PDTM-06. Alk Amplification and Rearrangements Are Recurrent Targetable Events in Glioblastoma

Blandin, Anne-Florence; Graham, Maya Srikanth; Ramkissoon, Shakti; Ramkissoon, Lori; Pelton, Kristine; Pagès, Mélanie; Jones, Robert T.; Becker, Sarah; Watkinson, Fiona; Schoolcraft, Kathleen; Haemels, Veerle; Goumnerova, Liliana; Chi, Susan; Wright, Karen; Kieran, Mark W.; Tauziède‐Espariat, Arnault; Varlet, Pascale; Alexandrescu, Sanda; Reardon, David A.; Carcamo, Benjamin; Charest, Al; Smet, Frederik De; Beroukhim, Rameen; Dubuc, Adrian M.; Kittler, Ralf; Wen, Patrick Y.; Alexander, Brian M.; Bandopadhayay, Pratiti; Bachoo, Robert; Ligon, Keith L.

doi:10.1093/neuonc/noy148.848

Cited by 4 publications

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“…ALK rearrangements have been reported in many brain tumors [34]. ALK and its ligand, pleiotrophin, are highly expressed during embryonic brain development and in high-grade brain tumors such as GBM compared to normal brain tissue [35], [36].…”

Section: Introductionmentioning

confidence: 99%

Expression of Anaplastic Lymphoma Kinase in Astrocytic Tumors (Histopathological and Immunohistochemical Study)

Hakeem

Khaled

Ismail

2021

Open Access Maced J Med Sci

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BACKGROUND: Astrocytic tumors are the most common primary brain tumors. Glioblastoma is the most common astrocytic tumor representing the highest World Health Organization (WHO) grade (WHO grade IV) with poor prognosis and short survival time. Anaplastic lymphoma kinase (ALK) has a role in embryonic central nervous system development. ALK receptor is thought to contribute to nervous system function, repair, and metabolic homeostasis and is expressed in high-grade tumors like anaplastic large cell lymphoma that makes it a potential target for therapeutic intervention. AIM: This work aimed to examine the immunohistochemical expression of ALK in astrocytic tumors and its correlation with age, sex, clinical presentation, location, laterality, recurrence, and WHO grade to implicate possible therapeutic potential. METHODS: This retrospective study was conducted on sixty cases of archived, formalin-fixed, paraffin-embedded tissue blocks that included different subtypes and grades of astrocytic tumors. Immunohistochemistry using ALK monoclonal antibody was performed using a standard avidin-biotin-peroxidase system. RESULTS: Of the sixty cases, 57 (95%) cases were negative for ALK, while three (5%) cases are positive for ALK; all showed the strong intensity of expression. No statistically significant association was found between ALK expression and astrocytic tumors in addition to other clinical variables of the studied tumors. CONCLUSIONS: Most cases of astrocytic tumors showed negative ALK expression apart from three positive cases seen in higher WHO grades, especially gliosarcoma. The high number of negative cases for ALK in our study group suggests that ALK expression is not associated with a prognostic significance toward astrocytic tumors whatever its grade.

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Section: Introductionmentioning

confidence: 99%

Expression of Anaplastic Lymphoma Kinase in Astrocytic Tumors (Histopathological and Immunohistochemical Study)

Hakeem

Khaled

Ismail

2021

Open Access Maced J Med Sci

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“…ALK can be overexpressed in 43%-70% of glioblastoma cases and may have biologic relevance [99][100][101][102] . PPP1CB-ALK fusions were observed in~43% (7/16) and ALK amplification in 31% (5/16) of ALK-expressing pediatric glioblastoma cases 89 ; ALK translocations are rare in adult GBM.…”

Section: Alk Alterations In Solid and Hematologic Malignanciesmentioning

confidence: 96%

“…ALK Mutations were observed in ~2.7% cases of GBM in the AACR Genie database. PPP1CB-ALK fusions were observed in ~43% (7/16) and ALK amplification was observed in 31% (5/16) of ALK-expressing pediatric glioblastoma cases 89 ALK overexpression by IHC may be present in over 40% of cases, but fusions are uncommon. 1 , 76 , 89 IMTs ALK fusions are found in ~50% of IMT patients.…”

Section: Alk Alterations In Solid and Hematologic Malignanciesmentioning

confidence: 99%

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ALK fusions in the pan-cancer setting: another tumor-agnostic target?

Shreenivas,

Janku,

Gouda

et al. 2023

npj Precis. Onc.

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Anaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers. ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors –alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib—are FDA approved for ALK-aberrant NSCLCs, and crizotinib is also approved for ALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of ALK alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of ALK fusions/rearrangements, and response rates of ~50–85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing ALK fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear ALK mutations (rather than fusions/rearrangements), but response rates are lower (~10–20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing ALK fusions/rearrangements.

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NovelPPP1CB‐ALKfusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive stromal and perivascular hyalinization

Lopez‐Nunez

Surrey

Alaggio

et al. 2020

Genes Chromosomes & Cancer

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A novel group of S100-and CD34-positive spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving kinases including RAF1, BRAF, NTRK1/2/3, and RET have been recently reported. To our knowledge, no such cases harboring ALK rearrangements have been identified. We report a previously healthy 41-year-old male with a 12-cm intramuscular shoulder mass. The tumor was composed of bland-appearing spindled to epithelioid cells, arranged in a patternless pattern in a background of loose myxoid stroma containing striking amianthoid-like stromal collagen and perivascular rings. In accordance with the previously reported tumors, the tumor cells showed diffuse immunopositivity with S100 and CD34, while lacking SOX10 expression.Targeted RNA-based next-generation sequencing identified a novel serine/threonineprotein phosphatase PP1-beta-catalytic subunit (PPP1CB)-ALK fusion gene. Although ALK break-apart was not detected by FISH, likely due to a paracentric inversion of chromosome 2, the presence of the fusion was confirmed by Sanger sequencing showing a 10-bp linker between exon 6 of PPP1CB and intron 19 of ALK while maintaining reading frame.Subsequent ALK-1 immunostain exhibited diffuse cytoplasmic staining in the tumor cells.Our case expands the molecular genetic spectrum of the distinctive group of spindle cell tumors with CD34/S100+ immunophenotype, supporting the important role of various kinases as drivers of oncogenesis. Awareness of this entity including its unique morphologic and immunophenotypic features as well as its interchangeable kinase gene fusions is crucial for correct classification and potential targeted therapy, particularly in aggressive subsets.

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PDTM-06. Alk Amplification and Rearrangements Are Recurrent Targetable Events in Glioblastoma

Cited by 4 publications

References 0 publications

Expression of Anaplastic Lymphoma Kinase in Astrocytic Tumors (Histopathological and Immunohistochemical Study)

Expression of Anaplastic Lymphoma Kinase in Astrocytic Tumors (Histopathological and Immunohistochemical Study)

ALK fusions in the pan-cancer setting: another tumor-agnostic target?

NovelPPP1CB‐ALKfusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive stromal and perivascular hyalinization

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