Michele Simbolo1, Stefano Barbi1, Matteo Fassan2, Andrea Mafficini2, Greta Ali3, Caterina Vicentini4, Nicola Sperandio4, Vincenzo Corbo1, Borislav Rusev2, Luca Mastracci5, Federica Grillo5, Sara Pilotto6, Giuseppe Pelosi7, Serena Pelliccioni3, Rita T Lawlor2, Giampaolo Tortora8, Gabriella Fontanini3, Marco Volante9, Aldo Scarpa10, Emilio Bria11. 1. Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy. 2. ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. 3. Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, AOU Pisana, Pisa, Italy. 4. Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. 5. Department of Surgical and Diagnostic Sciences, University of Genoa and IRCCS S. Martino-IST University Hospital, Genoa, Italy. 6. Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. 7. Department of Oncology and Hemato-Oncology, University of Milan, and Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy. 8. Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Sacred Hearth Catholic University, Rome, Italy. 9. Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy. 10. Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. Electronic address: aldo.scarpa@univr.it. 11. Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Sacred Hearth Catholic University, Rome, Italy.
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.
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.
Authors: Aurélie A G Gabriel; Emilie Mathian; Lise Mangiante; Catherine Voegele; Vincent Cahais; Akram Ghantous; James D McKay; Nicolas Alcala; Lynnette Fernandez-Cuesta; Matthieu Foll Journal: Gigascience Date: 2020-10-30 Impact factor: 6.524
Authors: B C M Hermans; J L Derks; H J M Groen; J A Stigt; R J van Suylen; L M Hillen; E C van den Broek; E J M Speel; A-M C Dingemans Journal: Endocr Connect Date: 2019-12 Impact factor: 3.335