Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions

Alena Skálová, Tomas Vanecek, Emmanuelle Uro-Coste, Justin A. Bishop, Ilan Weinreb, Lester D.R. Thompson, Stefano De Sanctis, Marco Schiavo-Lena, Jan Laco, Cécile Badoual, Thalita Santana Conceiçao, Nikola Ptáková, Martina Baněčkova, Marketa Miesbauerová, Michal Michal

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

Original languageEnglish (US)
Pages (from-to)1445-1455
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume42
Issue number11
DOIs
StatePublished - Nov 1 2018

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Carcinoma, Intraductal, Noninfiltrating
Salivary Glands
Neoplasms
Salivary Ducts
Exons
Fluorescence In Situ Hybridization
Reverse Transcription
Salivary Gland Neoplasms
Cystadenocarcinoma
Carcinoma
Polymerase Chain Reaction
Glandular and Epithelial Neoplasms
S100 Proteins
Genes

Keywords

  • cystadenocarcinoma
  • intraductal carcinoma
  • mammary analogue secretory carcinoma
  • MASC
  • NCOA4-RET
  • RET -targeted therapy
  • salivary gland neoplasm
  • TRIM27-RET

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions. / Skálová, Alena; Vanecek, Tomas; Uro-Coste, Emmanuelle; Bishop, Justin A.; Weinreb, Ilan; Thompson, Lester D.R.; De Sanctis, Stefano; Schiavo-Lena, Marco; Laco, Jan; Badoual, Cécile; Santana Conceiçao, Thalita; Ptáková, Nikola; Baněčkova, Martina; Miesbauerová, Marketa; Michal, Michal.

In: American Journal of Surgical Pathology, Vol. 42, No. 11, 01.11.2018, p. 1445-1455.

Research output: Contribution to journalArticle

Skálová, A, Vanecek, T, Uro-Coste, E, Bishop, JA, Weinreb, I, Thompson, LDR, De Sanctis, S, Schiavo-Lena, M, Laco, J, Badoual, C, Santana Conceiçao, T, Ptáková, N, Baněčkova, M, Miesbauerová, M & Michal, M 2018, 'Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions', American Journal of Surgical Pathology, vol. 42, no. 11, pp. 1445-1455. https://doi.org/10.1097/PAS.0000000000001133
Skálová, Alena ; Vanecek, Tomas ; Uro-Coste, Emmanuelle ; Bishop, Justin A. ; Weinreb, Ilan ; Thompson, Lester D.R. ; De Sanctis, Stefano ; Schiavo-Lena, Marco ; Laco, Jan ; Badoual, Cécile ; Santana Conceiçao, Thalita ; Ptáková, Nikola ; Baněčkova, Martina ; Miesbauerová, Marketa ; Michal, Michal. / Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions. In: American Journal of Surgical Pathology. 2018 ; Vol. 42, No. 11. pp. 1445-1455.
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abstract = "Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called {"}low-grade cribriform cystadenocarcinoma{"} and {"}low-grade salivary duct carcinoma.{"} The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47{\%} of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.",
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T1 - Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions

AU - Skálová, Alena

AU - Vanecek, Tomas

AU - Uro-Coste, Emmanuelle

AU - Bishop, Justin A.

AU - Weinreb, Ilan

AU - Thompson, Lester D.R.

AU - De Sanctis, Stefano

AU - Schiavo-Lena, Marco

AU - Laco, Jan

AU - Badoual, Cécile

AU - Santana Conceiçao, Thalita

AU - Ptáková, Nikola

AU - Baněčkova, Martina

AU - Miesbauerová, Marketa

AU - Michal, Michal

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

AB - Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

KW - cystadenocarcinoma

KW - intraductal carcinoma

KW - mammary analogue secretory carcinoma

KW - MASC

KW - NCOA4-RET

KW - RET -targeted therapy

KW - salivary gland neoplasm

KW - TRIM27-RET

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