The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms
High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated fro...
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| Vydáno v: | Endocrine-related cancer Ročník 29; číslo 1; s. 1 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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England
01.01.2022
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| ISSN: | 1479-6821, 1479-6821 |
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| Abstract | High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments. |
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| AbstractList | High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments. High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments. |
| Author | Kersten, Christian Elvebakken, Hege Svensson, Johanna Garresori, Harrish Knappskog, Stian Nikolaienko, Oleksii Hofsli, Eva Venizelos, Andreas Hjortland, Geir Olav Detlefsen, Sönke Lothe, Inger Marie B Sorbye, Halfdan Couvelard, Anne Deng, Wei Perren, Aurel Sundlöv, Anna Krogh, Merete |
| Author_xml | – sequence: 1 givenname: Andreas surname: Venizelos fullname: Venizelos, Andreas organization: Department of Oncology, Haukeland University Hospital, Bergen, Norway – sequence: 2 givenname: Hege surname: Elvebakken fullname: Elvebakken, Hege organization: Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway – sequence: 3 givenname: Aurel surname: Perren fullname: Perren, Aurel organization: Institute of Pathology, University of Bern, Bern, Switzerland – sequence: 4 givenname: Oleksii orcidid: 0000-0002-5910-4934 surname: Nikolaienko fullname: Nikolaienko, Oleksii organization: Department of Oncology, Haukeland University Hospital, Bergen, Norway – sequence: 5 givenname: Wei surname: Deng fullname: Deng, Wei organization: Department of Oncology, Haukeland University Hospital, Bergen, Norway – sequence: 6 givenname: Inger Marie B surname: Lothe fullname: Lothe, Inger Marie B organization: Department of Pathology, Oslo University Hospital, Oslo, Norway – sequence: 7 givenname: Anne surname: Couvelard fullname: Couvelard, Anne organization: Department of Pathology, Université de Paris, Bichat Hospital, AP-HP, Paris, France – sequence: 8 givenname: Geir Olav surname: Hjortland fullname: Hjortland, Geir Olav organization: Department of Oncology, Oslo University Hospital, Oslo, Norway – sequence: 9 givenname: Anna surname: Sundlöv fullname: Sundlöv, Anna organization: Department of Medical Radiation Physics, Lund University, Lund, Sweden – sequence: 10 givenname: Johanna surname: Svensson fullname: Svensson, Johanna organization: Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden – sequence: 11 givenname: Harrish surname: Garresori fullname: Garresori, Harrish organization: Department of Oncology, Stavanger University Hospital, Stavanger, Norway – sequence: 12 givenname: Christian surname: Kersten fullname: Kersten, Christian organization: Department of Research, Hospital of Southern Norway, Kristiansand, Norway – sequence: 13 givenname: Eva surname: Hofsli fullname: Hofsli, Eva organization: Department of Oncology, St.Olavs Hospital, Trondheim, Norway – sequence: 14 givenname: Sönke surname: Detlefsen fullname: Detlefsen, Sönke organization: Department of Clinical Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark – sequence: 15 givenname: Merete surname: Krogh fullname: Krogh, Merete organization: Department of Oncology, Odense University Hospital, Odense, Denmark – sequence: 16 givenname: Halfdan surname: Sorbye fullname: Sorbye, Halfdan organization: Department of Clinical Science, University of Bergen, Bergen, Norway – sequence: 17 givenname: Stian surname: Knappskog fullname: Knappskog, Stian organization: Department of Oncology, Haukeland University Hospital, Bergen, Norway |
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| SubjectTerms | Carcinoma, Neuroendocrine - genetics Humans Intestinal Neoplasms - genetics Intestinal Neoplasms - pathology Neuroendocrine Tumors - genetics Neuroendocrine Tumors - pathology Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Proto-Oncogene Proteins B-raf Retinoblastoma-Binding Protein 2 Stomach Neoplasms - genetics Stomach Neoplasms - pathology |
| Title | The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms |
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