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Peer-reviewedCC BY-NC-NDJournal of neuroendocrinology

Genetic intratumour heterogeneity in digestive high-grade neuroendocrine neoplasms.

  • Siren Morken1,2
  • Halfdan Sorbye1,2
  • Wei Deng1,2
  • Hatice Toprak Dogramaci1,2
  • Andreas Venizelos2
  • Lene Weber Vestermark3
  • Per Pfeiffer4
  • Geir Olav Hjortland5
  • Christian Kersten6
  • Eva Hofsli7
  • Hege Elvebakken8
  • Anne Couvelard9
3 more authors
  • Inger Marie Bowitz Lothe10
  • Aurel Perren11
  • Stian Knappskog1,2
11 affiliations
  1. 1Cancer Clinic, Haukeland University Hospital, Bergen, Norway.
  2. 2Department of Clinical Science, University of Bergen, Bergen, Norway.
  3. 3Department of Oncology, University Hospital of Southern Denmark, Esbjerg, Denmark.
  4. 4Department of Oncology, Odense University Hospital, Odense, Denmark.
  5. 5Department of Oncology, Oslo University Hospital, Oslo, Norway.
  6. 6Department of Research, Hospital of Southern Norway, Kristiansand, Norway.
  7. 7Department of Oncology, St. Olavs Hospital, Trondheim, Norway.
  8. 8Department of Oncology, Ålesund Hospital, Møre og Romsdal Hospital Trust, Ålesund, Norway.
  9. 9Pathology Department, Bichat Hospital AP-HP and Université Paris Cité, Paris, France.
  10. 10Department of Pathology, Oslo University Hospital, Oslo, Norway.
  11. 11Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
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Abstract

Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and heterogeneous tumours with an aggressive biology and limited treatment efficacy. Genetic intratumour heterogeneity (ITH) is a mechanism of progression and treatment resistance in other cancers, yet unexplored in digestive HG-NEN. Next-generation sequencing with a 360-cancer gene panel was performed on 51 digestive HG-NEN, suitable for multiregional sampling. The mutational status of each sample within a patient was assessed to calculate an ITH-index, defined as the average number of discordant mutations across all pair-wise comparisons between samples. An ITH-index based on primary tumour samples was calculated for chemotherapy-naïve cases: 28 neuroendocrine carcinomas (NEC), 9 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) and 3 neuroendocrine tumour grade 3 (NET G3). Median ITH-index in NEC/MiNEN was 5, with a wide range (0-98.8). Greater heterogeneity was associated with right-sided colonic primaries (p = .005) and higher tumour mutational burden (r = 0.74, p < .001). Median overall survival was 7 months longer in NEC/MiNEN with median ITH-index above compared to below median (22.5 vs. 15.5 months, p = .077), driven mostly by patients with locoregional disease. Response to first-line chemotherapy was not influenced by median ITH-index. No heterogeneity was found among driver mutations in BRAF and KRAS. NET G3 displayed low heterogeneity (ITH-index 2-3). Higher ITH-index was not associated with shorter survival or treatment response, suggesting that genetic ITH is not the primary resistance mechanism in digestive NEC/MiNEN. Moving towards targeted treatment strategies, our data indicate that a single biopsy may underestimate ITH. BRAF and KRAS may be favourable targets as they displayed no heterogeneity.

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Cite

BibTeXRIS
BibTeX
@article{morken2026genetic,
  title = {{Genetic intratumour heterogeneity in digestive high-grade neuroendocrine neoplasms.}},
  author = {Siren Morken and Halfdan Sorbye and Wei Deng and Hatice Toprak Dogramaci and Andreas Venizelos and Lene Weber Vestermark and Per Pfeiffer and Geir Olav Hjortland and Christian Kersten and Eva Hofsli and Hege Elvebakken and Anne Couvelard and Inger Marie Bowitz Lothe and Aurel Perren and Stian Knappskog},
  journal = {Journal of neuroendocrinology},
  year = {2026},
  month = oct,
  doi = {10.1111/jne.70296},
  url = {https://europepmc.org/article/MED/42893790},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Genetic intratumour heterogeneity in digestive high-grade neuroendocrine neoplasms.
AU  - Siren Morken
AU  - Halfdan Sorbye
AU  - Wei Deng
AU  - Hatice Toprak Dogramaci
AU  - Andreas Venizelos
AU  - Lene Weber Vestermark
AU  - Per Pfeiffer
AU  - Geir Olav Hjortland
AU  - Christian Kersten
AU  - Eva Hofsli
AU  - Hege Elvebakken
AU  - Anne Couvelard
AU  - Inger Marie Bowitz Lothe
AU  - Aurel Perren
AU  - Stian Knappskog
PY  - 2026
DA  - 2026/10/01
JO  - Journal of neuroendocrinology
DO  - 10.1111/jne.70296
UR  - https://europepmc.org/article/MED/42893790
AB  - Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and heterogeneous tumours with an aggressive biology and limited treatment efficacy. Genetic intratumour heterogeneity (ITH) is a mechanism of progression and treatment resistance in other cancers, yet unexplored in digestive HG-NEN. Next-generation sequencing with a 360-cancer gene panel was performed on 51 digestive HG-NEN, suitable for multiregional sampling. The mutational status of each sample within a patient was assessed to calculate an ITH-index, defined as the average number of discordant mutations across all pair-wise comparisons between samples. An ITH-index based on primary tumour samples was calculated for chemotherapy-naïve cases: 28 neuroendocrine carcinomas (NEC), 9 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) and 3 neuroendocrine tumour grade 3 (NET G3). Median ITH-index in NEC/MiNEN was 5, with a wide range (0-98.8). Greater heterogeneity was associated with right-sided colonic primaries (p = .005) and higher tumour mutational burden (r = 0.74, p < .001). Median overall survival was 7 months longer in NEC/MiNEN with median ITH-index above compared to below median (22.5 vs. 15.5 months, p = .077), driven mostly by patients with locoregional disease. Response to first-line chemotherapy was not influenced by median ITH-index. No heterogeneity was found among driver mutations in BRAF and KRAS. NET G3 displayed low heterogeneity (ITH-index 2-3). Higher ITH-index was not associated with shorter survival or treatment response, suggesting that genetic ITH is not the primary resistance mechanism in digestive NEC/MiNEN. Moving towards targeted treatment strategies, our data indicate that a single biopsy may underestimate ITH. BRAF and KRAS may be favourable targets as they displayed no heterogeneity.
SN  - 0953-8194
SN  - 1365-2826
ER  -