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      Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations

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          Abstract

          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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          Author and article information

          Journal
          7707904
          470
          Am J Surg Pathol
          Am. J. Surg. Pathol.
          The American journal of surgical pathology
          0147-5185
          1532-0979
          31 October 2015
          May 2016
          01 May 2017
          : 40
          : 5
          : 645-655
          Affiliations
          [1 ]Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan
          [2 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
          [3 ]Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
          [4 ]Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
          [5 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
          [6 ]Department of Medicine Weill Cornell Medical College, New York, NY
          Author notes
          [* ]Correspondence to: Cristina R Antonescu, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; antonesc@ 123456mskcc.org
          Article
          PMC4833528 PMC4833528 4833528 nihpa734593
          10.1097/PAS.0000000000000582
          4833528
          26735859
          31077996-5a44-405f-a638-8a16f962306a
          History
          Categories
          Article

          angiosarcoma,CIC,KDR,PLCG1,MYC,FLT4
          angiosarcoma, CIC, KDR, PLCG1, MYC, FLT4

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