BRST5:Adenoid cystic carcinoma

From Compendium of Cancer Genome Aberrations
Jump to navigation Jump to search

Primary Author(s)*

Katherine Geiersbach, MD, Mayo Clinic, and Jun Liao, PhD, Columbia University Irving Medical Center

Cancer Category/Type

Breast Cancer / Epithelial Tumours of the Breast

Cancer Sub-Classification / Subtype

Rare and Salivary Gland-type Tumours / Adenoid cystic carcinoma

Definition / Description of Disease

Invasive carcinoma with a characteristic histologic pattern, comprised of epithelial and myoepithelial cells. Epithelial cells form glands with lumina containing mucoid material; associated stromal matrix is present, forming irregular spaces called pseudolumina. Subtypes include classic adenoid cystic carcinoma, solid-basaloid adenoid cystic carcinoma, and adenoid cystic carcinoma with high-grade transformation.

Synonyms / Terminology

Cylindroma (Historical)

Epidemiology / Prevalence

Rare; approximately 0.1% of all breast cancers

Clinical Features

Signs and Symptoms Palpable breast mass, mainly in elderly patients

Suspicious lesion on mammography

Laboratory Findings N/A

Sites of Involvement

Any quadrant of the breast; retroareolar most common

Morphologic Features

Tubular, cribriform, and solid patterns are observed.

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).

The solid basaloid subtype contains solid nests of basaloid cells with high grade nuclear features (marked nuclear atypia, high mitotic count, and necrosis).

Rare cases of adenoid cystic carcinoma can undergo high-grade transformation.

Immunophenotype

Finding Marker
Positive (universal) Epithelial cells: low molecular weight cytokeratins CK7 and CK8; EMA; SOX10[1]

Myoepithelial cells: MYB[2]; CK14, CK5/6, SOX10[1]

Positive (subset) Epithelial cells: KIT (CD117)

Myoepithelial cells: heavy-chain myosin, calponin, S100, CD10, p63

Negative (universal) ER, PR, HER2, neuroendocrine markers (chromogranin, synaptophysin)
Negative (subset)

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 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.[3][4] Single cases of other fusions have been reported, including a KMT2C::WEE2 fusion reported by Schwartz and others[5],

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(6;9)(q23.3;p23) MYB::NFIB der(6) 54% Yes No Yes Most common fusion breakpoints involve exon 14 of MYB fused to exon 9 or exon 8c of NFIB.[3][6][7]
t(8;9)(q13.1;p23) MYBL1::NFIB Reported breakpoints involve exon 14 of MYBL1 fused to exon 9 of NFIB[4]
t(6;v)(q23.3;v) MYB 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[4]. Other reported MYB fusion partners include EWSR1 (with EWSR1 as the 5' partner, exon 10, fused to exon 2 of MYB)[8].
t(8;v)(q13.1;v) MYBL1 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[4].

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[9], 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[7], 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[10]. 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[11]. 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[12]. The common recurrent alterations are shown in the table below.

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
6 Amp chr6:135,502,453-135,540,311 [GRCh37/hg19] 6q23.3 Yes No No MYB amplification in one case reported as a range of 3-10 copies by FISH associated with MYB overexpression[4]; two others reported in a study by Yao and others without copy number specified[13]
6 Gain or Loss chr6:135,502,453-135,540,311 [GRCh37/hg19] 6q23.3 Yes No No Copy state transitions within MYB gene region typically associated with MYB fusion[10][11]

Characteristic Chromosomal Patterns

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
N/A N/A N/A N/A N/A

Gene Mutations (SNV/INDEL)

Common recurrent mutations are shown in the table below. Others include ARID1A[12], PIK3R1[12], and TLN2[7].

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
NOTCH1, NOTCH2, and NOTCH3; sequence variants [12] Gain of function 22-28% solid basaloid subtype [5] [12] Mostly solid basaloid subtype, with poorer prognosis [5] NOTCH mutations cause resistance to BET bromodomain inhibitors
CREBBP; inactivating sequence variants [12] Loss of function 17-33% solid basaloid subtype [5][12] Mostly solid basaloid subtype, with poorer prognosis
KMT2C; inactivating sequence variants, deletion [12] Loss of function 22% solid basaloid subtype in one study [5] Mostly solid basaloid subtype, with poorer prognosis
KDM6A; inactivating sequence variants Loss of function 22% solid basaloid subtype in one study [5] Mostly solid basaloid subtype, with poorer prognosis
CDK12; missense[12] Loss of function 38% solid basaloid subtype in one study [12] Mostly solid basaloid subtype, with poorer prognosis

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


Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
MYB; gene fusion or amplification Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair Promotes cellular proliferation
MYBL1; gene fusion Cell cycle (MYC and NOTCH signaling), DNA replication, DNA repair Promotes cellular proliferation
NOTCH1, NOTCH2, NOTCH3 NOTCH signaling Promotes cellular proliferation

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.[14]

Genetic Diagnostic Testing Methods

FISH for MYB rearrangement; RT-PCR for MYB-NFIB fusion transcript; RNA-based sequencing (whole transcriptome or targeted)

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).
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.


Familial Forms


Additional Information


Links


Reference

  1. ↑ 1.0 1.1 Yang, Chen; et al. (2019). "SOX10 Is a Sensitive Marker for Breast and Salivary Gland Adenoid Cystic Carcinoma: Immunohistochemical Characterization of Adenoid Cystic Carcinomas". Breast Cancer: Basic and Clinical Research. 13: 1178223419842185. doi:10.1177/1178223419842185. ISSN 1178-2234. PMC 6501487. PMID 31105427.
  2. ↑ Poling, Justin S.; et al. (2017-07). "MYB Labeling by Immunohistochemistry Is More Sensitive and Specific for Breast Adenoid Cystic Carcinoma than MYB Labeling by FISH". The American Journal of Surgical Pathology. 41 (7): 973–979. doi:10.1097/PAS.0000000000000878. ISSN 1532-0979. PMID 28498281. Check date values in: |date= (help)
  3. ↑ 3.0 3.1 Persson, Marta; et al. (2009-11-03). "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck". Proceedings of the National Academy of Sciences of the United States of America. 106 (44): 18740–18744. doi:10.1073/pnas.0909114106. ISSN 1091-6490. PMC 2773970. PMID 19841262.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Kim, Jisun; et al. (2018-02). "MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene". The Journal of Pathology. 244 (2): 143–150. doi:10.1002/path.5006. ISSN 1096-9896. PMC 5839480. PMID 29149504. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Schwartz, Christopher J.; et al. (2022-02). "The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 35 (2): 193–201. doi:10.1038/s41379-021-00931-6. ISSN 1530-0285. PMC 9197148 Check |pmc= value (help). PMID 34599282 Check |pmid= value (help). Check date values in: |date= (help)
  6. ↑ D'Alfonso, Timothy M.; et al. (2014-11). "MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features". Human Pathology. 45 (11): 2270–2280. doi:10.1016/j.humpath.2014.07.013. ISSN 1532-8392. PMID 25217885. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 Martelotto, Luciano G.; et al. (2015-10). "Genomic landscape of adenoid cystic carcinoma of the breast". The Journal of Pathology. 237 (2): 179–189. doi:10.1002/path.4573. ISSN 1096-9896. PMC 4676955. PMID 26095796. Check date values in: |date= (help)
  8. ↑ Lei, Ting; et al. (2023-01-31). "A novel EWSR1-MYB fusion in an aggressive advanced breast adenoid cystic carcinoma with mixed classical and solid-basaloid components". Virchows Archiv: An International Journal of Pathology. doi:10.1007/s00428-023-03500-1. ISSN 1432-2307. PMID 36719454 Check |pmid= value (help).
  9. ↑ Wetterskog, Daniel; et al. (2012-01). "Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers". The Journal of Pathology. 226 (1): 84–96. doi:10.1002/path.2974. ISSN 1096-9896. PMID 22015727. Check date values in: |date= (help)
  10. ↑ 10.0 10.1 Fusco, Nicola; et al. (2016-11). "Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 29 (11): 1292–1305. doi:10.1038/modpathol.2016.134. ISSN 1530-0285. PMC 5083185. PMID 27491809. Check date values in: |date= (help)
  11. ↑ 11.0 11.1 Kovács, Anikó; et al. (2017-09). "Genomic imbalances and MYB fusion in synchronous bilateral adenoid cystic carcinoma and invasive lobular carcinoma of the breast". Molecular and Clinical Oncology. 7 (3): 322–326. doi:10.3892/mco.2017.1330. ISSN 2049-9450. PMC 5582535. PMID 28894575. Check date values in: |date= (help)
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9 Massé, Julie; et al. (2020-06). "Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 33 (6): 1041–1055. doi:10.1038/s41379-019-0425-3. ISSN 1530-0285. PMID 31857685. Check date values in: |date= (help)
  13. ↑ Yao, Qian; et al. (2022). "Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer". Frontiers in Medicine. 9: 943887. doi:10.3389/fmed.2022.943887. ISSN 2296-858X. PMC 9366086 Check |pmc= value (help). PMID 35966872 Check |pmid= value (help).
  14. ↑ Drier, Yotam; et al. (2016-03). "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma". Nature Genetics. 48 (3): 265–272. doi:10.1038/ng.3502. ISSN 1546-1718. PMC 4767593. PMID 26829750. Check date values in: |date= (help)

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

Retrieved from "https://ccga.io/index.php?title=BRST5:Adenoid_cystic_carcinoma&oldid=14648"