Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland

Ilan Weinreb, Justin A. Bishop, Simion I. Chiosea, Raja R. Seethala, Bayardo Perez-Ordonez, Lei Zhang, Yun Shao Sung, Chun Liang Chen, Adel Assaad, Bahram R. Oliai, Cristina R. Antonescu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume42
Issue number4
DOIs
StatePublished - Jan 1 2018

Fingerprint

Carcinoma, Intraductal, Noninfiltrating
Gene Rearrangement
Salivary Glands
Carcinoma
Salivary Ducts
RNA Sequence Analysis
Mutation
Fluorescence In Situ Hybridization
Reverse Transcription
Cystadenocarcinoma
Polymerase Chain Reaction
Gene Fusion
Adenocarcinoma

Keywords

  • intraductal carcinoma
  • low-grade cribriform cystadenocarcinoma
  • low-grade salivary duct carcinoma
  • NCOA4-RET
  • RET

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Weinreb, I., Bishop, J. A., Chiosea, S. I., Seethala, R. R., Perez-Ordonez, B., Zhang, L., ... Antonescu, C. R. (2018). Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland. American Journal of Surgical Pathology, 42(4), 442-452. https://doi.org/10.1097/PAS.0000000000000952

Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland. / Weinreb, Ilan; Bishop, Justin A.; Chiosea, Simion I.; Seethala, Raja R.; Perez-Ordonez, Bayardo; Zhang, Lei; Sung, Yun Shao; Chen, Chun Liang; Assaad, Adel; Oliai, Bahram R.; Antonescu, Cristina R.

In: American Journal of Surgical Pathology, Vol. 42, No. 4, 01.01.2018, p. 442-452.

Research output: Contribution to journalArticle

Weinreb, I, Bishop, JA, Chiosea, SI, Seethala, RR, Perez-Ordonez, B, Zhang, L, Sung, YS, Chen, CL, Assaad, A, Oliai, BR & Antonescu, CR 2018, 'Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland', American Journal of Surgical Pathology, vol. 42, no. 4, pp. 442-452. https://doi.org/10.1097/PAS.0000000000000952
Weinreb, Ilan ; Bishop, Justin A. ; Chiosea, Simion I. ; Seethala, Raja R. ; Perez-Ordonez, Bayardo ; Zhang, Lei ; Sung, Yun Shao ; Chen, Chun Liang ; Assaad, Adel ; Oliai, Bahram R. ; Antonescu, Cristina R. / Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland. In: American Journal of Surgical Pathology. 2018 ; Vol. 42, No. 4. pp. 442-452.
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abstract = "Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47{\%}). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75{\%}) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.",
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