Compendium of Cancer Genome Aberrations

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BRST5:Adenoid Cystic Carcinoma (view source)

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==Morphologic Features==
 
==Morphologic Features==
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tubular, cribriform, and solid patterns
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Tubular, cribriform, and solid patterns are observed.
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The classic subtype contains epithelial and myoepithelial cells with spaces called pseudolamina that contain stromal matrix with stromal cells (endothelial cells, fibroblasts) and basement membrane material (stains positive for collagen IV and laminin). Two cell populations are observed: an epithelial component that stains with low molecular weight cytokeratins (CK7, CK8), EMA, and sometimes CK5/6, and a myoepithelial component that stains with high molecular weight cytokeratins (CK14, CK5/6, p63) and typically also with myoepithelial markers (heavy-chain myosin, calponin, S100, CD10).
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The solid basaloid subtype contains solid nests of basaloid cells with high grade nuclear features (marked nuclear atypia, high mitotic count, and necrosis).
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Rare cases of adenoid cystic carcinoma can undergo high-grade transformation.
 
==Immunophenotype==
 
==Immunophenotype==
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
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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>,   
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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 name=":8">{{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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|
 
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|
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|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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|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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!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>
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|''NOTCH1'', ''NOTCH2'', and ''NOTCH3''; sequence variants <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>
 
|Gain of function
 
|Gain of function
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|22-28% solid basaloid subtype <ref name=":8" /> <ref name=":5" />
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|
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|
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|
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|
 
|
 
|
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|Mostly solid basaloid subtype, with poorer prognosis <ref name=":8" /> NOTCH mutations cause resistance to BET bromodomain inhibitors<br />
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|-
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|''CREBBP''; inactivating sequence variants <ref name=":5" />
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|Loss of function
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|17-33% solid basaloid subtype <ref name=":8" /><ref name=":5" />
 
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|Mostly solid basaloid subtype<br />
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|Mostly solid basaloid subtype, with poorer prognosis
 
|-
 
|-
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|''CREBBP''; inactivating sequence variants (missense, nonsense, frameshift / truncating)<ref name=":5" />
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|''KMT2C''; inactivating sequence variants, deletion <ref name=":5" />
 
|Loss of function
 
|Loss of function
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|22% solid basaloid subtype in one study <ref name=":8" />
 
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|Mostly solid basaloid subtype, with poorer prognosis
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|-
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|''KDM6A''; inactivating sequence variants
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|Loss of function
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|22% solid basaloid subtype in one study <ref name=":8" />
 
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|Mostly solid basaloid subtype
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|
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|Mostly solid basaloid subtype, with poorer prognosis
 
|-
 
|-
 
|''CDK12''; missense<ref name=":5" />
 
|''CDK12''; missense<ref name=":5" />
 
|Loss of function
 
|Loss of function
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|38% solid basaloid subtype in one study <ref name=":5" />
 
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|Mostly solid basaloid subtype, with poorer prognosis
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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.  
 
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.  
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|''NOTCH1'', ''NOTCH2'', ''NOTCH3''
 
|''NOTCH1'', ''NOTCH2'', ''NOTCH3''
 
|NOTCH signaling
 
|NOTCH signaling
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|
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|Promotes cellular proliferation
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|-
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|''CREBBP''
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|
   
|}
 
|}
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A study of adenoid cystic carcinoma of salivary glands by Drier and others delineates the mechanism of ''MYB'' gene pathway upregulation via rearrangements that increase MYB expression. ''MYB'' rearrangements typically juxtapose ''MYB'' with strong enhancers in regions downstream of ''NFIB, TGFBR3'' and ''RAD51B.'' Gene fusions most often occur on the 3' side of ''MYB'', a subset of gene fusions occur on the 5' side, and all serve to bring the ''MYB'' gene locus close to strong enhancer elements, thus upregulating MYB expression. The authors note that TP63 signaling is active in the myoepithelial component of low grade adenoid cystic carcinomas, while Notch signaling is active in luminal epithelial components. Furthermore, the authors suggest that Notch pathway mutations may underlie the switch to solid histology and the more aggressive clinical course of these tumors.<ref>{{Cite journal|last=Drier|first=Yotam|last2=Cotton|first2=Matthew J.|last3=Williamson|first3=Kaylyn E.|last4=Gillespie|first4=Shawn M.|last5=Ryan|first5=Russell J. H.|last6=Kluk|first6=Michael J.|last7=Carey|first7=Christopher D.|last8=Rodig|first8=Scott J.|last9=Sholl|first9=Lynette M.|date=2016-03|title=An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/26829750|journal=Nature Genetics|volume=48|issue=3|pages=265–272|doi=10.1038/ng.3502|issn=1546-1718|pmc=4767593|pmid=26829750}}</ref>
 +
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
    
FISH for MYB rearrangement; RT-PCR for MYB-NFIB fusion transcript; RNA-based sequencing (whole transcriptome or targeted)
 
FISH for MYB rearrangement; RT-PCR for MYB-NFIB fusion transcript; RNA-based sequencing (whole transcriptome or targeted)
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[[File:MYB FISH break-apart probe.png|none|thumb|FISH with a break-apart probe targeting the 5' (red) and 3' (green) ''MYB'' gene region. Juxtaposed red and green signals indicate alleles with an intact ''MYB'' gene locus, and split / separated red and green signals indicate alleles with ''MYB'' rearrangement. The separation in this case is small, suggesting an inversion (i.e., intrachromosomal rearrangement).]]
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[[File:Negative MYB FISH.tif|none|thumb|FISH with a break-apart probe targeting the 5' (red) and 3' (green) ''MYB'' gene region. This sample was negative for ''MYB'' rearrangement, and the majority of cells showed 1-3 fused red/green signals (juxtaposed red and green probe signals), consistent with an intact (unrearranged) ''MYB'' gene region.]]
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==Familial Forms==
 
==Familial Forms==
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==Additional Information==
 
==Additional Information==
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==Links==
 
==Links==
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==References==
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==Reference==
 
<references />
 
<references />
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(use "Cite" icon at top of page)
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===EXAMPLE Book===
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#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
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==Notes==
 
==Notes==
 
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