Genetic intratumour heterogeneity in digestive high-grade neuroendocrine neoplasms.

Authors

Siren Morken, Halfdan Sorbye, Wei Deng, Hatice Toprak Dogramaci, Andreas Venizelos, Lene Weber Vestermark, Per Pfeiffer, Geir Olav Hjortland, Christian Kersten, Eva Hofsli, Hege Elvebakken, Anne Couvelard, Inger Marie Bowitz Lothe, Aurel Perren, Stian Knappskog

Published in

Journal of neuroendocrinology. Volume 38. Issue 10. Pages e70296.

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.

PMID:
42893790
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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