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BRST5:Adenoid Cystic Carcinoma (view source)
Revision as of 13:16, 28 October 2023
, 13:16, 28 October 2023→Primary Author(s)*
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|'''Laboratory Findings'''
|'''Laboratory Findings'''
|Not applicable
|N/A
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==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==
Recurrent rearrangements of MYB (or, more rarely, the paralogous gene ''MYBL1'') preserve the N-terminal DNA binding domain and transactivation domain in the chimeric gene product. The C-terminal regulatory domains of ''MYB'' or ''MYBL1'' may be lost, but the intact gene is retained in the case of MYB amplification and in the case of some ''MYBL1'' rearrangements.<ref name=":1">{{Cite journal|last=Persson|first=Marta|last2=Andrén|first2=Ywonne|last3=Mark|first3=Joachim|last4=Horlings|first4=Hugo M.|last5=Persson|first5=Fredrik|last6=Stenman|first6=Göran|date=2009-11-03|title=Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck|url=https://pubmed.ncbi.nlm.nih.gov/19841262|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=44|pages=18740–18744|doi=10.1073/pnas.0909114106|issn=1091-6490|pmc=2773970|pmid=19841262}}</ref><ref name=":2">{{Cite journal|last=Kim|first=Jisun|last2=Geyer|first2=Felipe C.|last3=Martelotto|first3=Luciano G.|last4=Ng|first4=Charlotte Ky|last5=Lim|first5=Raymond S.|last6=Selenica|first6=Pier|last7=Li|first7=Anqi|last8=Pareja|first8=Fresia|last9=Fusco|first9=Nicola|date=2018-02|title=MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene|url=https://pubmed.ncbi.nlm.nih.gov/29149504|journal=The Journal of Pathology|volume=244|issue=2|pages=143–150|doi=10.1002/path.5006|issn=1096-9896|pmc=5839480|pmid=29149504}}</ref>
Recurrent rearrangements of ''MYB'' (or, more rarely, the paralogous gene ''MYBL1'') preserve the N-terminal DNA binding domain and transactivation domain in the chimeric gene product. The C-terminal regulatory domains of ''MYB'' or ''MYBL1'' is generally absent in the active fusion, but the intact gene sequence is preserved in reported cases of ''MYB'' amplification and in some ''MYBL1'' rearrangements.<ref name=":1">{{Cite journal|last=Persson|first=Marta|last2=Andrén|first2=Ywonne|last3=Mark|first3=Joachim|last4=Horlings|first4=Hugo M.|last5=Persson|first5=Fredrik|last6=Stenman|first6=Göran|date=2009-11-03|title=Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck|url=https://pubmed.ncbi.nlm.nih.gov/19841262|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=44|pages=18740–18744|doi=10.1073/pnas.0909114106|issn=1091-6490|pmc=2773970|pmid=19841262}}</ref><ref name=":2">{{Cite journal|last=Kim|first=Jisun|last2=Geyer|first2=Felipe C.|last3=Martelotto|first3=Luciano G.|last4=Ng|first4=Charlotte Ky|last5=Lim|first5=Raymond S.|last6=Selenica|first6=Pier|last7=Li|first7=Anqi|last8=Pareja|first8=Fresia|last9=Fusco|first9=Nicola|date=2018-02|title=MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene|url=https://pubmed.ncbi.nlm.nih.gov/29149504|journal=The Journal of Pathology|volume=244|issue=2|pages=143–150|doi=10.1002/path.5006|issn=1096-9896|pmc=5839480|pmid=29149504}}</ref> Single cases of other fusions have been reported, including a ''KMT2C''::''WEE2'' fusion reported by Schwartz and others<ref>{{Cite journal|last=Schwartz|first=Christopher J.|last2=Brogi|first2=Edi|last3=Marra|first3=Antonio|last4=Da Cruz Paula|first4=Arnaud F.|last5=Nanjangud|first5=Gouri J.|last6=da Silva|first6=Edaise M.|last7=Patil|first7=Sujata|last8=Shah|first8=Shreena|last9=Ventura|first9=Katia|date=2022-02|title=The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features|url=https://pubmed.ncbi.nlm.nih.gov/34599282|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=35|issue=2|pages=193–201|doi=10.1038/s41379-021-00931-6|issn=1530-0285|pmc=9197148|pmid=34599282}}</ref>,
{| class="wikitable sortable"
{| class="wikitable sortable"
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|Reported breakpoints involve exon 14 of ''MYBL1'' fused to exon 9 of ''NFIB''<ref name=":2" />
|Reported breakpoints involve exon 14 of ''MYBL1'' fused to exon 9 of ''NFIB''<ref name=":2" />
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|t(8;14)(q13.1;q24.1)
|t(6;v)(q23.3;v)
|''MYBL1''::''ACTN1''
|''MYB''
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|Reported breakpoints involve exon 8 of ''MYBL1'' fused to exon 10 of ''ACTN1''<ref name=":2" />
|Fusions involving ''MYB'' with other gene partners or complex structural abnormalities associated with ''MYB'' gene fusion generate more complex karyotypes. Loss of 3' portion of ''MYB'' reported in one case<ref name=":2" />. Other reported ''MYB'' fusion partners include ''EWSR1'' (with ''EWSR1'' as the 5' partner, exon 10, fused to exon 2 of ''MYB'')<ref>{{Cite journal|last=Lei|first=Ting|last2=Shi|first2=Yongqiang|last3=Da|first3=Wenyue|last4=Xia|first4=Cunyan|last5=Wang|first5=Hui|date=2023-01-31|title=A novel EWSR1-MYB fusion in an aggressive advanced breast adenoid cystic carcinoma with mixed classical and solid-basaloid components|url=https://pubmed.ncbi.nlm.nih.gov/36719454|journal=Virchows Archiv: An International Journal of Pathology|doi=10.1007/s00428-023-03500-1|issn=1432-2307|pmid=36719454}}</ref>.
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|rea(6)(q23.3)
|t(8;v)(q13.1;v)
|MYB
|''MYBL1''
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|Loss of 3' portion of MYB reported in one case<ref name=":2" />
|Fusions involving ''MYBL1'' with other gene partners or more complex structural abnormalities associated with ''MYBL1'' gene fusion generate more complex karyotypes. Other reported ''MYBL1'' gene partners include ''ACTN1''<ref name=":2" />.
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==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Amplification or copy state transitions (gain or loss) on 6q23.3 associated with ''MYB'' rearrangement are the most commonly reported alterations in adenoid cystic carcinoma. Other individually reported alterations include gains of 1p36.12–p35.3, 11p15.5, 12p13.31, 16p13.3, and 19p13, and losses of 6q25.3-q26 and 9p11.1–q21.11 in an array CGH study of 14 adenoid cystic carcinomas by Wetterskog and others<ref name=":4">{{Cite journal|last=Wetterskog|first=Daniel|last2=Lopez-Garcia|first2=Maria Angeles|last3=Lambros|first3=Maryou B.|last4=A'Hern|first4=Roger|last5=Geyer|first5=Felipe C.|last6=Milanezi|first6=Fernanda|last7=Cabral|first7=Maria C.|last8=Natrajan|first8=Rachael|last9=Gauthier|first9=Arnaud|date=2012-01|title=Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers|url=https://pubmed.ncbi.nlm.nih.gov/22015727|journal=The Journal of Pathology|volume=226|issue=1|pages=84–96|doi=10.1002/path.2974|issn=1096-9896|pmid=22015727}}</ref>, gains of 17q21-q25.1 and losses of 12q12-q14.1 detected by whole exome sequencing on 12 adenoid cystic carcinoma in a study by Martelotto and others<ref name=":3" />, and a terminal 6q loss in one case (6q23.3-6q27) and whole chromosome losses (-4, -7, -14, -X) in a second case by targeted next generation sequencing in a study by Fusco and others<ref name=":6">{{Cite journal|last=Fusco|first=Nicola|last2=Geyer|first2=Felipe C.|last3=De Filippo|first3=Maria R.|last4=Martelotto|first4=Luciano G.|last5=Ng|first5=Charlotte K. Y.|last6=Piscuoglio|first6=Salvatore|last7=Guerini-Rocco|first7=Elena|last8=Schultheis|first8=Anne M.|last9=Fuhrmann|first9=Laetitia|date=2016-11|title=Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/27491809|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=29|issue=11|pages=1292–1305|doi=10.1038/modpathol.2016.134|issn=1530-0285|pmc=5083185|pmid=27491809}}</ref>. A terminal loss on 6q (6q23.3-6q27) detected by array CGH was separately reported in a case with ''MYB'' rearrangement by Kovacs and others<ref name=":7">{{Cite journal|last=Kovács|first=Anikó|last2=Persson|first2=Fredrik|last3=Persson|first3=Marta|last4=Andersson|first4=Mattias K.|last5=Stenman|first5=Göran|date=2017-09|title=Genomic imbalances and MYB fusion in synchronous bilateral adenoid cystic carcinoma and invasive lobular carcinoma of the breast|url=https://pubmed.ncbi.nlm.nih.gov/28894575|journal=Molecular and Clinical Oncology|volume=7|issue=3|pages=322–326|doi=10.3892/mco.2017.1330|issn=2049-9450|pmc=5582535|pmid=28894575}}</ref>. Recurrent copy number alterations reported in a study by Masse and others included losses on 12q, losses or gains on 17p, and amplification of ''CCND1'' on 11q13.3 detected by array CGH<ref name=":5" />. The common recurrent alterations are shown in the table below.
{| class="wikitable sortable"
{| class="wikitable sortable"
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
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|6
|6
|Gain/Amp
|Amp
|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|6q23.3
|6q23.3
|No
|No
|No
|No
|MYB amplification was a range of 3-10 copies by FISH associated with MYB overexpression<ref name=":2" />
|''MYB'' amplification in one case reported as a range of 3-10 copies by FISH associated with ''MYB'' overexpression<ref name=":2" />; two others reported in a study by Yao and others without copy number specified<ref>{{Cite journal|last=Yao|first=Qian|last2=Hou|first2=Wei|last3=Chen|first3=Junbing|last4=Bai|first4=Yanhua|last5=Long|first5=Mengping|last6=Huang|first6=Xiaozheng|last7=Zhao|first7=Chen|last8=Zhou|first8=Lixin|last9=Niu|first9=Dongfeng|date=2022|title=Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/35966872|journal=Frontiers in Medicine|volume=9|pages=943887|doi=10.3389/fmed.2022.943887|issn=2296-858X|pmc=9366086|pmid=35966872}}</ref>
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|12
|Gain
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|12p13.31<ref name=":4" />
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|16
|Gain
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|16p13.3<ref name=":4" />
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|17
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|19
|Gain
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|6
|6
|Loss
|Gain or Loss
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|chr6:135,502,453-135,540,311 [GRCh37/hg19]
|6q23.3
|Yes
|No
|No
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|Copy state transitions within ''MYB'' gene region typically associated with ''MYB'' fusion<ref name=":6" /><ref name=":7" />
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|9
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|9p11.1–q21.11<ref name=":4" />
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==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==
{| class="wikitable sortable"
{| class="wikitable sortable"
!Notes
!Notes
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|N/A
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|N/A
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|N/A
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|N/A
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|N/A
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==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Common recurrent mutations are shown in the table below. Others include ''ARID1A''<ref name=":5" />, ''PIK3R1''<ref name=":5" />, and ''TLN2''<ref name=":3" />.
{| class="wikitable sortable"
{| class="wikitable sortable"
!Notes
!Notes
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|NOTCH1, NOTCH2, and NOTCH3; inactivating sequence variants (missense, nonsense, frameshift truncating)<ref name=":5">{{Cite journal|last=Massé|first=Julie|last2=Truntzer|first2=Caroline|last3=Boidot|first3=Romain|last4=Khalifa|first4=Emmanuel|last5=Pérot|first5=Gaëlle|last6=Velasco|first6=Valérie|last7=Mayeur|first7=Laétitia|last8=Billerey-Larmonier|first8=Claire|last9=Blanchard|first9=Larry|date=2020-06|title=Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations|url=https://pubmed.ncbi.nlm.nih.gov/31857685|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=33|issue=6|pages=1041–1055|doi=10.1038/s41379-019-0425-3|issn=1530-0285|pmid=31857685}}</ref>
|''NOTCH1'', ''NOTCH2'', and ''NOTCH3''; inactivating sequence variants (missense, nonsense, frameshift / truncating)<ref name=":5">{{Cite journal|last=Massé|first=Julie|last2=Truntzer|first2=Caroline|last3=Boidot|first3=Romain|last4=Khalifa|first4=Emmanuel|last5=Pérot|first5=Gaëlle|last6=Velasco|first6=Valérie|last7=Mayeur|first7=Laétitia|last8=Billerey-Larmonier|first8=Claire|last9=Blanchard|first9=Larry|date=2020-06|title=Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations|url=https://pubmed.ncbi.nlm.nih.gov/31857685|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=33|issue=6|pages=1041–1055|doi=10.1038/s41379-019-0425-3|issn=1530-0285|pmid=31857685}}</ref>
|Loss of function
|Gain of function
|20-30%
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|Mostly solid basaloid subtype<br />
|Mostly solid basaloid subtype<br />
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|CREBBP; inactivating sequence variants (missense, nonsense, truncating)<ref name=":5" />
|''CREBBP''; inactivating sequence variants (missense, nonsense, frameshift / truncating)<ref name=":5" />
|Loss of function
|Loss of function
|15-20%
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|Mostly solid basaloid subtype
|Mostly solid basaloid subtype
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|CDK12; missense<ref name=":5" />
|''CDK12''; missense<ref name=":5" />
|Loss of function
|Loss of function
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Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases.
==Epigenomic Alterations==
==Epigenomic Alterations==
<br />
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
{| class="wikitable sortable"
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
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|MYB; gene fusion or amplification
|''MYB''; gene fusion or amplification
|Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair
|Promotes cellular proliferation
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|''MYBL1''; gene fusion
|Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair
|Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair
|Promotes cellular proliferation
|Promotes cellular proliferation
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|MYBL1; gene fusion
|''NOTCH1'', ''NOTCH2'', ''NOTCH3''
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|NOTCH signaling
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|''CREBBP''
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