Whole-Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ

Joshua Smith, Aditi Kulkarni, Andrew C. Birkeland, Jonathan B. McHugh, J. Chad Brenner

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objective: The pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole-exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC). Study Design: Case report and whole-exome sequencing of tumor DNA. Setting: Academic medical center. Subjects and Methods: A 52-year-old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole-exome genetic sequencing and copy-number variation (CNV) analysis of tumor and normal DNA extracted from flash-frozen, paraffin-embedded (FFPE) samples. Results: A total of 93 high-confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss-of-function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25-11.1, containing SOX4 and VEGFA, and 14q32.1-32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300. Conclusions: Small cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.

Original languageEnglish (US)
Pages (from-to)859-865
Number of pages7
JournalOtolaryngology - Head and Neck Surgery (United States)
Volume159
Issue number5
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

Fingerprint

Exome
Small Cell Carcinoma
Papillary Carcinoma
Carcinoma in Situ
DNA Sequence Analysis
Neoplasms
Ligands
Mutation
Receptor Protein-Tyrosine Kinases
Paraffin
Chromatin
Cell Cycle
Neck
Head
Lung
DNA

Keywords

  • NOTCH
  • sinonasal SCC
  • SOX4

ASJC Scopus subject areas

  • Surgery
  • Otorhinolaryngology

Cite this

Whole-Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ. / Smith, Joshua; Kulkarni, Aditi; Birkeland, Andrew C.; McHugh, Jonathan B.; Brenner, J. Chad.

In: Otolaryngology - Head and Neck Surgery (United States), Vol. 159, No. 5, 01.11.2018, p. 859-865.

Research output: Contribution to journalArticle

@article{14a69265ba2d4f6487a31999481ac815,
title = "Whole-Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ",
abstract = "Objective: The pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole-exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC). Study Design: Case report and whole-exome sequencing of tumor DNA. Setting: Academic medical center. Subjects and Methods: A 52-year-old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole-exome genetic sequencing and copy-number variation (CNV) analysis of tumor and normal DNA extracted from flash-frozen, paraffin-embedded (FFPE) samples. Results: A total of 93 high-confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss-of-function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25-11.1, containing SOX4 and VEGFA, and 14q32.1-32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300. Conclusions: Small cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.",
keywords = "NOTCH, sinonasal SCC, SOX4",
author = "Joshua Smith and Aditi Kulkarni and Birkeland, {Andrew C.} and McHugh, {Jonathan B.} and Brenner, {J. Chad}",
year = "2018",
month = "11",
day = "1",
doi = "10.1177/0194599818774004",
language = "English (US)",
volume = "159",
pages = "859--865",
journal = "Otolaryngology - Head and Neck Surgery (United States)",
issn = "0194-5998",
publisher = "Mosby Inc.",
number = "5",

}

TY - JOUR

T1 - Whole-Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ

AU - Smith, Joshua

AU - Kulkarni, Aditi

AU - Birkeland, Andrew C.

AU - McHugh, Jonathan B.

AU - Brenner, J. Chad

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Objective: The pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole-exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC). Study Design: Case report and whole-exome sequencing of tumor DNA. Setting: Academic medical center. Subjects and Methods: A 52-year-old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole-exome genetic sequencing and copy-number variation (CNV) analysis of tumor and normal DNA extracted from flash-frozen, paraffin-embedded (FFPE) samples. Results: A total of 93 high-confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss-of-function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25-11.1, containing SOX4 and VEGFA, and 14q32.1-32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300. Conclusions: Small cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.

AB - Objective: The pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole-exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC). Study Design: Case report and whole-exome sequencing of tumor DNA. Setting: Academic medical center. Subjects and Methods: A 52-year-old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole-exome genetic sequencing and copy-number variation (CNV) analysis of tumor and normal DNA extracted from flash-frozen, paraffin-embedded (FFPE) samples. Results: A total of 93 high-confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss-of-function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25-11.1, containing SOX4 and VEGFA, and 14q32.1-32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300. Conclusions: Small cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.

KW - NOTCH

KW - sinonasal SCC

KW - SOX4

UR - http://www.scopus.com/inward/record.url?scp=85047426734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047426734&partnerID=8YFLogxK

U2 - 10.1177/0194599818774004

DO - 10.1177/0194599818774004

M3 - Article

C2 - 29734873

AN - SCOPUS:85047426734

VL - 159

SP - 859

EP - 865

JO - Otolaryngology - Head and Neck Surgery (United States)

JF - Otolaryngology - Head and Neck Surgery (United States)

SN - 0194-5998

IS - 5

ER -