Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

Cesar Ernesto Payan Gomez, Semir Vranic, Caterina Marchiò, Cristina Botta, Maria Stella Scalzo, Ryan P. Bender, Ludovica Verdun Di Cantogno, Fabrizio Tondat, Paola Francia Di Celle, Sara Mariani, Zoran Gatalica, Anna Sapino

Resultado de la investigación: Contribución a RevistaArtículo

Resumen

Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10%) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the "luminal-complex" phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations
Idioma originalEnglish (US)
Páginas (desde-hasta)1350-1359
Número de páginas9
PublicaciónHuman Pathology
Volumen46
N.º9
DOI
EstadoPublished - 2015

Huella dactilar

Multiplex Polymerase Chain Reaction
Breast Neoplasms
Carcinoma
Molecular Biology
Immunohistochemistry
Fluorescence In Situ Hybridization
TNF Receptor-Associated Factor 4
Biomarkers
Genes
Caveolin 1
Cyclin D1
Cadherins
Cluster Analysis
Phenotype
Mutation

Citar esto

Payan Gomez, Cesar Ernesto ; Vranic, Semir ; Marchiò, Caterina ; Botta, Cristina ; Scalzo, Maria Stella ; Bender, Ryan P. ; Di Cantogno, Ludovica Verdun ; Tondat, Fabrizio ; Di Celle, Paola Francia ; Mariani, Sara ; Gatalica, Zoran ; Sapino, Anna. / Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast. En: Human Pathology. 2015 ; Vol. 46, N.º 9. pp. 1350-1359.
@article{dc614ba2d53443b38c0cf54686e0e7d9,
title = "Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast",
abstract = "Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89{\%}), moderate (16{\%}) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10{\%}) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83{\%}), and overexpression of HER2 (32{\%}), EGFR (41{\%}), cyclin D1 (50{\%}), and MUC-1 (88{\%}). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50{\%} or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75{\%}), ADAM9 (54{\%}), and BRCA1 (46{\%}). HER2 gain, detected by MLPA in 38{\%} of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21{\%}) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29{\%}), BRAF/KRAS (2 of 7, 29{\%}), and PI3KCA/PTEN genes (7 of 7, 100{\%}). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the {"}luminal-complex{"} phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations",
author = "{Payan Gomez}, {Cesar Ernesto} and Semir Vranic and Caterina Marchi{\`o} and Cristina Botta and Scalzo, {Maria Stella} and Bender, {Ryan P.} and {Di Cantogno}, {Ludovica Verdun} and Fabrizio Tondat and {Di Celle}, {Paola Francia} and Sara Mariani and Zoran Gatalica and Anna Sapino",
year = "2015",
doi = "http://dx.doi.org/10.1016/j.humpath.2015.05.017",
language = "English (US)",
volume = "46",
pages = "1350--1359",
journal = "Human Pathology",
issn = "0046-8177",
publisher = "W.B. Saunders Ltd",
number = "9",

}

Payan Gomez, CE, Vranic, S, Marchiò, C, Botta, C, Scalzo, MS, Bender, RP, Di Cantogno, LV, Tondat, F, Di Celle, PF, Mariani, S, Gatalica, Z & Sapino, A 2015, 'Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast', Human Pathology, vol. 46, n.º 9, pp. 1350-1359. https://doi.org/10.1016/j.humpath.2015.05.017

Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast. / Payan Gomez, Cesar Ernesto; Vranic, Semir; Marchiò, Caterina; Botta, Cristina; Scalzo, Maria Stella; Bender, Ryan P.; Di Cantogno, Ludovica Verdun; Tondat, Fabrizio; Di Celle, Paola Francia; Mariani, Sara; Gatalica, Zoran; Sapino, Anna.

En: Human Pathology, Vol. 46, N.º 9, 2015, p. 1350-1359.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

AU - Payan Gomez, Cesar Ernesto

AU - Vranic, Semir

AU - Marchiò, Caterina

AU - Botta, Cristina

AU - Scalzo, Maria Stella

AU - Bender, Ryan P.

AU - Di Cantogno, Ludovica Verdun

AU - Tondat, Fabrizio

AU - Di Celle, Paola Francia

AU - Mariani, Sara

AU - Gatalica, Zoran

AU - Sapino, Anna

PY - 2015

Y1 - 2015

N2 - Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10%) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the "luminal-complex" phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations

AB - Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10%) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the "luminal-complex" phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations

U2 - http://dx.doi.org/10.1016/j.humpath.2015.05.017

DO - http://dx.doi.org/10.1016/j.humpath.2015.05.017

M3 - Article

VL - 46

SP - 1350

EP - 1359

JO - Human Pathology

JF - Human Pathology

SN - 0046-8177

IS - 9

ER -