Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid

Clara Domingo‐Sabugo; Saffron AG Willis‐Owen; Amit Mandal; Anca Nastase; Sarah Dwyer; Cecilia Brambilla; José Héctor Gálvez; Qinwei Zhuang; Sanjay Popat; Robert Eveleigh; Markus Munter; Eric Lim; Andrew G Nicholson; G Mark Lathrop; William OC Cookson; Miriam F Moffatt

doi:10.1002/path.6352

journal article Open Access Sep 27, 2024

Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid

Saffron AG Willis‐Owen Amit Mandal Anca Nastase Sarah Dwyer Cecilia Brambilla José Héctor Gálvez Qinwei Zhuang Sanjay Popat

Robert Eveleigh Markus Munter Eric Lim

Andrew G Nicholson G Mark Lathrop William OC Cookson

Miriam F Moffatt

The Journal of Pathology Vol. 264 No. 3 pp. 332-343 · Wiley

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Abstract

AbstractLung carcinoids (L‐CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L‐CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L‐CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole‐exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L‐CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L‐CD‐PanC and L‐CD‐NeU. L‐CD‐PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion (p < 1 × 10−6). These tumours were centrally located and showed mutational signatures of activation‐induced deaminase/apolipoprotein B editing complex activity, together with genome‐wide DNA methylation loss enriched in repetitive elements (p = 2.2 × 10−16). By contrast, the L‐CD‐NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology (p = 0.04), peripheral location (p = 0.01), high mutational load (p = 2.17 × 10−4), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L‐CD‐NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid (p = 0.05), suggesting a possible environmental exposure in their pathogenesis. Immunologically, myeloid and T‐cell markers were enriched in L‐CD‐PanC and B‐cell markers in L‐CD‐NeU tumours. The substantial epigenetic and non‐coding differences between L‐CD‐PanC and L‐CD‐NeU open new possibilities for biomarker selection and targeted treatment of L‐CD. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Details

Published: Sep 27, 2024
Vol/Issue: 264(3)
Pages: 332-343
License: View

Authors

C

Clara Domingo‐Sabugo

National Heart and Lung Institute Imperial College London London UK

S

Saffron AG Willis‐Owen

National Heart and Lung Institute Imperial College London London UK

A

Amit Mandal

National Heart and Lung Institute Imperial College London London UK

A

Anca Nastase

National Heart and Lung Institute Imperial College London London UK

S

Sarah Dwyer

National Heart and Lung Institute Imperial College London London UK

C

Cecilia Brambilla

National Heart and Lung Institute Imperial College London London UK; Department of Histopathology, Royal Brompton and Harefield Hospitals Guy's and St Thomas’ NHS Foundation Trust London UK

J

José Héctor Gálvez

Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University Montréal QC Canada

Q

Qinwei Zhuang

Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University Montréal QC Canada

S

Sanjay Popat

Royal Marsden Hospital NHS Foundation Trust London and Surrey UK; The Institute of Cancer Research London UK

R

Robert Eveleigh

Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University Montréal QC Canada

M

Markus Munter

Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University Montréal QC Canada

E

Eric Lim

Department of Thoracic Surgery Royal Brompton Hospital London UK

A

Andrew G Nicholson

National Heart and Lung Institute Imperial College London London UK; Department of Histopathology, Royal Brompton and Harefield Hospitals Guy's and St Thomas’ NHS Foundation Trust London UK

G

G Mark Lathrop

Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University Montréal QC Canada

W

William OC Cookson

National Heart and Lung Institute Imperial College London London UK

M

Miriam F Moffatt

National Heart and Lung Institute Imperial College London London UK

Funding

Wellcome Trust Award: WT096964MA

Cite This Article

Clara Domingo‐Sabugo, Saffron AG Willis‐Owen, Amit Mandal, et al. (2024). Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid. The Journal of Pathology, 264(3), 332-343. https://doi.org/10.1002/path.6352

Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid

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