The utility of MYC and FLT4 in the diagnosis and treatment of postradiation atypical vascular lesion and angiosarcoma of the breast

Cornejo, Kristine M.; Deng, April; Wu, Hong Gyun; Cosar, Ediz F.; Khan, Ashraf; Cyr, Maryann St.; Tomaszewicz, Keith; Dresser, Karen; O’Donnell, Patrick; Hutchinson, Lloyd

doi:10.1016/j.humpath.2015.02.014

Cited by 45 publications

(49 citation statements)

References 30 publications

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“…VEGFR3 ) amplification, which mostly occurs in association with MYC amplification. 11,14 FLT4 amplification was identified in 13% (5/39) of MYC -amplified AS, mutually exclusive from KDR / PLCG1 mutations, and associated with a poor outcome. All except one FLT4 -amplified secondary AS occurred in the breast/chest wall area, being co-amplified with MYC .…”

Section: Discussionmentioning

confidence: 99%

“…A recent study suggested that diffuse and strong cytoplasmic FLT4 immunostaining is a potential surrogate ancillary test for FLT4 gene amplification by FISH. 14 …”

Section: Discussionmentioning

confidence: 99%

“…10–12 Analysis of MYC amplification by fluorescence in situ hybridization (FISH) or MYC expression by immunohistochemistry has been confirmed by a number of studies as a reliable ancillary technique to distinguish radiation-related AS from other radiation-induced conditions, particularly atypical vascular lesions (AVL). 11–14 …”

Section: Introductionmentioning

confidence: 99%

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Recurrent CIC Gene Abnormalities in Angiosarcomas

Huang

Zhang

Sung

et al. 2016

American Journal of Surgical Pathology

166

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Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show MYC gene amplifications, with a subset of cases harboring KDR, PTPRB and PLCG1 mutations. Despite recent advances, the genetic abnormalities of most primary AS remain undefined. Whole transcriptome sequencing was initiated in 2 index cases of primary soft tissue AS with epithelioid morphology occurring in young adults for novel gene discovery. The candidate abnormalities were validated and then screened by targeted sequencing and FISH in a large cohort of 120 well-characterized AS. Findings were subsequently correlated with the status of KDR, PLCG1, MYC and FLT4 gene abnormalities. The clinicopathologic relevance and prognostic significance of these genetic changes were analyzed by statistical methods. Concurrent CIC mutations and CIC rearrangements were identified in both index cases, with a CIC-LEUTX fusion detected in one case. Upon screening, an additional visceral AS in a young adult had a complex CIC rearrangement, while 6 others harbored only CIC mutations. All 3 CIC-rearranged AS lacked vasoformation and had a solid growth of round, epithelioid to rhabdoid cells, showing immunoreactivity for CD31 and ERG and sharing a transcriptional signature with other round cell sarcomas, including CIC-rearranged tumors. Overall, CIC abnormalities occurred in 9% (9/98) of cases, affecting younger patients with primary AS, with an inferior disease-free survival. In contrast, PLCG1 and KDR mutations occurred in both primary and secondary AS, accounting for 9.5% and 7%, respectively, with a predilection for breast and bone/viscera location, regardless of MYC status. MYC amplification was present in most secondary AS related to breast cancer (91%) compared to other causes (25%) or primary AS (7%). FLT4-amplified AS lacked PLCG1/KDR mutations, occurring predominantly in MYC-amplified population, and showed poor prognosis.

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Section: Discussionmentioning

confidence: 99%

“…A recent study suggested that diffuse and strong cytoplasmic FLT4 immunostaining is a potential surrogate ancillary test for FLT4 gene amplification by FISH. 14 …”

Section: Discussionmentioning

confidence: 99%

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Recurrent CIC Gene Abnormalities in Angiosarcomas

Huang

Zhang

Sung

et al. 2016

American Journal of Surgical Pathology

166

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“…The positive control for survivin and YAP was human infantile hemangioma and the negative control was normal human adipocytes. Regarding MYC positivity, nuclear immunoreactivity in more than 10% of angiosarcoma cells was deemed positive and no nuclear staining (cytoplasmic staining only) was considered as not positive …”

Section: Methodsmentioning

confidence: 99%

Survivin: A novel marker and potential therapeutic target for human angiosarcoma

et al. 2017

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Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO‐HAS‐B patient‐derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes‐associated protein (YAP) ‐positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti‐survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO‐HAS‐B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.

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“…Using IHC, strong positive nuclear staining for MYC was seen in cases of postradiation cutaneous AS, in contrast to atypical vascular proliferations. Cornejo et al [68] confirmed that detection of MYC protein expression by IHC and MYC gene amplification by FISH are valuable to distinguish AVL from postradiation AS. Moreover, MYC immunostaining is helpful to control resection margins [67] .…”

Section: Vascular Tumorsmentioning

confidence: 95%

Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors

2017

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Bone and soft-tissue tumors are in general rare. Diagnosing these tumors is challenging based on the significant number of different tumor entities, the rareness of these tumors, and the considerable morphological heterogeneity which can be found within a single tumor entity. Considering that more than half of the described soft-tissue tumors and approximately 25% of the bone tumors harbor recurrent genetic alterations, the use of auxiliary molecular examinations should be strongly considered. Molecular analyses are important to confirm the diagnosis, to guide treatment, to provide information about prognosis, and to allow patient recruitment for basket trials based on the molecular signature of a tumor. In addition, novel molecular alterations detected by next-generation sequencing (NGS) obtain further insights into the pathogenesis of these rare tumors and allow a more detailed genetic classification. Based on our single-center results of NGS using the Ion AmpliSeq Cancer Hotspot Panel v2 and the Ion AmpliSeq Comprehensive Cancer Panel (Thermo Fisher Scientific) for mutational analyses as well as the Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) to detect gene fusions in 26 genes since early 2016, we have experienced NGS as a very sensitive method to detect genetic alterations. In our experience, the use of the Archer FusionPlex Sarcoma Kit is superior to fluorescent in situ hybridization as an auxiliary tool in the routine workup of soft-tissue and bone tumors.

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The utility of MYC and FLT4 in the diagnosis and treatment of postradiation atypical vascular lesion and angiosarcoma of the breast

Cited by 45 publications

References 30 publications

Recurrent CIC Gene Abnormalities in Angiosarcomas

Recurrent CIC Gene Abnormalities in Angiosarcomas

Survivin: A novel marker and potential therapeutic target for human angiosarcoma

Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors

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