Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations
Identifieur interne : 003701 ( Pmc/Corpus ); précédent : 003700; suivant : 003702Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations
Auteurs : Shih-Chiang Huang ; Lei Zhang ; Yun-Shao Sung ; Chun-Liang Chen ; Yu-Chien Kao ; Narasimhan P. Agaram ; Samuel Singer ; William D. Tap ; Sandra D Ngelo ; Cristina R. AntonescuSource :
- The American journal of surgical pathology [ 0147-5185 ] ; 2016.
Abstract
Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show
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DOI: 10.1097/PAS.0000000000000582
PubMed: 26735859
PubMed Central: 4833528
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Recurrent <italic>CIC</italic>
Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of <italic>PLCG1, KDR, MYC,</italic>
and <italic>FLT4</italic>
Gene Alterations</title>
<author><name sortKey="Huang, Shih Chiang" sort="Huang, Shih Chiang" uniqKey="Huang S" first="Shih-Chiang" last="Huang">Shih-Chiang Huang</name>
<affiliation><nlm:aff id="A1">Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Lei" sort="Zhang, Lei" uniqKey="Zhang L" first="Lei" last="Zhang">Lei Zhang</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sung, Yun Shao" sort="Sung, Yun Shao" uniqKey="Sung Y" first="Yun-Shao" last="Sung">Yun-Shao Sung</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen, Chun Liang" sort="Chen, Chun Liang" uniqKey="Chen C" first="Chun-Liang" last="Chen">Chun-Liang Chen</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kao, Yu Chien" sort="Kao, Yu Chien" uniqKey="Kao Y" first="Yu-Chien" last="Kao">Yu-Chien Kao</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Agaram, Narasimhan P" sort="Agaram, Narasimhan P" uniqKey="Agaram N" first="Narasimhan P" last="Agaram">Narasimhan P. Agaram</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singer, Samuel" sort="Singer, Samuel" uniqKey="Singer S" first="Samuel" last="Singer">Samuel Singer</name>
<affiliation><nlm:aff id="A4">Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tap, William D" sort="Tap, William D" uniqKey="Tap W" first="William D" last="Tap">William D. Tap</name>
<affiliation><nlm:aff id="A5">Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Ngelo, Sandra" sort="D Ngelo, Sandra" uniqKey="D Ngelo S" first="Sandra" last="D Ngelo">Sandra D Ngelo</name>
<affiliation><nlm:aff id="A5">Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A6">Department of Medicine Weill Cornell Medical College, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antonescu, Cristina R" sort="Antonescu, Cristina R" uniqKey="Antonescu C" first="Cristina R" last="Antonescu">Cristina R. Antonescu</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Recurrent <italic>CIC</italic>
Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of <italic>PLCG1, KDR, MYC,</italic>
and <italic>FLT4</italic>
Gene Alterations</title>
<author><name sortKey="Huang, Shih Chiang" sort="Huang, Shih Chiang" uniqKey="Huang S" first="Shih-Chiang" last="Huang">Shih-Chiang Huang</name>
<affiliation><nlm:aff id="A1">Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Lei" sort="Zhang, Lei" uniqKey="Zhang L" first="Lei" last="Zhang">Lei Zhang</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sung, Yun Shao" sort="Sung, Yun Shao" uniqKey="Sung Y" first="Yun-Shao" last="Sung">Yun-Shao Sung</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen, Chun Liang" sort="Chen, Chun Liang" uniqKey="Chen C" first="Chun-Liang" last="Chen">Chun-Liang Chen</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kao, Yu Chien" sort="Kao, Yu Chien" uniqKey="Kao Y" first="Yu-Chien" last="Kao">Yu-Chien Kao</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Agaram, Narasimhan P" sort="Agaram, Narasimhan P" uniqKey="Agaram N" first="Narasimhan P" last="Agaram">Narasimhan P. Agaram</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singer, Samuel" sort="Singer, Samuel" uniqKey="Singer S" first="Samuel" last="Singer">Samuel Singer</name>
<affiliation><nlm:aff id="A4">Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tap, William D" sort="Tap, William D" uniqKey="Tap W" first="William D" last="Tap">William D. Tap</name>
<affiliation><nlm:aff id="A5">Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Ngelo, Sandra" sort="D Ngelo, Sandra" uniqKey="D Ngelo S" first="Sandra" last="D Ngelo">Sandra D Ngelo</name>
<affiliation><nlm:aff id="A5">Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A6">Department of Medicine Weill Cornell Medical College, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antonescu, Cristina R" sort="Antonescu, Cristina R" uniqKey="Antonescu C" first="Cristina R" last="Antonescu">Cristina R. Antonescu</name>
<affiliation><nlm:aff id="A2">Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The American journal of surgical pathology</title>
<idno type="ISSN">0147-5185</idno>
<idno type="eISSN">1532-0979</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p id="P1">Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show <italic>MYC</italic>
gene amplifications, with a subset of cases harboring <italic>KDR</italic>
, <italic>PTPRB</italic>
and <italic>PLCG1</italic>
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 <italic>KDR, PLCG1, MYC</italic>
and <italic>FLT4</italic>
gene abnormalities. The clinicopathologic relevance and prognostic significance of these genetic changes were analyzed by statistical methods. Concurrent <italic>CIC</italic>
mutations and <italic>CIC</italic>
rearrangements were identified in both index cases, with a <italic>CIC-LEUTX</italic>
fusion detected in one case. Upon screening, an additional visceral AS in a young adult had a complex <italic>CIC</italic>
rearrangement, while 6 others harbored only <italic>CIC</italic>
mutations. All 3 <italic>CIC</italic>
-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 <italic>CIC</italic>
-rearranged tumors. Overall, <italic>CIC</italic>
abnormalities occurred in 9% (9/98) of cases, affecting younger patients with primary AS, with an inferior disease-free survival. In contrast, <italic>PLCG1</italic>
and <italic>KDR</italic>
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 <italic>MYC</italic>
status. <italic>MYC</italic>
amplification was present in most secondary AS related to breast cancer (91%) compared to other causes (25%) or primary AS (7%). <italic>FLT4</italic>
-amplified AS lacked <italic>PLCG1/KDR</italic>
mutations, occurring predominantly in <italic>MYC</italic>
-amplified population, and showed poor prognosis.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">7707904</journal-id>
<journal-id journal-id-type="pubmed-jr-id">470</journal-id>
<journal-id journal-id-type="nlm-ta">Am J Surg Pathol</journal-id>
<journal-id journal-id-type="iso-abbrev">Am. J. Surg. Pathol.</journal-id>
<journal-title-group><journal-title>The American journal of surgical pathology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0147-5185</issn>
<issn pub-type="epub">1532-0979</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26735859</article-id>
<article-id pub-id-type="pmc">4833528</article-id>
<article-id pub-id-type="doi">10.1097/PAS.0000000000000582</article-id>
<article-id pub-id-type="manuscript">NIHMS734593</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Recurrent <italic>CIC</italic>
Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of <italic>PLCG1, KDR, MYC,</italic>
and <italic>FLT4</italic>
Gene Alterations</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Shih-Chiang</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Lei</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sung</surname>
<given-names>Yun-Shao</given-names>
</name>
<degrees>MSc</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Chun-Liang</given-names>
</name>
<degrees>MSc</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kao</surname>
<given-names>Yu-Chien</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Agaram</surname>
<given-names>Narasimhan P</given-names>
</name>
<degrees>MBBS</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Singer</surname>
<given-names>Samuel</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tap</surname>
<given-names>William D</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>D’Angelo</surname>
<given-names>Sandra</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A5">5</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Antonescu</surname>
<given-names>Cristina R</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="A2">2</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan</aff>
<aff id="A2"><label>2</label>
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY</aff>
<aff id="A3"><label>3</label>
Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan</aff>
<aff id="A4"><label>4</label>
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY</aff>
<aff id="A5"><label>5</label>
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</aff>
<aff id="A6"><label>6</label>
Department of Medicine Weill Cornell Medical College, New York, NY</aff>
<author-notes><corresp id="FN1"><label>*</label>
Correspondence to: Cristina R Antonescu, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; <email>antonesc@mskcc.org</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>31</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>5</month>
<year>2017</year>
</pub-date>
<volume>40</volume>
<issue>5</issue>
<fpage>645</fpage>
<lpage>655</lpage>
<pmc-comment>elocation-id from pubmed: 10.1097/PAS.0000000000000582</pmc-comment>
<abstract><p id="P1">Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show <italic>MYC</italic>
gene amplifications, with a subset of cases harboring <italic>KDR</italic>
, <italic>PTPRB</italic>
and <italic>PLCG1</italic>
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 <italic>KDR, PLCG1, MYC</italic>
and <italic>FLT4</italic>
gene abnormalities. The clinicopathologic relevance and prognostic significance of these genetic changes were analyzed by statistical methods. Concurrent <italic>CIC</italic>
mutations and <italic>CIC</italic>
rearrangements were identified in both index cases, with a <italic>CIC-LEUTX</italic>
fusion detected in one case. Upon screening, an additional visceral AS in a young adult had a complex <italic>CIC</italic>
rearrangement, while 6 others harbored only <italic>CIC</italic>
mutations. All 3 <italic>CIC</italic>
-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 <italic>CIC</italic>
-rearranged tumors. Overall, <italic>CIC</italic>
abnormalities occurred in 9% (9/98) of cases, affecting younger patients with primary AS, with an inferior disease-free survival. In contrast, <italic>PLCG1</italic>
and <italic>KDR</italic>
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 <italic>MYC</italic>
status. <italic>MYC</italic>
amplification was present in most secondary AS related to breast cancer (91%) compared to other causes (25%) or primary AS (7%). <italic>FLT4</italic>
-amplified AS lacked <italic>PLCG1/KDR</italic>
mutations, occurring predominantly in <italic>MYC</italic>
-amplified population, and showed poor prognosis.</p>
</abstract>
<kwd-group><kwd>angiosarcoma</kwd>
<kwd>CIC</kwd>
<kwd>KDR</kwd>
<kwd>PLCG1</kwd>
<kwd>MYC</kwd>
<kwd>FLT4</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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