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Whole-genome landscape of pancreatic neuroendocrine tumours
Abstract
The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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“substitution signatures were dominated by C>A transversions in NpCpA or NpCpT contexts (Figures 2 and 3) previously associated with inactivation of the BER gene MUTYH [11].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [11]
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“Associations between clinicopathologic factors and genomic and proteomic signatures, however, remain poorly described and most large-scale studies have limited their focus on correlating DAXX/ATRX to prognostic variables [3, 4, 6, 7].”
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“We suggest NETs should be added to the diagnostic criteria for CS. Relevance Given these results, providers should be mindful that patients with CS are at an increased risk for development of NETs.”
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“A larger proportion of germline mutations are found in sporadic pancreatic neuroendocrine tumors (PanNETs) than in other NETs in genes such as the DNA repair genes MUTYH, CHEK2, and BRCA2, affecting processes such as chromatin remodeling, activation of mTOR signaling (including previously undescribed EWSR1 gene fusion…”
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“Mutations in the MEN1 , DAXX / ATRX , mTOR , MUTYH , and BRCA2 genes are closely related to the occurrence of pancreatic NETs (Jiao et al., 2011; Scarpa et al., 2017) and the heterozygosity loss of MEN1 gene was shown to induce diverse NETs in mice (Wong et al., 2020).”
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“Co-mutations of MEN1 and PTEN were observed in a small percentage of human PanNETs [170,171], suggesting that menin and Pten may function synergistically to suppress tumorigenesis.”
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“In addition, the mutational status of DAXX and ATRX is strongly correlated with the alternative lengthening of telomeres (ALT), with ALT emerging as a reliable indicator of increased risk of metastasis for primary pancreatic NETs, supporting its introduction in clinical practice (58).”
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“Transcriptome studies have identified at least three PanNET subtypes including one with potential clinical relevance, characterized by a metastasis like signature, in conjunction with increased tumor size, hypoxia, necroptosis and enhanced immune gene expression [ 5 , 15 , 18].”
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Whole genome sequencing of colorectal neuroendocrine tumors and in-depth mutational analyses
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Hasegawa, S., Kobayashi, N., Okubo, N., Tokuhisa, M., Goto, A., Kurita, Y., Sato, T., Hosono, K., Endo, I., Nakajima, A., et al. (2020) · Internal Medicine · doi:10.2169/internalmedicine.5648-20 · Cited by 6
“A previous genomic analysis classified NENs with a low tumor mutation burden and low MSI status as tumors with a cold-type immunoreaction (26).”
MethodDetjen, K. M., Otto, R., Giesecke, Y., Geisler, L. J., Riemer, P., Jann, H., Grötzinger, C., Sers, C., Pascher, A., Luedde, T., et al. (2021) · Cancers · doi:10.3390/cancers13174463 · Cited by 6
“To explore Flt3L mRNA expression in GEP-NEN at the transcriptome level, we identified publicly available datasets from 29 patients that could be used for transcriptomic analysis [8].”
BackgroundMethodMismatch repair deficiency and MUTYH variants in small intestine-neuroendocrine tumors
Helderman, N. C., Elsayed, F. A., van Wezel, T., Terlouw, D., Langers, A. M. J., van Egmond, D., Kilinç, G., Hristova, H., Sarasqueta, A. F., Morreau, H. M., et al. (2022) · Human Pathology · doi:10.1016/j.humpath.2022.04.003 · Cited by 6
Prognostic and Predictive Biomarkers for Pancreatic Neuroendocrine Tumors
Hackeng, W. M., Assi, H., Westerbeke, F. H. M., Brosens, L. A. A., & Heaphy, C. M. (2022) · Surgical pathology clinics · doi:10.1016/j.path.2022.05.007 · Cited by 6
Gaspar, T. B., Macedo, S., Sá, A., Soares, M. A., Rodrigues, D. F., Sousa, M., Mendes, N. M., Martins, R. S., Cardoso, L., Borges, I., et al. (2022) · Cancers · doi:10.3390/cancers14163865 · Cited by 6
Li, K., Liu, Y., Han, J.-G., Gui, J., & Zhang, X. (2022) · Endocrine Journal · doi:10.1507/endocrj.ej22-0262 · Cited by 6
Robb, T. J., Tsai, P., Fitzgerald, S. J., Shields, P., Houseman, P. S., Patel, R., Fan, V., Curran, B., Tse, R. D., Ting, J., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-22-0101 · Cited by 7
Mapelli, P., Bezzi, C., Muffatti, F., Ghezzo, S., Baldassi, F., Lena, M. S., Andreasi, V., Canevari, C., Magnani, P., COBELLI, F. D., et al. (2023) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-023-06210-7 · Cited by 6
“The role of DAXX/ATRX loss of expression as a negative prognostic factor for patients with PanNETs has been largely demonstrated [8, 22].”
BackgroundSelf-citationMetastatic insulinoma: exploration from clinicopathological signatures and genetic characteristics
Zhang, J., Jiang, R., Hong, X., Wu, H., Han, X., & Wu, W. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1109330 · Cited by 6
Kiesewetter, B., Melhorn, P., Macheiner, S., Wolff, L., Kretschmer‐Chott, E., Haug, A. R., Mazal, P. R., & Raderer, M. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13319 · Cited by 6
“In recent years, these findings have also been confirmed on a molecular level, as mutations of genes involved in the mTOR pathway have been detected in a subgroup (14% and 12%) of pancreatic NET patients.(12,13) Small intestinal (SI) NET sequencing studies disclosed actionable PI3K/Akt/mTOR pathway variances in 29% of…”
BackgroundLoss of Pkd1 limits susceptibility to colitis and colorectal cancer
Nikonova, A. S., Deneka, A. Y., Silva, F. N., Pirestani, S., Tricarico, R., Kiseleva, A. A., Zhou, Y., Nicolas, É., Flieder, D. B., Grivennikov, S. I., et al. (2023) · Oncogenesis · doi:10.1038/s41389-023-00486-y · Cited by 7
“A number of modi fi er genes have been recognized as in fl uencing CRC risk, tumor aggressiveness and response to therapy, and overall survival [4, 5].”
BackgroundBreaking point: the genesis and impact of structural variation in tumours
Ewing, A., & Semple, C. A. M. (2018) · F1000Research · doi:10.12688/f1000research.16079.1 · Cited by 6
Menin Associates With the Mitotic Spindle and Is Important for Cell Division
Sawicki, M. P., Gholkar, A. A., & Torres, J. Z. (2019) · Endocrinology · doi:10.1210/en.2019-00274 · Cited by 6
Perspective of neo-adjuvant/conversion and adjuvant therapy for pancreatic neuroendocrine tumors
Chen, L., & Chen, J. (2019) · Journal of Pancreatology · doi:10.1097/jp9.0000000000000023 · Cited by 6
Mutation Status in Yin Yang 1 Gene in X-ray–Induced Insulinoma Cell Line Rin-5F
Kiba, T. (2020) · Pancreas · doi:10.1097/mpa.0000000000001565 · Cited by 6
“Wholeexome sequencing has showed somatic MEN1mutation in 37% to 44% of nonfunctioning sporadic pancreatic neuroendocrine tumors.(1) Some researchers investigated that whole-exome sequencing studies of sporadic insulinomas found <2% with somatic MEN1mutation, but rather, they found a somatic heterozygous recurrent muta…”
BackgroundLuley, K. B., Gebauer, J., Gebauer, N., Tharun, L., Buchmann, I., Barkhausen, J., von Bubnoff, N. C. C., Lindner, K., Keck, T., Lehnert, H., et al. (2020) · Der Internist · doi:10.1007/s00108-020-00832-x · Cited by 6
Bai, R., Li, W., & Cui, J. (2022) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2022.0489 · Cited by 6
Gulde, S., Foscarini, A., April-Monn, S., Genio, E., Marangelo, A., Satam, S., Helbling, D., Falconi, M., Toledo, R. A., Schrader, J., et al. (2022) · Cancers · doi:10.3390/cancers14225481 · Cited by 6
“PI3K/AKT/mTOR pathway activation correlates with worse patient outcome [10].”
BackgroundSelf-citationKharade, S. S., Parekh, V. I., & Agarwal, S. K. (2018) · Endocrinology · doi:10.1210/en.2017-03155 · Cited by 6
Hayes, A. R., Furnace, M., Shah, R., Rundell, C., Muller, G., Dehbi, H., Luong, T. V., Toumpanakis, C., Caplin, M. E., Krell, D., et al. (2021) · Pancreas · doi:10.1097/mpa.0000000000001808 · Cited by 6
Leptomeningeal metastases of a well-differentiated neuroendocrine tumour: a rare entity
Versluis, J. M., Brandsma, D., van den Berg, J. G., & Tesselaar, M. E. T. (2018) · BMJ Case Reports · doi:10.1136/bcr-2018-226557 · Cited by 6
Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mCPreprint
Sanders, M., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., Hinai, A. A. A., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., et al. (2017) · bioRxiv · doi:10.1101/180588 · Cited by 6
Bräutigam, K., Straub, J., Bihi, A. K., Maire, R., Avanthay, S., Fillipova, K., Andreasi, V., Battistella, A., Kirchner, P., Dettmer, M. S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.31.635625 · Cited by 6
Self-citationWee, K., Yang, K., Schaeffer, D. F., Zhou, C., Leung, E. W., Feng, X., Laskin, J. J., Marra, M. A., Loree, J. M., & Gorski, S. M. (2025) · Scientific Reports · doi:10.1038/s41598-025-00549-7 · Cited by 6
“Biopsied specimens obtained from the patients supported the pathology of PanNENs in 10, six of which were previously described in detail 5,6 , PulNENs in seven, MTCs in three, and NENs of other PASs in the remaining 8 patients.”
InfluentialWhole-Exome Sequencing Reveals High Prevalence of Germline Alterations in Neuroendocrine Neoplasms
Sukrithan, V., Boateng, I., Liyanarachchi, S., Jain, P., Buss, J. L., Parwani, A. V., Shah, M. H., Das, K., Yearsley, M., Konda, B., et al. (2025) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2025.7035 · Cited by 5
Novel concepts of cell-of origin in neuroendocrine neoplasms
Marinoni, I., Avanthay, S., & Alcala, N. (2025) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-025-04311-2 · Cited by 5
“Indeed, based on CNVs, PanNETs can be divided into three groups [44, 45].”
Matrood, S., Melms, L., Bartsch, D. K., & Fazio, P. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043636 · Cited by 5
“The alterations of ATRX, DAXX, and MEN1 are the most frequent mutations in sporadic pNET [12,15].”
BackgroundWeich, A., Rogoll, D., Peschka, M. T., Weich, W., Pongracz, J. E., Brand, M., Fröhlich, M., Serfling, S. E., Rowe, S. P., Kosmala, A., et al. (2023) · Nuclear Medicine Communications · doi:10.1097/mnm.0000000000001666 · Cited by 5
The Role of PHLDA3 in Cancer Progression and Its Potential as a Therapeutic Target
Kamel, W., Krishnaraj, J., & Ohki, R. (2025) · Cancers · doi:10.3390/cancers17071069 · Cited by 5
“Building on the identification of PHLDA3 as a two-hit inactivated tumor suppressor in PanNETs, studies reported a connection between this gene and the tumor suppressor genes associated with multiple endocrine neoplasia type 1 ( MEN1 ) in these tumors [50–53].”
Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms
Pastorino, L., Grillo, F., Albertelli, M., Ghiorzo, P., & Bruno, W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910328 · Cited by 5
Cuny, T., van Koetsveld, P. M., Mondielli, G., Dogan, F., de Herder, W. W., Barlier, A., & Hofland, L. J. (2022) · Cancers · doi:10.3390/cancers14143481 · Cited by 5
“The rationale of its use in PNENs relies on the existence of overactivation of the mTOR signaling pathway in neuroendocrine tumoral cells [10,11].”
Background
Metadata
- Authors
- Initiative, A. P. C. G., Scarpa, A., Chang, D. K., Nones, K., Corbo, V., Patch, A.-M., Bailey, P., Lawlor, R. T., Johns, A. L., Miller, D. K., Mafficini, A., Rusev, B., Scardoni, M., Antonello, D., Barbi, S., Sikora, K. O., Cingarlini, S., Vicentini, C., McKay, S., Quinn, M. C. J., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., McLean, S., Nourse, C., Nourbakhsh, E., Wilson, P. J., Anderson, M. J., Fink, J. L., Newell, F., Waddell, N., Holmes, O., Kazakoff, S. H., Leonard, C., Wood, S., Xu, Q., Nagaraj, S. H., Amato, E., Dalai, I., Bersani, S., Cataldo, I., Dei Tos, A. P., Capelli, P., Davì, M. V., Landoni, L., Malpaga, A., Miotto, M., Whitehall, V. L. J., Leggett, B. A., Harris, J. L., Harris, J., Jones, M. D., Humphris, J., Chantrill, L. A., Chin, V., Nagrial, A. M., Pajic, M., Scarlett, C. J., Pinho, A., Rooman, I., Toon, C., Wu, J., Pinese, M., Cowley, M., Barbour, A., Mawson, A., Humphrey, E. S., Colvin, E. K., Chou, A., Lovell, J. A., Jamieson, N. B., Duthie, F., Gingras, M.-C., Fisher, W. E., Dagg, R. A., Lau, L. M. S., Lee, M., Pickett, H. A., Reddel, R. R., Samra, J. S., Kench, J. G., Merrett, N. D., Epari, K., Nguyen, N. Q., Zeps, N., Falconi, M., Simbolo, M., Butturini, G., Van Buren, G., Partelli, S., Fassan, M., Khanna, K. K., Gill, A. J., Wheeler, D. A., Gibbs, R. A., Musgrove, E. A., Bassi, C., Tortora, G., Pederzoli, P., Pearson, J. V., Waddell, N., Biankin, A. V., & Grimmond, S. M.
- Affiliations
- University of Verona (IT)
- Garvan Institute of Medical Research (AU)
- The University of Queensland (AU)
- Queensland University of Technology (AU)
- Glasgow Royal Infirmary (GB)
- Baylor College of Medicine (US)
- Children's Hospital at Westmead (AU)
- The University of Sydney (AU)
- Fremantle Hospital (AU)
- Royal Adelaide Hospital (AU)
- The University of Melbourne (AU)
- Corresponding author
- Scarpa, Aldo
- Biankin, Andrew V.
- Grimmond, Sean M.
- ORCID
- Scarpa, Aldo
- Chang, David K.
- Corbo, Vincenzo
- Patch, Ann-Marie
- Bailey, Peter
- Lawlor, Rita T.
- Johns, Amber L.
- Mafficini, Andrea
- Rusev, Borislav
- Antonello, Davide
- Barbi, Stefano
- Cingarlini, Sara
- Vicentini, Caterina
- Quinn, Michael C. J.
- Bruxner, Timothy J. C.
- Christ, Angelika N.
- Harliwong, Ivon
- Nourbakhsh, Ehsan
- Wilson, Peter J.
- Anderson, Matthew J.
- Fink, J. Lynn
- Newell, Felicity
- Holmes, Oliver
- Kazakoff, Stephen H.
- Leonard, Conrad
- Wood, Scott
- Nagaraj, Shivashankar Hiriyur
- Bersani, Samantha
- Cataldo, Ivana
- Davì, Maria Vittoria
- Landoni, Luca
- Malpaga, Anna
- Miotto, Marco
- Whitehall, Vicki L. J.
- Leggett, Barbara A.
- Harris, Jonathan
- Jones, Marc D.
- Chantrill, Lorraine A.
- Chin, Venessa
- Nagrial, Adnan M.
- Pajic, Marina
- Scarlett, Christopher J.
- Pinho, Andreia
- Rooman, Ilse
- Toon, Christopher
- Wu, Jianmin
- Pinese, Mark
- Cowley, Mark
- Barbour, Andrew
- Mawson, Amanda
- Colvin, Emily K.
- Chou, Angela
- Jamieson, Nigel B.
- Gingras, Marie-Claude
- Dagg, Rebecca A.
- Lau, Loretta M. S.
- Lee, Michael
- Pickett, Hilda A.
- Reddel, Roger R.
- Samra, Jaswinder S.
- Kench, James G.
- Merrett, Neil D.
- Nguyen, Nam Q.
- Zeps, Nikolajs
- Falconi, Massimo
- Simbolo, Michele
- Partelli, Stefano
- Fassan, Matteo
- Khanna, Kum Kum
- Gill, Anthony J.
- Wheeler, David A.
- Gibbs, Richard A.
- Bassi, Claudio
- Tortora, Giampaolo
- Pearson, John V.
- Waddell, Nicola
- Biankin, Andrew V.
- Grimmond, Sean M.
- Venue
- Nature
- Published
- 2017-02-15
- Volume
- 543
- Issue
- 7643
- Pages
- 65-71
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2589112207
- Cited by
- 999
- References
- 62
- Citations by year
- 2026: 65 · 2025: 101 · 2024: 103 · 2023: 110 · 2022: 126 · 2021: 108 · 2020: 131 · 2019: 89 · 2018: 103 · 2017: 52
- FWCI
- 81.15
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-09-27)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Pancreatic Cancer UK (RIF2015_A06_Jamieson, FLF2015_04_GLASGOW)
- Wellcome Trust (103721/Z/14/Z)
- Cancer Research UK (23526, 17263, 22533)
- Academy of Medical Sciences (AMS-SGCL9-Jamieson)
- Medical Research Council (MR/N005813/1)
- Topics
- Health Sciences › Medicine › Oncology › Neuroendocrine Tumor Research Advances
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- pancreatic neuroendocrine tumors, mutational signatures, MUTYH, germline mutations, CHEK2, BRCA2, MEN1, VHL, chromatin remodeling, DNA repair, mTOR signaling, telomere maintenance, hypoxia, carcinogenesis
- MeSH terms
- Base Sequence, Calmodulin-Binding Proteins, Chromosome Aberrations, DNA Mutational Analysis, DNA Repair, Female, Humans, Male, Pancreatic Neoplasms, Genome, Human, RNA-Binding Proteins, Telomere, Germ-Line Mutation, Carcinoma, Neuroendocrine, Genomics, RNA-Binding Protein EWS, Chromatin Assembly and Disassembly, DNA Glycosylases, DNA Copy Number Variations, TOR Serine-Threonine Kinases
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