ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

Yu-Chien Kao, Yun Shao Sung, Chun Liang Chen, Lei Zhang, Brendan C. Dickson, David Swanson, Sumathi Vaiyapuri, Farida Latif, Abdullah Alholle, Shih Chiang Huang, Jason L. Hornick, Cristina R. Antonescu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs). However, a number of SBRCTs remain unclassified despite exhaustive analysis. Fourteen SBRCTs lacking driver genetic events by RNA sequencing (RNAseq) analysis were collected. Unsupervised hierarchical clustering was performed using samples from our RNAseq database, including 13 SBRCTs with non-CIC genetic abnormalities and 2 CIC-rearranged angiosarcomas among others. Remarkably, all 14 study cases showed high mRNA levels of ETV1/4/5, and by unsupervised clustering most grouped into a distinct cluster, separate from other tumors. Based on these results indicating a close relationship with CIC-rearranged tumors, we manually inspected CIC reads in RNAseq data. FISH for CIC and DUX4 abnormalities and immunohistochemical stains for ETV4 were also performed. In the control group, only 2 CIC-rearranged angiosarcomas had high ETV1/4/5 expression. Upon manual inspection of CIC traces, 7 of 14 cases showed CIC-DUX4 fusion reads, 2 cases had DUX4-CIC reads, while the remaining 5 were negative. FISH showed CIC break-apart in 7 cases, including 5 cases lacking CIC-DUX4 or DUX4-CIC fusion reads on RNAseq manual inspection. However, no CIC abnormalities were detected by FISH in 6 cases with CIC-DUX4 or DUX4-CIC reads. ETV4 immunoreactivity was positive in 7 of 11 cases. Our results highlight the underperformance of FISH and RNAseq methods in diagnosing SBRCTs with CIC gene abnormalities. The downstream ETV1/4/5 transcriptional up-regulation appears highly sensitive and specific and can be used as a reliable molecular signature and diagnostic method for CIC fusion positive SBRCTs.

Original languageEnglish
Pages (from-to)501-510
Number of pages10
JournalGenes Chromosomes and Cancer
Volume56
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

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RNA Sequence Analysis
Gene Rearrangement
Sarcoma
Up-Regulation
Neoplasms
Hemangiosarcoma
Cluster Analysis
Molecular Pathology
Nucleic Acid Databases
Coloring Agents
Control Groups
Messenger RNA

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements. / Kao, Yu-Chien; Sung, Yun Shao; Chen, Chun Liang; Zhang, Lei; Dickson, Brendan C.; Swanson, David; Vaiyapuri, Sumathi; Latif, Farida; Alholle, Abdullah; Huang, Shih Chiang; Hornick, Jason L.; Antonescu, Cristina R.

In: Genes Chromosomes and Cancer, Vol. 56, No. 6, 01.06.2017, p. 501-510.

Research output: Contribution to journalArticle

Kao, Y-C, Sung, YS, Chen, CL, Zhang, L, Dickson, BC, Swanson, D, Vaiyapuri, S, Latif, F, Alholle, A, Huang, SC, Hornick, JL & Antonescu, CR 2017, 'ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements', Genes Chromosomes and Cancer, vol. 56, no. 6, pp. 501-510. https://doi.org/10.1002/gcc.22454
Kao, Yu-Chien ; Sung, Yun Shao ; Chen, Chun Liang ; Zhang, Lei ; Dickson, Brendan C. ; Swanson, David ; Vaiyapuri, Sumathi ; Latif, Farida ; Alholle, Abdullah ; Huang, Shih Chiang ; Hornick, Jason L. ; Antonescu, Cristina R. / ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements. In: Genes Chromosomes and Cancer. 2017 ; Vol. 56, No. 6. pp. 501-510.
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abstract = "CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs). However, a number of SBRCTs remain unclassified despite exhaustive analysis. Fourteen SBRCTs lacking driver genetic events by RNA sequencing (RNAseq) analysis were collected. Unsupervised hierarchical clustering was performed using samples from our RNAseq database, including 13 SBRCTs with non-CIC genetic abnormalities and 2 CIC-rearranged angiosarcomas among others. Remarkably, all 14 study cases showed high mRNA levels of ETV1/4/5, and by unsupervised clustering most grouped into a distinct cluster, separate from other tumors. Based on these results indicating a close relationship with CIC-rearranged tumors, we manually inspected CIC reads in RNAseq data. FISH for CIC and DUX4 abnormalities and immunohistochemical stains for ETV4 were also performed. In the control group, only 2 CIC-rearranged angiosarcomas had high ETV1/4/5 expression. Upon manual inspection of CIC traces, 7 of 14 cases showed CIC-DUX4 fusion reads, 2 cases had DUX4-CIC reads, while the remaining 5 were negative. FISH showed CIC break-apart in 7 cases, including 5 cases lacking CIC-DUX4 or DUX4-CIC fusion reads on RNAseq manual inspection. However, no CIC abnormalities were detected by FISH in 6 cases with CIC-DUX4 or DUX4-CIC reads. ETV4 immunoreactivity was positive in 7 of 11 cases. Our results highlight the underperformance of FISH and RNAseq methods in diagnosing SBRCTs with CIC gene abnormalities. The downstream ETV1/4/5 transcriptional up-regulation appears highly sensitive and specific and can be used as a reliable molecular signature and diagnostic method for CIC fusion positive SBRCTs.",
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T1 - ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

AU - Kao, Yu-Chien

AU - Sung, Yun Shao

AU - Chen, Chun Liang

AU - Zhang, Lei

AU - Dickson, Brendan C.

AU - Swanson, David

AU - Vaiyapuri, Sumathi

AU - Latif, Farida

AU - Alholle, Abdullah

AU - Huang, Shih Chiang

AU - Hornick, Jason L.

AU - Antonescu, Cristina R.

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AB - CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs). However, a number of SBRCTs remain unclassified despite exhaustive analysis. Fourteen SBRCTs lacking driver genetic events by RNA sequencing (RNAseq) analysis were collected. Unsupervised hierarchical clustering was performed using samples from our RNAseq database, including 13 SBRCTs with non-CIC genetic abnormalities and 2 CIC-rearranged angiosarcomas among others. Remarkably, all 14 study cases showed high mRNA levels of ETV1/4/5, and by unsupervised clustering most grouped into a distinct cluster, separate from other tumors. Based on these results indicating a close relationship with CIC-rearranged tumors, we manually inspected CIC reads in RNAseq data. FISH for CIC and DUX4 abnormalities and immunohistochemical stains for ETV4 were also performed. In the control group, only 2 CIC-rearranged angiosarcomas had high ETV1/4/5 expression. Upon manual inspection of CIC traces, 7 of 14 cases showed CIC-DUX4 fusion reads, 2 cases had DUX4-CIC reads, while the remaining 5 were negative. FISH showed CIC break-apart in 7 cases, including 5 cases lacking CIC-DUX4 or DUX4-CIC fusion reads on RNAseq manual inspection. However, no CIC abnormalities were detected by FISH in 6 cases with CIC-DUX4 or DUX4-CIC reads. ETV4 immunoreactivity was positive in 7 of 11 cases. Our results highlight the underperformance of FISH and RNAseq methods in diagnosing SBRCTs with CIC gene abnormalities. The downstream ETV1/4/5 transcriptional up-regulation appears highly sensitive and specific and can be used as a reliable molecular signature and diagnostic method for CIC fusion positive SBRCTs.

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