Sex cord-stromal tumors are rare in pediatric patients. Leydig cell tumors are a rare subset of sex cord-stromal tumors characterized by unique molecular alterations, including TERT fusions and mutations of CTNNB1, FOXO4, TP53, NBN, MTOR, BAP1, MEN1, and CREBBP. We report a case of a testicular Leydig cell tumor with an EWSR1::CREM fusion, which to our knowledge has not been previously reported in this setting.
Approximately 10% of Ph-Like patients have ABL class gene fusions, which include the FIP1L1::PDGFRA rearrangement. We report a case of a pediatric patient with Ph-like B-lymphoblastic leukemia (B-LL) with a FIP1L1::PDGFRA fusion and their treatment course using a combination of chemotherapy and targeted therapy with imatinib. A 10-year-old female presented with lethargy, palpitations, and fevers. She had pancytopenia, no eosinophilia, and flow cytometry consistent with B-LL. FISH identified a CHIC2 deletion, suggestive of FIP1L1::PDGFRA fusion, confirmed on next-generation RNA sequencing. The patient commenced targeted therapy with imatinib, which she continued until completion of standard chemotherapy per COG AALL1732. She remains in remission 6 months post-completion of therapy. B-ALL with a FIP1L1::PDGFRA fusion is extremely rare, particularly in pediatrics. FIP1L1::PDGFRA rearrangements can be difficult to detect on routine testing and may not always be seen in association with eosinophilia. Identification of FIP1L1::PDGFRA rearrangements is important as they enable treatment with a tyrosine kinase inhibitor, which has significantly improved the overall prognosis for PDGFRA-rearranged neoplasms. Prospective studies assessing imatinib dosage, duration, and long-term safety are warranted in this cohort.
Plexiform neurofibromas (PNFs) are benign tumors of the peripheral nervous system that affect approximately 30% of people with neurofibromatosis type 1 (NF1). Schwann cells (SCs), the tumor progenitor cells, respond to and use biomechanical signals like tissue stiffness and mechanical loads in their maintenance and repair functions in healthy tissues. PNFs are described as having altered biomechanics, and we hypothesize this plays a role in PNF development. As a first step in studying the role that altered biomechanics may play in the development of PNFs, we aimed to determine how PNF SCs alter in their response to various biomechanical signals as compared to healthy SCs.
We examined the behavior of healthy and PNF SCs in three different tissue-mimicking biomechanical models. First, we examined their spreading behavior on extracellular matrix (ECM) protein-coated polyacrylamide hydrogels of varying stiffness in the healthy and pathological range. Second, we investigated their collective migration with respect to substrate stiffness and ECM protein-coating. Finally, we generated multicellular spheroid tissue models using healthy and PNF SCs and measured their mechanical properties as a function of spheroid size.
We found that PNF SCs are differently sensitive to substrate stiffness in a physiological range compared to healthy SCs, lack sensitivity to ECM protein coating when collectively migrating, and lack sensitivity to environmental deficiencies in oxygen and nutrient supplies when in spheroid culture.
We propose that PNF SC altered biomechanics likely play a role in tumor initiation and progression, and that further biomechanical-based investigations of NF1 tumor growth are needed.
Neurofibromatosis type 1 (NF1) is associated with a high risk for cancer. Benign cutaneous neurofibromas of women with NF1 may increase in size and number during pregnancy. However, it is not known whether pregnancy affects the risk for cancer in NF1.
We retrieved the pregnancies of women in the Finnish NF1 cohort and in a 10-fold control cohort from the Finnish Medical Birth Register. Cancers occurring during or after pregnancy were obtained from the Finnish Cancer Registry and summarized using standardized incidence ratio (SIR). The cancer incidence of nonNF1 mothers of individuals with NF1 was also estimated.
Totals of 263 pregnancies in 136 women with NF1 and 3176 pregnancies in 1720 controls were observed. In the NF1 group, two cancers were identified during pregnancy and the year following the delivery (SIR 6.44, 95% CI 1.07–19.89). Among controls, the SIR was markedly lower (0.25, 95% CI 0.01–1.08). Within 1–10 years after pregnancy, the SIR of women with NF1 was 7.54 (95% CI 4.15–12.41). The SIR of women with NF1 aged 20–49 years, and without a known history of deliveries was 8.63 (95% CI 6.08–11.81). The nonNF1 mothers displayed a SIR of 0.81 (95% CI 0.66–1.00) after giving birth to a child with NF1.
The pregnancy-related cancer incidence in women with NF1 is similar to women with NF1 aged 20–49 years overall, although notably higher than in the general population. Giving birth to a child with NF1 does not affect the risk for cancer in women without NF1.
Small round cell sarcomas (SRCSs) constitute a heterogeneous group of high-grade tumors with a poor prognosis, predominantly affecting children and young adults. According to the 2020 WHO Soft Tissue Tumor classification, SRCSs are categorized into Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. Herein, we report a case of a 10-month-old boy presenting with a progressively enlarging left lumbar mass. Histopathological examination revealed a well-demarcated lesion composed of small, round to oval cells with scant cytoplasm and mildly irregular nuclei. Immunohistochemical staining demonstrated strong, diffuse positivity for S100 and SOX10, indicating neurocristic differentiation. Next-generation sequencing identified an in-frame fusion between MAZ exon 3 on chromosome 16 and NCOA2 exon 12 on chromosome 8. Fluorescence in situ hybridization (FISH) confirmed a break-apart signal at the NCOA2 locus. To the best of our knowledge, this represents the first documented instance of an NCOA2 rearrangement involving MAZ in SRCSs. This case broadens the molecular spectrum of SRCSs, highlights the importance of incorporating molecular techniques into diagnostic workflows, and may have implications for future diagnostic and therapeutic strategies.
PDGFRA::USP8 fusions have recently been described in neoplasms in the provisional category of calcified chondroid mesenchymal neoplasm (CCMN). Here, we describe a cutaneous inflammatory myofibroblastic tumor (IMT) on the upper leg of a 24-year-old male harboring the same fusion product. The tumor showed a morphology typical of IMT, including a concomitant inflammatory infiltrate; in addition, there was strong immunohistochemical PDGFRα overexpression. Methylation profiling (Sarcoma classifier v12.2) was consistent with IMT (calibrated score 0.99). Herein, we review other soft tissue tumors with PDGFRA fusions, emphasizing PDGFRA::USP8 fusions, further highlighting the genetic pleiotropy of kinase gene fusions in soft tissue tumors. In addition, this case expands the landscape of kinase fusions in IMT, presented by an extremely rare cutaneous IMT.
Kinase-rearranged spindle cell sarcomas are characterized by unique molecular features. The advent of next-generation sequencing (NGS) has enabled the detection of a multitude of kinase fusions, thereby contributing to the accurate categorization of these tumors.
A 37-year-old woman experienced the fourth recurrence of a cranial base tumor 25 years following the initial surgery and radiation therapy. Histological analysis disclosed spindle-shaped and oval tumor cells, along with a high number of mitotic figures. Immunohistochemistry showed a null immunophenotype, negative for pan-TRK, S-100, CD34, pan-CK, GFAP, and Olig2. Molecular analysis of the tumor tissue identified a novel ACVR2A::RAF1 fusion, comprising the first four exons of ACVR2A and the last nine exons of RAF1. The resulting fusion protein retains the extracellular and transmembrane domains of ACVR2A, while its kinase domain is replaced by the kinase domain of RAF1. This hybrid protein likely contributes to tumorigenesis by activating RAF1 signaling in response to ACVR2A ligands from the TGF-β superfamily.
The patient was treated with the MEK1 inhibitor Trametinib, 2 mg per time and once a day. One month later, MRI showed significant tumor shrinkage and pain relief.
The ACVR2A::RAF1 fusion represents a novel genomic profile in RAF1-rearranged spindle cell sarcoma, offering a rational basis for targeted therapy. This case highlights the importance of molecular diagnostics in identifying actionable targets and guiding treatment, potentially leading to significant clinical benefits.
Identifying genes involved in cancer is crucial for understanding the underlying molecular mechanisms of the disease and developing effective treatment strategies. Differential expression analysis (DEA) is the predominant method used to identify cancer-related genes. This approach involves comparing gene expression levels between different samples, such as cancerous and non-cancerous tissues, to identify genes that are significantly upregulated or downregulated in cancer. DEA is based on the commonly believed assumption that genes upregulated in cancerous tissues have the potential to function as oncogenes. Their expression levels often correlate with cancer advancement and unfavorable prognosis, whereas downregulated genes display the opposite correlation. However, contrary to the prevailing belief, our analysis utilizing The Cancer Genome Atlas (TCGA) databases revealed that the upregulated or downregulated genes in cancer do not always align with cancer progression or prognosis. These findings emphasize the need for alternative approaches for identifying cancer-related genes that may be more accurate and effective. To address this need, we compared the effectiveness of machine learning (ML) methods with that of traditional DEA in the identification of cancer-related genes. ML algorithms have the advantage of being able to analyze large-scale genomic data and identify complex patterns that may go unnoticed by traditional methods. Our results demonstrated that ML methods significantly outperformed DEA in the screening of cancer-related genes.
Breast cancer, a molecularly heterogeneous disease, is classified into hormone receptor-positive luminal breast cancer (LBC), human epidermal growth factor receptor 2-positive breast cancer, and triple-negative breast cancer (TNBC). Precursor microRNAs (pre-miRNAs), typically form hairpin structures with a length from 65 to 80 bases, are shown to play crucial roles in breast cancer carcinogenesis. We hypothesized that these pre-miRNAs could have been sequenced in total RNA sequencing (RNA-seq) and developed a novel algorithm to profile pre-miRNAs from raw total RNA-seq data. A total of 907 breast cancer samples curated by Malaysian Breast Cancer Genetic Study (MyBrCa) were profiled using this algorithm and a comparison was made between pre-miRNA profiles and mature miRNA profiles obtained from The Cancer Genome Atlas (TCGA) dataset. We explored differentially expressed pre-miRNAs in TNBC in comparison to LBC and conducted downstream functional analyses of the target genes. A prognostic signature was built by LASSO–Cox regression on selected pre-miRNAs and validated internally and externally by MyBrCa and TCGA datasets, respectively. As a result, 10 common differentially expressed pre-miRNAs were identified. Functional analyses of these pre-miRNAs captured certain aggressive TNBC behaviors. Importantly, a pre-miRNA signature composed of 4 out of these 10 pre-miRNAs significantly prognosticated the breast cancer patients in the MyBrCa cohort and TCGA cohort, independent of conventional prognostic factors. In conclusion, this novel algorithm allows profiling pre-miRNAs from raw total RNA-seq data, which could be cross-validated with mature miRNA profiles for cross-platform comparison. The findings of this study underscore the importance of pre-miRNAs in breast cancer carcinogenesis and as prognostic factors.
In myelodysplastic syndromes (MDS), cytogenetic characteristics of the malignant bone marrow cells influence the clinical course. The aim of this study was to evaluate whether cytogenetics is useful to predict outcome and response in patients with del(5q) under azacitidine (AZA) ± lenalidomide (LEN) therapy. We therefore performed comprehensive cytogenetic analyses in MDS patients with del(5q) treated within the randomized phase II trial NMDSG10B. Seventy-two patients were enrolled in the study and 46 patients (64%) had sufficient cytogenetics at inclusion and response evaluation. Karyotyping was significantly more sensitive during follow-up to detect del(5q) compared to FISH, 34 patients (97%) versus 27 patients (77%) (p = 0.027). The overall response rate (ORR) did not differ between the 11 patients with < 3 aberrations (median 1 aberration) and the 59 patients with ≥ 3 aberrations (median 7 aberrations, range 3–16), while ≥ 3 aberrations were associated with shorter overall survival (OS), 9.9 months versus 25.2 months (p = 0.004). OS was significantly shorter in patients with unbalanced translocation of 5q than patients with del (5)(q14q34), 8.4 months versus 21.1 months (p = 0.004). Both complex karyotype and multi-hit TP53 alterations were more frequent in patients with unbalanced translocations of 5q versus del (5)(q14q34), 98% and 88% versus 67% and 47% (each p = < 0.001). Most patients with cytogenetic progression had multi-hit TP53 alterations at inclusion. Cytogenetic progression occurred at a similar frequency in the AZA arm and in the AZA + LEN arm. In summary, this study in homogenously treated MDS patients with different abnormalities of 5q demonstrates the influence of cytogenetics on treatment results.
Trial Registration: EudraCT number: 2011-001639-21; ClinicalTrials.gov identifier: NCT01556477.
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