Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations

Michele Simbolo, Stefano Barbi, Matteo Fassan, Andrea Mafficini, Greta Ali, Caterina Vicentini, Nicola Sperandio, Vincenzo Corbo, Borislav Rusev, Luca Mastracci, Federica Grillo, Sara Pilotto, Giuseppe Pelosi, Serena Pelliccioni, Rita T. Lawlor, Giampaolo Tortora, Gabriella Fontanini, Marco Volante, Aldo Scarpa, Emilio Bria

Research output: Contribution to journalArticle

Abstract

Introduction: DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature. Methods: Transcriptomic and genomic alterations were investigated by next-generation sequencing in a discovery set of 14 ACs and 14 LCNECs and validated on 21 ACs and 18 LCNECs by using custom gene panels and immunohistochemistry for Men1 and Rb1. Results: A 58-gene signature distinguished three transcriptional clusters. Cluster 1 comprised 20 LCNECs and one AC harboring concurrent inactivation of tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) in the absence of menin 1 gene (MEN1) mutations; all cases lacked Rb1 nuclear immunostaining. Cluster 3 included 20 ACs and four LCNECs lacking RB1 alterations and having frequent MEN1 (37.5%) and TP53 mutations (16.7%); menin nuclear immunostaining was lost in 75% of cases. Cluster 2 included 14 ACs and eight LCNECs showing intermediate features: TP53, 40.9%; MEN1, 22.7%; and RB1, 18.2%. Patients in cluster C1 had a shorter cancer-specific survival than did patients in C2 or C3. Conclusions: ACs and LCNECs comprise three different and clinically relevant molecular diseases, one AC-enriched group in which MEN1 inactivation plays a major role, one LCNEC-enriched group whose hallmark is RB1 inactivation, and one mixed group with intermediate molecular features. These data support a progression of malignancy that may be traced by using combined molecular and immunohistochemical analysis.

Original languageEnglish
JournalJournal of Thoracic Oncology
DOIs
Publication statusPublished - Jan 1 2019

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Neuroendocrine Carcinoma
Large Cell Carcinoma
Carcinoid Tumor
Gene Expression Profiling
Lung
Retinoblastoma Genes
p53 Genes
Gene Silencing
Genes
Neoplasms
Mutation
DNA Fingerprinting
Immunohistochemistry

Keywords

  • Atypical carcinoid
  • Gene expression profiling
  • Large cell neuroendocrine carcinoma
  • Lung neuroendocrine tumors
  • Next-generation sequencing
  • Transcriptomics

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations. / Simbolo, Michele; Barbi, Stefano; Fassan, Matteo; Mafficini, Andrea; Ali, Greta; Vicentini, Caterina; Sperandio, Nicola; Corbo, Vincenzo; Rusev, Borislav; Mastracci, Luca; Grillo, Federica; Pilotto, Sara; Pelosi, Giuseppe; Pelliccioni, Serena; Lawlor, Rita T.; Tortora, Giampaolo; Fontanini, Gabriella; Volante, Marco; Scarpa, Aldo; Bria, Emilio.

In: Journal of Thoracic Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Simbolo, Michele ; Barbi, Stefano ; Fassan, Matteo ; Mafficini, Andrea ; Ali, Greta ; Vicentini, Caterina ; Sperandio, Nicola ; Corbo, Vincenzo ; Rusev, Borislav ; Mastracci, Luca ; Grillo, Federica ; Pilotto, Sara ; Pelosi, Giuseppe ; Pelliccioni, Serena ; Lawlor, Rita T. ; Tortora, Giampaolo ; Fontanini, Gabriella ; Volante, Marco ; Scarpa, Aldo ; Bria, Emilio. / Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations. In: Journal of Thoracic Oncology. 2019.
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abstract = "Introduction: DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature. Methods: Transcriptomic and genomic alterations were investigated by next-generation sequencing in a discovery set of 14 ACs and 14 LCNECs and validated on 21 ACs and 18 LCNECs by using custom gene panels and immunohistochemistry for Men1 and Rb1. Results: A 58-gene signature distinguished three transcriptional clusters. Cluster 1 comprised 20 LCNECs and one AC harboring concurrent inactivation of tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) in the absence of menin 1 gene (MEN1) mutations; all cases lacked Rb1 nuclear immunostaining. Cluster 3 included 20 ACs and four LCNECs lacking RB1 alterations and having frequent MEN1 (37.5{\%}) and TP53 mutations (16.7{\%}); menin nuclear immunostaining was lost in 75{\%} of cases. Cluster 2 included 14 ACs and eight LCNECs showing intermediate features: TP53, 40.9{\%}; MEN1, 22.7{\%}; and RB1, 18.2{\%}. Patients in cluster C1 had a shorter cancer-specific survival than did patients in C2 or C3. Conclusions: ACs and LCNECs comprise three different and clinically relevant molecular diseases, one AC-enriched group in which MEN1 inactivation plays a major role, one LCNEC-enriched group whose hallmark is RB1 inactivation, and one mixed group with intermediate molecular features. These data support a progression of malignancy that may be traced by using combined molecular and immunohistochemical analysis.",
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author = "Michele Simbolo and Stefano Barbi and Matteo Fassan and Andrea Mafficini and Greta Ali and Caterina Vicentini and Nicola Sperandio and Vincenzo Corbo and Borislav Rusev and Luca Mastracci and Federica Grillo and Sara Pilotto and Giuseppe Pelosi and Serena Pelliccioni and Lawlor, {Rita T.} and Giampaolo Tortora and Gabriella Fontanini and Marco Volante and Aldo Scarpa and Emilio Bria",
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T1 - Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations

AU - Simbolo, Michele

AU - Barbi, Stefano

AU - Fassan, Matteo

AU - Mafficini, Andrea

AU - Ali, Greta

AU - Vicentini, Caterina

AU - Sperandio, Nicola

AU - Corbo, Vincenzo

AU - Rusev, Borislav

AU - Mastracci, Luca

AU - Grillo, Federica

AU - Pilotto, Sara

AU - Pelosi, Giuseppe

AU - Pelliccioni, Serena

AU - Lawlor, Rita T.

AU - Tortora, Giampaolo

AU - Fontanini, Gabriella

AU - Volante, Marco

AU - Scarpa, Aldo

AU - Bria, Emilio

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature. Methods: Transcriptomic and genomic alterations were investigated by next-generation sequencing in a discovery set of 14 ACs and 14 LCNECs and validated on 21 ACs and 18 LCNECs by using custom gene panels and immunohistochemistry for Men1 and Rb1. Results: A 58-gene signature distinguished three transcriptional clusters. Cluster 1 comprised 20 LCNECs and one AC harboring concurrent inactivation of tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) in the absence of menin 1 gene (MEN1) mutations; all cases lacked Rb1 nuclear immunostaining. Cluster 3 included 20 ACs and four LCNECs lacking RB1 alterations and having frequent MEN1 (37.5%) and TP53 mutations (16.7%); menin nuclear immunostaining was lost in 75% of cases. Cluster 2 included 14 ACs and eight LCNECs showing intermediate features: TP53, 40.9%; MEN1, 22.7%; and RB1, 18.2%. Patients in cluster C1 had a shorter cancer-specific survival than did patients in C2 or C3. Conclusions: ACs and LCNECs comprise three different and clinically relevant molecular diseases, one AC-enriched group in which MEN1 inactivation plays a major role, one LCNEC-enriched group whose hallmark is RB1 inactivation, and one mixed group with intermediate molecular features. These data support a progression of malignancy that may be traced by using combined molecular and immunohistochemical analysis.

AB - Introduction: DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature. Methods: Transcriptomic and genomic alterations were investigated by next-generation sequencing in a discovery set of 14 ACs and 14 LCNECs and validated on 21 ACs and 18 LCNECs by using custom gene panels and immunohistochemistry for Men1 and Rb1. Results: A 58-gene signature distinguished three transcriptional clusters. Cluster 1 comprised 20 LCNECs and one AC harboring concurrent inactivation of tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) in the absence of menin 1 gene (MEN1) mutations; all cases lacked Rb1 nuclear immunostaining. Cluster 3 included 20 ACs and four LCNECs lacking RB1 alterations and having frequent MEN1 (37.5%) and TP53 mutations (16.7%); menin nuclear immunostaining was lost in 75% of cases. Cluster 2 included 14 ACs and eight LCNECs showing intermediate features: TP53, 40.9%; MEN1, 22.7%; and RB1, 18.2%. Patients in cluster C1 had a shorter cancer-specific survival than did patients in C2 or C3. Conclusions: ACs and LCNECs comprise three different and clinically relevant molecular diseases, one AC-enriched group in which MEN1 inactivation plays a major role, one LCNEC-enriched group whose hallmark is RB1 inactivation, and one mixed group with intermediate molecular features. These data support a progression of malignancy that may be traced by using combined molecular and immunohistochemical analysis.

KW - Atypical carcinoid

KW - Gene expression profiling

KW - Large cell neuroendocrine carcinoma

KW - Lung neuroendocrine tumors

KW - Next-generation sequencing

KW - Transcriptomics

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