title: Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases With Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations.
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 fluorescence in situ hybridization in a large cohort of 120 well-characterized AS cases. 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 1 case. Upon screening, an additional visceral AS in a young adult had a complex CIC rearrangement, whereas 6 others harbored only CIC mutations. All 3 CIC-rearranged AS cases lacked vasoformation and had a solid growth of round, epithelioid to rhabdoid cells, showing immunoreactivity for CD31 and Ets-related gene 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 cases, 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 with other causes (25%) or primary AS (7%). FLT4-amplified AS lacked PLCG1/KDR mutations, occurring predominantly in MYC-amplified population, and showed poor prognosis.
authors.affiliation: *Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan ‡Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan Departments of †Pathology §Surgery ∥Medicine, Memorial Sloan Kettering Cancer Center ¶Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.forename: Narasimhan P
authors.initials: NP
authors.lastname: Agaram
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Angelo
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D050939:Gene Fusion; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006394:Hemangiosarcoma / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D051966:Phospholipase C gamma / Q000235:genetics*; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C498610:CIC protein, human; D018398:Homeodomain Proteins; C000590731:LEUTX protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C581309:FLT4 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma