1‐related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low‐grade and high‐grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.
Gandhi, Jatin; Mantilla, Jose G.; Ricciotti, Robert W.; Chen, Eleanor Y.; Liu, Yajuan J.; Bandhlish, Anshu
doi: 10.1002/gcc.23101pmid: 36331420
We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46‐year‐old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in myoepithelial carcinoma. A 46‐year‐old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan‐cytokeratin (OSCAR), and S‐100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115‐gene gene panel by targeted RNA sequencing, showed an in‐frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.
Ibstedt, Sebastian; Mattos, Camila Bedeschi Rego; Köster, Jan; Mertens, Fredrik
doi: 10.1002/gcc.23103pmid: 36379683
Myxoid liposarcoma (MLS) is molecularly characterized by fusions involving the DDIT3 gene in chromosome band 12q13; the fusion partner is FUS in band 16p11 in 90–95% of the cases and EWSR1 in band 22q12 in the remaining 5–10%. Hence, molecular studies, often fluorescence in situ hybridization (FISH) for DDIT3 rearrangement, are useful for establishing a correct diagnosis. Although all MLS tumors should have DDIT3 fusions, it is important to be aware of reasons for potential false‐negative results. We here present a case of MLS that was negative for FISH for DDIT3, that showed an unexpected t(11;22) at G‐banding, but that displayed a characteristic EWSR1::DDIT3 fusion at RNA‐sequencing. The results suggest that neoplasia‐associated fusions that, due to the transcriptional orientations of the two genes involved, cannot arise through only two double‐strand breaks are more likely to be associated with negative FISH‐findings and unexpected karyotypes.
Miller, Timothy Isaac; Mantilla, Jose G.; Wang, Wenjing; Liu, Yajuan J.; Tretiakova, Maria
doi: 10.1002/gcc.23105pmid: 36416671
HEY1‐NCOA2 fusion is most described in mesenchymal chondrosarcoma. This is the first case report of a primary renal spindle cell neoplasm of uncertain malignant potential with a HEY1::NCOA2 fusion identified by Fusionplex RNA‐sequencing that is histologically distinct from mesenchymal chondrosarcoma. The neoplasm was identified in a 33‐year‐old woman without significant past medical history who underwent partial nephrectomy for an incidentally discovered renal mass. The histologic features of the mass included spindle cells with variable cellularity and monotonous bland cytology forming vague fascicles and storiform architecture within a myxoedematous and collagenous stroma with areas of calcification. The morphologic and immunophenotypic features were not specific for any entity but were most similar to low‐grade fibromyxoid sarcoma. To date, the patient has not had recurrence, and the malignant potential of the neoplasm is uncertain.
Patton, Ashley; Speeckaert, Amy; Zeltman, Micayla; Cui, Xiaoyan; Oghumu, Steve; Iwenofu, O. Hans
doi: 10.1002/gcc.23108pmid: 36448218
Soft tissue myoepitheliomas (STM) are benign myoepithelial neoplasms (of nonsalivary gland origin) arising, most commonly within subcutaneous and deep soft tissues of the extremities and rarely within bones. To the best of our knowledge, the intravascular location of STM as well as the identification of a novel IRF2BP2::CDX2 fusion have not been previously reported. Herein, we report a case of spindle cell myoepithelioma arising within the intravascular space of the right index finger in a 52‐year‐old male of more than 20 years duration. Histopathology demonstrated an intravascular tumefactive lesion composed of predominantly plump banal spindle cells in a fascicular arrangement within a mixed collagenous and chondromyxoid stroma colliding with papillary endothelial hyperplasia (Masson tumor). By immunohistochemistry, the lesional cells were positive for keratin‐AE1/3, epithelial membrane antigen, S100, SOX10, glial fibrillary acid protein, calponin and negative for CD34, smooth muscle actin, desmin, p63, and ERG. Fluorescence in situ hybridization for EWSR1 gene rearrangement was negative. Next‐generation sequencing detected a novel IRF2BP2::CDX2 fusion involving Exon 1 of the IRF2BP2 gene and Exon 2 of the CDX2 gene confirmed by reverse transcriptase polymerase chain reaction and Sanger sequencing. Further, clinical evaluation for a salivary gland mass in the head and neck region and magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed with no evidence of tumor elsewhere. Taken together, the overall features were considered diagnostic of STM. Our current case underscores the novelty of the IRF2BP2::CDX2 gene fusion in STM and its exceptionally rare intravascular location.
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