Subependymal giant cell astrocytoma harboring a <i>PRRC2B‐ALK</i> fusion: A case report

Tsurubuchi, Takao; Nakano, Yoshiko; Hirato, Junko; Yoshida, Akihiko; Muroi, Ai; Sakamoto, Noriaki; Alexander, Z.; Matsuda, Masahide; Ishikawa, Eiichi; Yoshioka, Takako; Honda‐Kitahara, Mai; Ichimura, Koichi; Yamamoto, Tetsuya; Matsumura, Akira

doi:10.1002/pbc.27995

Cited by 5 publications

(6 citation statements)

References 22 publications

(52 reference statements)

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“…PRRC2B-ALK was previously reported in only one patient with pediatric subependymal giant cell astrocytoma (SEGA), and may play a key oncogenic role in the SEGA tumor ( 10 ). As we prepared the manuscript, Gupta et al reported the first PRRC2B-ALK fusion in EIMS of the omentum, which was the same diagnosis as our patient ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

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Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report

et al. 2022

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Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm and patients with IMT tend to have a favorable outcome after complete surgical resection. However, some tumors of IMT cases have recurred and grown rapidly after successful surgery. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive intra-abdominal IMT variant with epithelioid-to-round cell morphology. Currently, no standard therapy exists for recurrent or invasive IMTs and EIMS, but anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are recommended for those harboring ALK gene rearrangements. We herein report the first case of PRRC2B-ALK fusion associated IMTs with clinical and pathological manifestation matched the diagnosis criteria of EIMS and the durable clinical response of the sequential use of ALK TKIs (crizotinib, alectinib, ceritinib, and lorlatinib). A female patient with EIMS of the greater omentum was suffering from a rapid recurrence after cytoreductive surgery was done. Crizotinib was administered when PRRC2B-ALK fusion was detected, and partial response was achieved. The progression-free survival (PFS) of crizotinib was 5 months. Alectinib was administered based on the results of second next-generation sequencing (NGS) analysis, which identified the secondary mutation ALK R1192P. The best overall response of alectinib treatment was a partial response (PR) and the PFS was 5.5 months. Ceritinib was prescribed as third-line therapy after alectinib resistance with ALK L1196M mutation. PR was achieved and the PFS of ceritinib was 6 months. The patient was taking lorlatinib after ceritinib resistance and achieved a stable disease at 2 months with the PFS more than 5 months. The overall survival was more than two years as of the time of manuscript preparation. We describe an EIMS of greater omentum caused by PRRC2B-ALK fusion gene and showed durable clinical response to the sequential use of ALK TKIs.

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Section: Discussionmentioning

confidence: 99%

“…Recently, EML4-ALK fusion is reported as an alternative fusion gene in EIMS (8). PRRC2B-ALK was previously reported in only one patient with pediatric subependymal giant cell astrocytoma (SEGA) (10) but never in IMT or EMIS patients.…”

Section: Introductionmentioning

confidence: 99%

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report

et al. 2022

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“…Raw data were also converted into RSEM format for comparison to other brain and adult solid tumors from The Cancer Genome Atlas (TCGA) consortium and 10 gangliogliomas [26][27][28][29]. We also performed gene fusion analysis to identify any gene rearrangements using FusionInspector (https:// github.com/FusionInspector/FusionInspector/), as a previous study reported a single SEGA case with PRRC2B-ALK fusion [30].…”

Section: Pre-processing and Bioinformatics Analysis Of Mps Datamentioning

confidence: 99%

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

et al. 2021

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Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5-10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumornormal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/ TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2-46 Mb) was seen in 76% (16/ 21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0-7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation.

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“…PRRC2B is highly expressed in fast-proliferating tumor cells such as Wilms' tumor, and its high expression is tightly associated with poor overall survival of patients (24,25). In addition, fusion genes of PRRC2B with MGMT, DEK, and ALK have been reported in multiple different tumors (26)(27)(28)(29)(30). Therefore, understanding the function of PRRC2B may shed light on translational regulation with relevance to tumor cell proliferation and human diseases.…”

Section: Introductionmentioning

confidence: 99%

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Jiang

Hedaya

Khor

et al. 2022

Preprint

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Accumulating evidence suggests that posttranscriptional control of gene expression, including RNA splicing, transport, modification, translation, and degradation, primarily relies on RNA binding proteins (RBPs). However, the functions of many RBPs remain understudied. Here, we characterized the function of a novel RBP, Proline-Rich Coiled-coil 2B (PRRC2B). Through photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and sequencing (PAR-CLIP-seq), we identified transcriptome-wide CU- or GA-rich PRRC2B binding sites around the translation initiation codon on a specific cohort of mRNAs in HEK293T cells. These mRNAs, including oncogenes and cell cycle regulators such asCCND2(cyclin D2), exhibited decreased translation upon PRRC2B knockdown as revealed by polysome-associated RNA-seq, resulting in reduced G1/S phase transition and cell proliferation. Antisense oligonucleotides blocking PRRC2B interactions withCCND2mRNA decreased its translation, thus inhibiting G1/S transition and cell proliferation. Mechanistically, PRRC2B interactome analysis revealed RNA-independent interactions with eukaryotic translation initiation factors 3 (eIF3) and 4G2 (eIF4G2). The interaction with translation initiation factors is essential for PRRC2B function since the eIF3/eIF4G2-interacting defective mutant, unlike wild-type PRRC2B, failed to rescue the translation deficiency or cell proliferation inhibition caused by PRRC2B knockdown. Altogether, our findings reveal that PRRC2B is essential for efficient translation of specific proteins required for cell cycle progression and cell proliferation.

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Subependymal giant cell astrocytoma harboring a PRRC2B‐ALK fusion: A case report

Cited by 5 publications

References 22 publications

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

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