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Mavroeidis L, Kalofonou F, Casey R, Napolitano A, Bulusu R, Jones RL. Identifying and managing rare subtypes of gastrointestinal stromal tumors. Expert Rev Gastroenterol Hepatol 2025; 19:549-561. [PMID: 40156874 DOI: 10.1080/17474124.2025.2486304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/23/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
INTRODUCTION A subset of gastrointestinal stromal tumors (GISTs) lacks the common mutations in KIT/PDGFRa genes. This is a rare and heterogeneous group of challenging GISTs due to their diversity and absence of sensitivity to the tyrosine kinase inhibitor (TKI) imatinib. AREAS COVERED In this manscript, we review the pathogenesis, natural history, diagnostic features and management of KIT/PDGFRa wild-type (WT) GISTs, including SDH-deficient GISTs, GISTs with mutations in the RAS/RAF pathway, and quadruple WT GISTs which lack mutations in either KIT/PDGFRa and SDH genes or components of the RAS/RAF pathway, and syndromic GISTs as well as GISTs with rare KIT/PDGFRa mutations. EXPERT OPINION Patients should be managed in reference centers. There has been progress in the understanding of the biology of these GISTs, and promising therapeutic targets have been identified. In SDH-deficient GISTs, the TKI olverembatinib has shown encouraging clinical activity but requires further clinical validation, while the HIF2a inhibitor bezultifan and temozolomide alone or in combination with the death receptor agonist 5 are under clinical investigation. Targeting the RAS/RAF pathway in RAS/RAF-mutated GISTs warrants evaluation in clinical trials. Rare molecular alterations in quadruple WT GISTs require investigation for their oncogenic potential. Collaborative research and patient advocacy is critical for these extremely rare tumors.
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Affiliation(s)
- Leonidas Mavroeidis
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
- Department of Oncology, Oxford University Hospitals, Oxford, UK
| | - Foteini Kalofonou
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ruth Casey
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ramesh Bulusu
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Robin L Jones
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
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Kővári BP, Lauwers GY. Mesenchymal Tumors of the Tubular Gastrointestinal Tract (Non-GIST): The GI Pathologist's Approach. Adv Anat Pathol 2025; 32:110-131. [PMID: 39588681 DOI: 10.1097/pap.0000000000000469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Mesenchymal neoplasms of the gastrointestinal tract are rare compared with epithelial lesions. However, over the past few decades, the increasing volume of gastrointestinal endoscopy has expedited the recognition of several novel entities with varying clinical significance. Its spectrum extends from reactive changes and benign neoplasms to highly aggressive sarcomas. At the malignant end of the spectrum, the importance of correctly diagnosing these tumors is underscored by the specific therapeutic implications available for some tumor types (eg, tyrosine kinase inhibitors for gastrointestinal stromal tumors) that allow personalized treatments. Benign lesions frequently surface among routine polypectomy specimens, sometimes offering diagnostic challenges. However, precise classification is the only way to avoid prognostic uncertainty and overtreatment, and to recognize possible syndromic associations. Hereby, we offer a pragmatic review of the topic from the gastrointestinal pathologist's perspective, who, although more accustomed to epithelial neoplasms, can use an algorithmic approach to diagnose mesenchymal entities successfully.
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Affiliation(s)
- Bence P Kővári
- Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA
| | - Gregory Y Lauwers
- Department of Pathology, Henry Lee Moffitt Cancer Center & Research Institute, Tampa, FL
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Nigro MC, Marchetti A, Fumagalli ER, De Luca I, Bertuzzi AF, Grimaudo MS, Grignani G, D’Ambrosio L, Merlini A, Badalamenti G, Incorvaia L, Dimino A, Gasperoni S, Vincenzi B, Fanti S, Di Federico A, Campana D, Pantaleo MA, Nannini M. 18F-Fluorodeoxyglucose Uptake in PDGFRA-Mutant Gastrointestinal Stromal Tumors. JAMA Netw Open 2025; 8:e2456058. [PMID: 39853981 PMCID: PMC11762236 DOI: 10.1001/jamanetworkopen.2024.56058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/15/2024] [Indexed: 01/26/2025] Open
Abstract
Importance The D842V platelet-derived growth factor receptor α (PDGFRA) mutation identifies a molecular subgroup of gastrointestinal stromal tumors (GISTs), primarily resistant to standard tyrosine kinase inhibitors and with an overall more indolent behavior. Although functional imaging with 18F-fluorodeoxyglucose-labeled positron emission tomography ([18F]FDG-PET) plays a proven role in GISTs, especially in early assessment of tumor response, less is known about [18F]FDG uptake according to the GIST molecular subtypes. Objective To evaluate the degree of [18F]FDG uptake in PDGFRA-mutant GISTs and better define the role of functional imaging in this rare and peculiar subset of GISTs. Design, Setting, and Participants This multi-institutional retrospective cohort study involving 7 GIST reference centers in Italy included patients with PDGFRA-mutant GIST who underwent [18F]FDG-PET from January 1, 2000, to December 31, 2023. Data on the maximum standardized uptake value (SUVmax) of primary tumor or metastatic disease were collected. Exposure PDGFRA-mutant GIST and [18F]FDG-PET. Main Outcome and Measure The primary outcome was the degree of [18F]FDG uptake of PDGFRA-mutant GISTs, with a focus on the D842V-mutant subgroup. Secondary objectives were to assess the association between the degree of [18F]FDG uptake and main clinicopathologic features. Results A total of 71 patients with PDGFRA-mutant GISTs were included in the analysis: 37 (52.1%) in the D842V subgroup (group A) and 34 (47.9%) in the non-D842V subgroup (group B). Additionally, 70 patients with KIT exon 11-mutant GIST served as a control group (group C). For all 141 participants, the median age at diagnosis was 59 (range, 26-89) years, and 81 patients (57.4%) were male. Overall, the median SUVmax was 4.4 (IQR, 0-10.1), while the median SUVmax for group A was 0 (IQR, 0-3.2); for group B, 3.6 (IQR, 0-5.1); and for group C, 10.1 (IQR, 5.1-13.9). The median SUVmax of PDGFRA-mutant GISTs was significantly lower than the median value of KIT exon 11-mutant GISTs (0 [IQR, 0-4.3] vs 10.1 [IQR, 5.1-14.0]; P < .001). Median [18F]FDG uptake was significantly lower in the D842V subgroup compared with the non-D842V subgroup (0 [IQR, 0-3.2] vs 3.6 [IQR, 0-5.1]; P = .02). Moreover, the triad of gastric primary tumor, tumor size greater than 10 cm, and SUVmax of 5.75 or less was associated with identification of PDGFRA-mutant GISTs. Conclusions and Relevance In this cohort study of patients with PDGFRA-mutant GISTs, the D842V-mutant GISTs were associated with an overall lower [18F]FDG uptake compared with other GIST subgroups. Therefore, the role of functional imaging with [18F]FDG-PET in this subset of GISTs may be limited and should be further explored for its potential prognostic and predictive value.
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Affiliation(s)
- Maria Concetta Nigro
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Marchetti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Elena Rosa Fumagalli
- Medical Oncology Unit 2, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale dei Tumori, Milano, Italy
| | - Ida De Luca
- Medical Oncology Unit 2, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale dei Tumori, Milano, Italy
| | - Alexia Francesca Bertuzzi
- Department of Medical Oncology, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Maria Susanna Grimaudo
- Department of Medical Oncology, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Giovanni Grignani
- Department of Medical Oncology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Torino, Italy
- Candiolo Cancer Institute, Fondazione del Piemonte–IRCCS, Candiolo (Turin), Turin, Italy
| | - Lorenzo D’Ambrosio
- Department of Medical Oncology, University of Turin, Turin, Italy
- Azienda Ospedaliera Universitaria San Luigi Gonzaga University Hospital, Orbassano, Italy
| | - Alessandra Merlini
- Candiolo Cancer Institute, Fondazione del Piemonte–IRCCS, Candiolo (Turin), Turin, Italy
- Department of Medical Oncology, University of Turin, Turin, Italy
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Lorena Incorvaia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Alessandra Dimino
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Silvia Gasperoni
- Department of Oncology, Clinical Oncology Unit, University Hospital Careggi, Firenze, Italy
| | - Bruno Vincenzi
- Department of Medical Oncology, Campus Biomedico University of Rome, Rome, Italy
| | - Stefano Fanti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Nuclear Medicine, IRCCS, Azienda Ospedaliero Universitaria Di Bologna, Bologna, Italy
| | | | - Davide Campana
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Department of Medical Oncology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Department of Medical Oncology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
| | - Margherita Nannini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Department of Medical Oncology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
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Xie Z, Zhang Q, Zhang R, Zhao Y, Zhang W, Song Y, Yu D, Lin J, Li X, Suo S, Zhou Y. Identification of D842V mutation in gastrointestinal stromal tumors based on CT radiomics: a multi-center study. Cancer Imaging 2024; 24:169. [PMID: 39707515 DOI: 10.1186/s40644-024-00815-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Recent advent of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of GIST patients. However, responses to TKI therapy can vary depending on the specific gene mutation. D842V, which is the most common mutation in platelet-derived growth factor receptor alpha exon 18, shows no response to imatinib and sunitinib. Radiomics features based on venous-phase contrast-enhanced computed tomography (CECT) have shown potential in non-invasive prediction of GIST genotypes. This study sought to determine whether radiomics features could help distinguish GISTs with D842V mutations. METHODS A total of 872 pathologically confirmed GIST patients with CECT data available from three independent centers were included and divided into the training cohort ( n = 487 ) and the external validation cohort ( n = 385 ). Clinical features including age, sex, tumor size and location were collected. Radiomics features on the largest axial image of venous-phase CECT were analyzed and a total of two radiomics features were selected after feature selection. Random forest models trained on non-radiomics features only (the non-radiomics model) and on both non-radiomics and radiomics features (the combined model) were compared. RESULTS The combined model showed better average precision (0.250 vs. 0.102, p = 0.039) and F1 score (0.253 vs. 0.155, p = 0.012) than the non-radiomics model. There was no significant difference in ROC-AUC (0.728 vs. 0.737, p = 0.836) and geometric mean (0.737 vs. 0.681, p = 0.352). CONCLUSIONS This study demonstrated the potential of radiomics features based on venous-phase CECT images to identify D842V mutation in GISTs. Our model may provide an alternative approach to guide TKI therapy for patients inaccessible to sequence variant testing, potentially improving treatment outcomes for GIST patients especially in resource-limited settings.
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Affiliation(s)
- Zhenhui Xie
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Pudong District, 200127, Shanghai, China
| | - Qingwei Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Pujian Road 160, Pudong District, 200127, Shanghai, China
| | - Ranying Zhang
- Department of Radiology, Zhongshan Hospital, Fudan University, and Shanghai Institute of Medical Imaging, 108 Fenglin Road, 200032, Shanghai, China
| | - Yuxuan Zhao
- Department of Radiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China
| | - Wang Zhang
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Pudong District, 200127, Shanghai, China
| | - Yang Song
- MR Research Collaboration Team, Siemens Healthineers Ltd., 399 Haiyang West Road, 200126, Shanghai, China
| | - Dexin Yu
- Department of Radiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China.
| | - Jiang Lin
- Department of Radiology, Zhongshan Hospital, Fudan University, and Shanghai Institute of Medical Imaging, 108 Fenglin Road, 200032, Shanghai, China.
| | - Xiaobo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Pujian Road 160, Pudong District, 200127, Shanghai, China.
| | - Shiteng Suo
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Pudong District, 200127, Shanghai, China.
| | - Yan Zhou
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Pudong District, 200127, Shanghai, China.
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Wang XK, Shen LF, Yang X, Su H, Wu T, Tao PX, Lv HY, Yao TH, Yi L, Gu YH. Two different mutational types of familial gastrointestinal stromal tumors: Two case reports. World J Gastrointest Oncol 2024; 16:4028-4036. [PMID: 39350996 PMCID: PMC11438775 DOI: 10.4251/wjgo.v16.i9.4028] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/03/2024] [Accepted: 07/19/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and cases of GISTs tend to be of the disseminated type, with a global incidence of 10 to 15 cases/million each year. The rarer familial GISTs, which often represent a population, differ in screening, diagnosis, and treatment. Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs. However, whether the same genetic family has different phenotypes has not been reported. CASE SUMMARY We report two cases of rare GISTs in the same family: A male patient with the V561D mutation in exon 12 of the PDGFRA gene, who has been taking the targeted drug imatinib since undergoing surgery, and a female patient diagnosed with wild-type GIST, who has been taking imatinib for 3 years since undergoing surgery. The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy, and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease. CONCLUSION Different mutation types of familial GISTs in the same family are very rare, thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.
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Affiliation(s)
- Xiao-Ke Wang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Lu-Fan Shen
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Xin Yang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - He Su
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Tao Wu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Peng-Xian Tao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hong-Ying Lv
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Tong-Han Yao
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Lin Yi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yuan-Hui Gu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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Ali RH, Alsaber AR, Mohanty AK, Alnajjar A, Mohammed EMA, Alateeqi M, Jama H, Almarzooq A, Benobaid N, Alqallaf Z, Ahmed AA, Bahzad S, Alkandari M. Molecular Profiling of KIT/PDGFRA-Mutant and Wild-Type Gastrointestinal Stromal Tumors (GISTs) with Clinicopathological Correlation: An 18-Year Experience at a Tertiary Center in Kuwait. Cancers (Basel) 2024; 16:2907. [PMID: 39199677 PMCID: PMC11352935 DOI: 10.3390/cancers16162907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of KIT, PDGFRA, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15-91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: KIT (61%), PDGFRA (25%), NF1 (2%), and one NTRK1 rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5-8.0) (p = 0.018), with mitosis ≤5/5 mm2, and were of lower risk (p = 0.019). KIT mutations were an adverse indicator of disease progression (p = 0.049), while wild-type status did not significantly impact progression (p = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants.
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Affiliation(s)
- Rola H. Ali
- Department of Pathology, College of Medicine, Kuwait University, Safat 13110, Kuwait
- Histopathology Laboratory, Sabah Hospital, Sabah Medical District, Safat 13001, Kuwait
| | - Ahmad R. Alsaber
- Department of Management, College of Business and Economics, American University of Kuwait, Safat 13034, Kuwait;
| | - Asit K. Mohanty
- Department of Medical Oncology, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (A.K.M.); (A.A.)
| | - Abdulsalam Alnajjar
- Department of Medical Oncology, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (A.K.M.); (A.A.)
| | - Eiman M. A. Mohammed
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Mona Alateeqi
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Hiba Jama
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Ammar Almarzooq
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Noelle Benobaid
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Zainab Alqallaf
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Amir A. Ahmed
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Shakir Bahzad
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Mohammad Alkandari
- Histopathology Laboratory, Farwaniya Hospital, Sabah Al Nasser Area 92426, Kuwait;
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Khaled I, Hafez Mousa A, Yasir Nukaly H, Mohammed Zubair MT, Alsharif MH, Abujamai JZ, Ahmed RA, Alklani T, Ennab F. Hybrid surgical approach excision of gastrointestinal stromal tumor (GIST): A case report of GIST at an unusual location and review of the literature. Clin Case Rep 2024; 12:e8778. [PMID: 38659501 PMCID: PMC11039485 DOI: 10.1002/ccr3.8778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 02/02/2024] [Accepted: 03/27/2024] [Indexed: 04/26/2024] Open
Abstract
Gastrointestinal stromal tumors are the most common malignant subepithelial lesions involving the gastrointestinal tract. Surgical techniques have been the mainstay of treatment, however, in recent times hybrid surgeries are being introduced yielding better clinical outcomes.
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Affiliation(s)
- Islam Khaled
- Department of SurgerySaudi German HospitalsJeddahSaudi Arabia
- Department of Surgery, Faculty of MedicineSuez Canal University HospitalsIsmailiaEgypt
| | - Ahmed Hafez Mousa
- Department of SurgerySaudi German HospitalsJeddahSaudi Arabia
- College of Medicine and SurgeryBatterjee Medical CollegeJeddahSaudi Arabia
| | | | | | | | | | - Ruqayyah Ali Ahmed
- College of Medicine and SurgeryBatterjee Medical CollegeJeddahSaudi Arabia
| | | | - Farah Ennab
- College of MedicineMohammed Bin Rashid University of Medicine and Health SciencesDubaiUnited Arab Emirates
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Adle-Biassette H, Ricci R, Martin A, Martini M, Ravegnini G, Kaci R, Gélébart P, Poirot B, Sándor Z, Lehman-Che J, Tóth E, Papp B. Sarco/endoplasmic reticulum calcium ATPase 3 (SERCA3) expression in gastrointestinal stromal tumours. Pathology 2024; 56:343-356. [PMID: 38184384 DOI: 10.1016/j.pathol.2023.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/18/2023] [Indexed: 01/08/2024]
Abstract
Accurate characterisation of gastrointestinal stromal tumours (GIST) is important for prognosis and the choice of targeted therapies. Histologically the diagnosis relies on positive immunostaining of tumours for KIT (CD117) and DOG1. Here we report that GISTs also abundantly express the type 3 Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA3). SERCA enzymes transport calcium ions from the cytosol into the endoplasmic reticulum and play an important role in regulating the intensity and the periodicity of calcium-induced cell activation. GISTs from various localisations, histological and molecular subtypes or risk categories were intensely immunopositive for SERCA3 with the exception of PDGFRA-mutated cases where expression was high or moderate. Strong SERCA3 expression was observed also in normal and hyperplastic interstitial cells of Cajal. Decreased SERCA3 expression in GIST was exceptionally observed in a zonal pattern, where CD117 staining was similarly decreased, reflecting clonal heterogeneity. In contrast to GIST, SERCA3 immunostaining of spindle cell tumours and other gastrointestinal tumours resembling GIST was negative or weak. In conclusion, SERCA3 immunohistochemistry may be useful for the diagnosis of GIST with high confidence, when used as a third marker in parallel with KIT and DOG1. Moreover, SERCA3 immunopositivity may be particularly helpful in cases with negative or weak KIT or DOG1 staining, a situation that may be encountered de novo, or during the spontaneous or therapy-induced clonal evolution of GIST.
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Affiliation(s)
- Homa Adle-Biassette
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, and Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France; INSERM NeuroDiderot, DMU DREAM, France
| | - Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy; UOC di Anatomia Patologica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Rome, Italy
| | - Antoine Martin
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Paris, France; Inserm UMR U978, Université Sorbonne Paris Nord, Alliance Sorbonne Paris Cité, Labex Inflamex, Bobigny, France
| | - Maurizio Martini
- Dipartimento di patologia umana dell'adulto e dell'età evolutiva 'Gaetano Barresi' Azienda Ospedaliera Universitaria Policlinico 'G. Martino', Messina, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy
| | - Rachid Kaci
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, and Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
| | - Pascal Gélébart
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Brigitte Poirot
- Molecular Oncology Unit, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Zsuzsanna Sándor
- Department of Pathology, National Institute of Oncology, Budapest, Hungary
| | - Jacqueline Lehman-Che
- Molecular Oncology Unit, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR U976, Hôpital Saint-Louis, Paris, France; Institut de Recherche Saint-Louis, Université de Paris, France
| | - Erika Tóth
- Department of Pathology, National Institute of Oncology, Budapest, Hungary
| | - Bela Papp
- INSERM UMR U976, Hôpital Saint-Louis, Paris, France; Institut de Recherche Saint-Louis, Université de Paris, France; CEA, DRF-Institut Francois Jacob, Department of Hemato-Immunology Research, Hôpital Saint-Louis, Paris, France.
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9
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Thirasastr P, Sutton TL, Joseph CP, Lin H, Amini B, Mayo SC, Araujo D, Benjamin RS, Conley AP, Livingston JA, Ludwig J, Patel S, Ratan R, Ravi V, Zarzour MA, Nassif Haddad EF, Nakazawa MS, Zhou X, Heinrich MC, Somaiah N. Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter? Cancers (Basel) 2024; 16:904. [PMID: 38473266 PMCID: PMC10931337 DOI: 10.3390/cancers16050904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.
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Affiliation(s)
- Prapassorn Thirasastr
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Thomas L. Sutton
- Division of Surgical Oncology, OHSU Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA; (T.L.S.)
| | - Cissimol P. Joseph
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Heather Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Behrang Amini
- Department of Musculoskeletal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Skye C. Mayo
- Division of Surgical Oncology, OHSU Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA; (T.L.S.)
| | - Dejka Araujo
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Robert S. Benjamin
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Anthony P. Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - John A. Livingston
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Joseph Ludwig
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Shreyaskumar Patel
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Ravin Ratan
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Maria A. Zarzour
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Elise F. Nassif Haddad
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Michael S. Nakazawa
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Xiao Zhou
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
| | - Michael C. Heinrich
- Cell and Developmental Biology, OHSU Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA;
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.T.); (C.P.J.); (D.A.); (R.S.B.); (A.P.C.); (J.A.L.); (J.L.); (S.P.); (R.R.); (V.R.); (M.A.Z.); (E.F.N.H.); (M.S.N.); (X.Z.)
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10
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Mirovic M, Stojanovic MD, Jovanovic M, Stankovic V, Milosev D, Zdravkovic N, Milosevic B, Cvetkovic A, Spasic M, Vekic B, Jovanovic I, Stojanovic BS, Petrovic M, Bogut A, Peulic M, Stojanovic B. Exploring Perforated Jejunal GIST: A Rare Case Report and Review of Molecular and Clinical Literature. Curr Issues Mol Biol 2024; 46:1192-1207. [PMID: 38392194 PMCID: PMC10887764 DOI: 10.3390/cimb46020076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/13/2024] [Accepted: 01/24/2024] [Indexed: 02/24/2024] Open
Abstract
This case report details a rare instance of a perforated jejunal gastrointestinal stromal tumor (GIST) in a 76-year-old female patient. The patient presented with acute abdominal pain and distension without any changes in bowel habits or episodes of nausea and vomiting. Initial diagnostics, including abdominal plain radiography and ultrasonography, were inconclusive; however, a computed tomography (CT) scan revealed pneumoperitoneum and an irregular fluid collection suggestive of small intestine perforations. Surgical intervention uncovered a 35 mm jejunal GIST with a 10 mm perforation. Histopathological examination confirmed a mixed cell type GIST with high malignancy potential, further substantiated by immunohistochemistry markers CD117, DOG1, and vimentin. Molecular analysis illuminated the role of key oncogenes, primarily KIT and PDGFRA mutations, emphasizing the importance of molecular diagnostics in GIST management. Despite the severity of the presentation, the patient's postoperative recovery was favorable, highlighting the effectiveness of prompt surgical and multidisciplinary approaches in managing complex GIST cases.
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Affiliation(s)
- Milos Mirovic
- Department of General Surgery, Clinical Hospital Center Kotor, 85330 Kotor, Montenegro
| | - Milica Dimitrijevic Stojanovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Department of Pathology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Marina Jovanovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Vesna Stankovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Department of Pathology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Danijela Milosev
- Department of Pathology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Natasa Zdravkovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Bojan Milosevic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Aleksandar Cvetkovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marko Spasic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Berislav Vekic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Ivan Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Bojana S Stojanovic
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marko Petrovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Ana Bogut
- City Medical Emergency Department, 11000 Belgrade, Serbia
| | - Miodrag Peulic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Bojan Stojanovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
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11
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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12
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Wang C, Yantiss RK, Lieberman MD, Tubito-Massarano F, Qin L, Yemelyanova A, Solomon JP, Hissong E. A Rare PDGFRA Exon 15 Germline Mutation Identified in a Patient With Phenotypic Manifestations Concerning for GIST-Plus Syndrome: A Case Report and Review of Literature. Int J Surg Pathol 2023; 31:1139-1145. [PMID: 36802986 DOI: 10.1177/10668969231152588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Molecular alterations in PDGFRA are well-described as drivers of sporadic gastrointestinal stromal tumors (GISTs) and inflammatory fibroid polyps (IFPs). However, a small number of families with germline PDGFRA mutations in exons 12, 14, and 18 have been reported, forming the basis of an autosomal dominant inherited disorder with incomplete penetrance and variable expressivity, now referred to as PDGFRA-mutant syndrome or GIST-plus syndrome. Phenotypic manifestations of this rare syndrome include multiple gastrointestinal GISTS, IFPs, fibrous tumors, and other variable features. Herein, we report the case of a 58-year-old female who presented with a gastric GIST and numerous small intestinal IFPs, found to harbor a previously undescribed germline PDGFRA exon 15 p.G680R mutation. Somatic tumor testing was performed on the GIST, a duodenal IFP, and an ileal IFP utilizing a targeted next-generation sequencing panel, revealing additional and distinct secondary PDGFRA exon 12 somatic mutations in each of the 3 tumors. Our findings raise important considerations regarding mechanisms of tumor development in patients with underlying germline PDGFRA alterations and highlight the potential utility of expanding currently available germline and somatic testing panels to include exons outside the typical hotspot regions.
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Affiliation(s)
- Chiyun Wang
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | | | - Lihui Qin
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Anna Yemelyanova
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - James P Solomon
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Erika Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
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13
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Watkins JA, Hatcher H, Malhotra S, Amen F, Bruty J, Trotman J, Tarpey P, Tadross JA. Identification of an Activating PDGFRA Deletion in a Novel Sinonasal Soft Tissue Neoplasm. Head Neck Pathol 2023; 17:576-580. [PMID: 36723852 PMCID: PMC10293132 DOI: 10.1007/s12105-023-01526-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/07/2023] [Indexed: 02/02/2023]
Abstract
BACKGROUND Spindle cell tumours in the sinonasal area are diagnostically challenging. We identified a neoplasm that defied histopathological classification using current criteria. METHODS The case was subjected to histopathological, immunohistochemical and molecular analysis using a large small variant DNA panel. RESULTS The tumour comprised cytologically bland epithelioid spindle cells with a rich vasculature, which lack expression of actin and other smooth muscle markers, CD34 and beta-catenin. An activating insertion/deletion in exon 12 of the PDGFRA gene was detected. This alteration has previously been described in gastrointestinal stromal tumours and inflammatory fibroid polyps of the GI tract, but the site, histological, and immunophenotypic features in this tumour are distinct. CONCLUSION We describe a novel sinonasal spindle cell tumour characterised by an activating insertion/deletion in exon 12 of PDGFRA. The diagnosis of PDGFRA-activated sinonasal spindle cell tumour should be considered in difficult to classify mesenchymal lesions at this site.
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Affiliation(s)
- James A. Watkins
- Department of Histopathology, Level 5, Laboratory Block, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ UK
- Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Helen Hatcher
- Department of Oncology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Shalini Malhotra
- Department of Histopathology, Level 5, Laboratory Block, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ UK
| | - Furrat Amen
- Department of Surgery, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Jonathan Bruty
- Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Jamie Trotman
- Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Patrick Tarpey
- Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - John A. Tadross
- Department of Histopathology, Level 5, Laboratory Block, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ UK
- Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
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14
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Wu Y, Gao B, Xia Q, Zhu Y, Wang N, Chang X, Huang B, Luo D, Zhang J, Zhang P, Shi H, Fan J, Nie X. Anaplastic lymphoma kinase expression in PDGFRA-mutated gastrointestinal stromal tumors probably correlates with poor prognosis. World J Surg Oncol 2023; 21:138. [PMID: 37120571 PMCID: PMC10148552 DOI: 10.1186/s12957-023-03019-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/23/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). METHODS A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. RESULTS Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA-mutant GISTs (7.7%, 4/52) but negative for c-KIT-mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. CONCLUSION Our study revealed 7.7% (4/52) of ALK expression in PDGFRA-mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA-mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.
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Affiliation(s)
- Ying Wu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Beibei Gao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Qin Xia
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Yili Zhu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Na Wang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Xiaona Chang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Bo Huang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Danju Luo
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Jiwei Zhang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Heshui Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
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15
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Li B, Chen H, Yang S, Chen F, Xu L, Li Y, Li M, Zhu C, Shao F, Zhang X, Deng C, Zeng L, He Y, Zhang C. Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers. Mol Cancer 2023; 22:71. [PMID: 37072770 PMCID: PMC10111719 DOI: 10.1186/s12943-023-01770-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023] Open
Abstract
Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.
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Affiliation(s)
- Bo Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Hui Chen
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Shaohua Yang
- Guangdong-Hong Kong-Macau University Joint Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Feng Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Liangliang Xu
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Yan Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Mingzhe Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Chengming Zhu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Fangyuan Shao
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhongshan Road, Guangzhou, 510080, China
| | - Chuxia Deng
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China.
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Changhua Zhang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
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Masucci MT, Motti ML, Minopoli M, Di Carluccio G, Carriero MV. Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors. Int J Mol Sci 2023; 24:6026. [PMID: 37046997 PMCID: PMC10094678 DOI: 10.3390/ijms24076026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 04/14/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2-3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.
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Affiliation(s)
- Maria Teresa Masucci
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Letizia Motti
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
- Department of Movement Sciences and Wellbeing, University “Parthenope”, 80133 Naples, Italy
| | - Michele Minopoli
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Gioconda Di Carluccio
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Vincenza Carriero
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
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Huang W, Yuan W, Ren L, Liang H, Du X, Sun X, Fang Y, Gao X, Fu M, Sun Y, Shen K, Hou Y. Clinicopathological and therapeutic analysis of PDGFRA mutated gastrointestinal stromal tumor. Pathol Res Pract 2022; 239:154138. [PMID: 36183438 DOI: 10.1016/j.prp.2022.154138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/04/2022] [Accepted: 09/16/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutation has causes a rare subgroup of gastrointestinal stromal tumor (GIST) and not too much attention has been paid on it until the appearance of Avapritinib. This study aims to explore the clinicopathological features, therapy and prognosis of PDGFRA-mutant GIST for better understanding and clinical practice. METHOD 119 PDGFRA-mutant GIST patients were retrospectively collected from 2038 patients who underwent genetic testing. Kaplan-Meier method was used. RESULTS The incidence rate of PDGFRA-mutant GIST in our center was 5.8 %, with 79 males, 40 females, and a median age of 57 (25⁃80) years old. All the tumors were in the stomach, among which 60 were epithelioid type, 25 were spindle type and 34 were mixed type. There were 13 cases of exon 12 mutation and 106 cases of exon 18 mutation including 83 cases of D842V mutation (69.7 %). During a median follow⁃up of 49.6 (range, 1⁃154) months, progression could be observed in 12 patients with gene mutation at the codon 842 of exon 18, another case was V561D mutation in exon 12. The 5-year diseases⁃free survival (DFS) was 90.1 %, which was associated with the loss of CD34 expression (P＜0.001). Patients in D842V group showed a marginal worse prognosis than those in non-D842V group (P = 0.163). According to the NIH criteria, high risk group showed a poorer prognosis than non-high risk group (P = 0.003), however, there were no significant differences among the three non-high risk groups (P = 0.495, P = 0.652). Among 13 advanced patients, 5 cases (treated with Avapritinib) achieved partial remission. CONCLUSION PDGFRA-mutant GIST mostly derived from stomach, with a relative indolent behavior. D842V mutation and lose of CD34 expression were adverse prognostic factors. Avapritinib can effectively control advanced patients in a certain period of time.
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Affiliation(s)
- Wen Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Yuan
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Ren
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huaiyu Liang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiangyang Du
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiangfei Sun
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaodong Gao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Min Fu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
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Salmikangas S, Böhling T, Merikoski N, Jagdeo J, Sampo M, Vesterinen T, Sihto H. Tensin2 Is a Novel Diagnostic Marker in GIST, Associated with Gastric Location and Non-Metastatic Tumors. Cancers (Basel) 2022; 14:3212. [PMID: 35804982 PMCID: PMC9265085 DOI: 10.3390/cancers14133212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
GIST is a rare soft tissue sarcoma, for which KIT and DOG1 are used as highly sensitive diagnostic markers. Other diagnostic markers include CD34, protein kinase C θ, deficiency of succinate dehydrogenase complex subunit B, carbonic anhydrase II, and type I insulin-like growth factor receptor. We investigated the role of TNS2 as a diagnostic biomarker by using immunohistochemistry in 176 GISTs and 521 other sarcomas. All GISTs expressed TNS2, with intermediate or high expression in 71.4% of samples. The majority (89.8%) of other sarcomas were negative for TNS2, and intermediate to strong staining was only seen in 2.9% of samples. Strong TNS2 staining was associated with gastric location (gastric 52.8% vs. non-gastric 7.2%; p < 0.001), absence of metastases (non-metastatic tumors 44.3% vs. metastatic tumors 5.9%; p = 0.004), female sex (female 45.9% vs. male 33.8%; p = 0.029), and tumors of lower risk categories (very low or low 46.9% vs. intermediate 51.7% vs. high 29.0%; p = 0.020). TNS2 expression did not correlate with overall survival or metastasis-free survival. No associations between TNS2 expression and KIT/PDGFRA mutation status, tumor size, mitotic count, or age of the patient were detected. The results provide conclusive evidence for the value of TNS2 as a sensitive and specific diagnostic biomarker for GIST.
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Affiliation(s)
- Sami Salmikangas
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Tom Böhling
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Nanna Merikoski
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Joanna Jagdeo
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Mika Sampo
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, FI-00029 Helsinki, Finland; (M.S.); (T.V.)
| | - Tiina Vesterinen
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, FI-00029 Helsinki, Finland; (M.S.); (T.V.)
| | - Harri Sihto
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
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Puri P, Grimmett G, Faraj R, Gibson L, Gilbreath E, Yoder BK. Elevated Protein Kinase A Activity in Stomach Mesenchyme Disrupts Mesenchymal-epithelial Crosstalk and Induces Preneoplasia. Cell Mol Gastroenterol Hepatol 2022; 14:643-668.e1. [PMID: 35690337 PMCID: PMC9421585 DOI: 10.1016/j.jcmgh.2022.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Mesenchymal-epithelial crosstalk (MEC) in the stomach is executed by pathways such as bone morphogenetic protein (BMP) and extracellular signal-regulated kinase (ERK). Mis-regulation of MEC disrupts gastric homeostasis and causes tumorigenesis. Protein Kinase A (PKA) crosstalks with BMP and ERK signaling; however, PKA function(s) in stomach development and homeostasis remains undefined. METHODS We generated a novel Six2-Cre+/-PKAcαRfl/wt (CA-PKA) mouse in which expression of constitutive-active PKAcαR was induced in gastric mesenchyme progenitors. Lineage tracing determined spatiotemporal activity of Six2-Cre in the stomach. For phenotyping CA-PKA mice histological, co-immunofluorescence, immunoblotting, mRNA sequencing, and bioinformatics analyses were performed. RESULTS Lineage tracing showed that Six2-Cre activity in the stomach is restricted to the mesenchymal compartment. CA-PKA mice showed disruption of gastric homeostasis characterized by aberrant mucosal development and epithelial hyperproliferation; ultimately developing multiple features of gastric corpus preneoplasia including decreased parietal cells, mucous cell hyperplasia, spasmolytic peptide expressing metaplasia with intestinal characteristics, and dysplastic and invasive cystic glands. Furthermore, mutant corpus showed marked chronic inflammation characterized by infiltration of lymphocytes and myeloid-derived suppressor cells along with the upregulation of innate and adaptive immune system components. Striking upregulation of inflammatory mediators and STAT3 activation was observed. Mechanistically, we determined there is an activation of ERK1/2 and downregulation of BMP/SMAD signaling characterized by marked upregulation of BMP inhibitor gremlin 1. CONCLUSIONS We report a novel role of PKA signaling in gastric MEC execution and show that PKA activation in the gastric mesenchyme drives preneoplasia by creating a proinflammatory and proproliferative microenvironment associated with the downregulation of BMP/SMAD signaling and activation of ERK1/2.
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Affiliation(s)
- Pawan Puri
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama,Correspondence Address correspondence to: Pawan Puri, DVM, PhD, Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, A310 Patterson Hall, Tuskegee, AL 36088; tel. (334) 724-4486; fax: (334) 727-8177.
| | - Garfield Grimmett
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Rawah Faraj
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Laurielle Gibson
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Ebony Gilbreath
- Department of Pathobiology, College of Veterinary Medicine, Tuskegee University, Tuskegee, Alabama
| | - Bradley K. Yoder
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama, Birmingham, Alabama
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Dudzisz-Śledź M, Klimczak A, Bylina E, Rutkowski P. Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients. Cancers (Basel) 2022; 14:2831. [PMID: 35740497 PMCID: PMC9221273 DOI: 10.3390/cancers14122831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 01/27/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originate from Cajal's cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.
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Affiliation(s)
- Monika Dudzisz-Śledź
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland; (A.K.); (E.B.); (P.R.)
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Xu Y, Hu W, Xiao K, Wang F, Guan W, Zong L. The current state of chemotherapy for the treatment of gastrointestinal stromal tumors with different genotypes: a narrative review. JOURNAL OF BIO-X RESEARCH 2022; 05:14-17. [DOI: 10.1097/jbr.0000000000000113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the digestive system and are not sensitive to traditional chemotherapy. Therefore, historically, surgical resection was the only effective therapy. However, the emergence of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of GISTs, because they target c-Kit and PDGF receptor-α (PDGFRA), which are important in GIST development and progression. As research into c-Kit and PDGFRA continues, an increasing number of different TKIs are being used in the clinical setting. This review aims to discuss the current state of chemotherapy for the treatment of GISTs with different genotypes.
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Affiliation(s)
- Yingying Xu
- Department of General Surgery, Yizhen People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province,
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College,
| | - Keyuan Xiao
- Central Laboratory, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi, Shanxi Province,
| | - Feng Wang
- Department of General Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wenxian Guan
- Department of General Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Liang Zong
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College,
- Central Laboratory, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi, Shanxi Province,
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Gorunova L, Boye K, Panagopoulos I, Berner JM, Bjerkehagen B, Hompland I, Lobmaier I, Hølmebakk T, Hveem TS, Heim S, Micci F. Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity. Oncotarget 2022; 13:508-517. [PMID: 35284037 PMCID: PMC8901076 DOI: 10.18632/oncotarget.28209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/17/2022] [Indexed: 12/02/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric (P < 0.001), larger (P < 0.001), more mitotically active (P = 0.009) and had a higher risk of rupture (P < 0.001) and recurrence (P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA-mutated tumors, compared with gastric KIT-mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors’ development.
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Affiliation(s)
- Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjetil Boye
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Jeanne-Marie Berner
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Bodil Bjerkehagen
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Ivar Hompland
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ingvild Lobmaier
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Toto Hølmebakk
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Tarjei S. Hveem
- Section for Applied Informatics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Cho H, Nishida T, Takahashi T, Masuzawa T, Hirota S. Impact of the KIT/PDGFRA genotype on prognosis in imatinib-naïve Japanese patients with gastrointestinal stromal tumor. Ann Gastroenterol Surg 2022; 6:241-248. [PMID: 35261949 PMCID: PMC8889858 DOI: 10.1002/ags3.12527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 11/12/2022] Open
Abstract
Background Most gastrointestinal stromal tumors (GIST) harbor a mutation in KIT or platelet-derived growth factor receptor alfa (PDGFRA). Although genotyping is a useful predictive marker of tyrosine kinase inhibitors, whether it can predict prognosis remains controversial. Methods Data on 402 patients with GIST who underwent macroscopically complete surgery and received no neoadjuvant/adjuvant therapy were selected from a prospective GIST database at the three, participating hospitals. The types and locations of KIT and PDGFRA mutations were analyzed by direct sequencing of the amplified genes. The association between the genotypic characteristics and prognosis was then examined. Results Tumor genotypes were analyzed in 398 of 402 (99%) patients, and 120 mutation patterns were identified. KIT mutations had broad malignancy potential which differed according to the type of mutation. Deletion and deletion-insertion type mutations were associated with worse RFS while duplication and substitution type mutations were associated with favorable RFS KIT deletion/deletion-insertion, including codons 557 and 558, were especially associated with worse RFS on multivariate analysis both of all the patients and those with KIT mutations. Conclusions Specific GIST genotypes were significantly associated with a risk of recurrence. Genotype analysis may be useful for predicting the prognosis and determining the indications for adjuvant imatinib in patients with GIST.
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Affiliation(s)
- Haruhiko Cho
- Department of SurgeryTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
- Department of Gastrointestinal SurgeryKanagawa Cancer CenterYokohamaJapan
| | - Toshirou Nishida
- Department of SurgeryNational Cancer Center HospitalTokyoJapan
- Department of SurgeryJapan Community Health Care OrganizationOsaka HospitalOsakaJapan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversitySuitaJapan
| | - Toru Masuzawa
- Department of SurgeryOsaka Police HospitalOsakaJapan
- Department of Gastrointestinal SurgeryKansai Rosai HospitalAmagasakiJapan
| | - Seiichi Hirota
- Department of Surgical PathologyHyogo College of MedicineNishinomiyaJapan
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Li J, Guo S, Sun Z, Fu Y. Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor. Front Cell Dev Biol 2022; 10:808591. [PMID: 35174150 PMCID: PMC8841737 DOI: 10.3389/fcell.2022.808591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tracts and a model for the targeted therapy of solid tumors because of the oncogenic driver mutations in KIT and PDGDRA genes, which could be effectively inhibited by the very first targeted agent, imatinib mesylate. Most of the GIST patients could benefit a lot from the targeted treatment of this receptor tyrosine kinase inhibitor. However, more than 50% of the patients developed resistance within 2 years after imatinib administration, limiting the long-term effect of imatinib. Noncoding RNAs (ncRNAs), the non-protein coding transcripts of human, were demonstrated to play pivotal roles in the resistance of various chemotherapy drugs. In this review, we summarized the mechanisms of how ncRNAs functioning on the drug resistance in GIST. During the drug resistance of GIST, there were five regulating mechanisms where the functions of ncRNAs concentrated: oxidative phosphorylation, autophagy, apoptosis, drug target changes, and some signaling pathways. Also, these effects of ncRNAs in drug resistance were divided into two aspects. How ncRNAs regulate drug resistance in GIST was further summarized according to ncRNA types, different drugs and categories of resistance. Moreover, clinical applications of these ncRNAs in GIST chemotherapies concentrated on the prognostic biomarkers and novel therapeutic targets.
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Affiliation(s)
- Jiehan Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuning Guo
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
| | - Yang Fu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
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Al-Share B, Alloghbi A, Al Hallak MN, Uddin H, Azmi A, Mohammad RM, Kim SH, Shields AF, Philip PA. Gastrointestinal stromal tumor: a review of current and emerging therapies. Cancer Metastasis Rev 2021; 40:625-641. [PMID: 33876372 DOI: 10.1007/s10555-021-09961-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Abdulrahman Alloghbi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Hafiz Uddin
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Asfar Azmi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Ramzi M Mohammad
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Steve H Kim
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA.
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.
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Rizzo A, Pantaleo MA, Astolfi A, Indio V, Nannini M. The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST). Cancers (Basel) 2021; 13:cancers13040705. [PMID: 33572358 PMCID: PMC7916155 DOI: 10.3390/cancers13040705] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/02/2021] [Accepted: 02/07/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Among the platelet-derived growth factor receptor (PDGFRA) mutations in gastrointestinal stromal tumors (GIST), the most frequent is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), widely recognized as D842V, a two-sided mutation providing primary resistance to all currently approved agents for GIST treatment. In recent years, new specific inhibitors have been studied in preclinical and clinical settings, and molecular findings have been accumulated, well describing this complex entity. This paper aims at offering a comprehensive picture of the clinical features and the molecular background of this rare subtype of GIST. Abstract The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor—avapritinib—that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
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Affiliation(s)
- Alessandro Rizzo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.R.); (M.A.P.)
| | - Maria Abbondanza Pantaleo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.R.); (M.A.P.)
- Department of Experimental, Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy
| | - Annalisa Astolfi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Valentina Indio
- “Giorgio Prodi” Cancer Research Center, University of Bologna, 40138 Bologna, Italy;
| | - Margherita Nannini
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.R.); (M.A.P.)
- Correspondence: ; Tel.: +39-0512-142-708
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Hedenström P, Andersson C, Sjövall H, Enlund F, Nilsson O, Nilsson B, Sadik R. Pretreatment Tumor DNA Sequencing of KIT and PDGFRA in Endosonography-Guided Biopsies Optimizes the Preoperative Management of Gastrointestinal Stromal Tumors. Mol Diagn Ther 2021; 24:201-214. [PMID: 32124386 PMCID: PMC7113213 DOI: 10.1007/s40291-020-00451-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Neoadjuvant tyrosine kinase inhibitor (TKI) therapy increases the chance of organ-preserving, radical resection in selected patients with gastrointestinal stromal tumors (GISTs). We aimed to evaluate systematic, immediate DNA sequencing of KIT and PDGFRA in pretreatment GIST tissue to guide neoadjuvant TKI therapy and optimize preoperative tumor response. METHODS All patients who were candidates for neoadjuvant therapy of a suspected GIST [the study cohort (SC)] were prospectively included from January 2014 to March 2018. Patients were subjected to pretreatment endosonography-guided fine-needle biopsy (EUS-FNB) or transabdominal ultrasound-guided needle biopsy (TUS-NB), followed by immediate tumor DNA sequencing (< 2 weeks). A historic (2006-2013) reference cohort (RC) underwent work-up without sequencing before neoadjuvant imatinib (n = 42). The rate of optimal neoadjuvant therapy (TherapyOPTIMAL) was calculated, and the induced tumor size reduction (Tumor RegressionMAX, %) was evaluated by computed tomography (CT) scan. RESULTS The success rate of pretreatment tumor DNA sequencing in the SC (n = 81) was 77/81 (95%) [EUS-FNB 71/74 (96%); TUS-NB 6/7 (86%)], with mutations localized in KIT (n = 58), PDGFRA (n = 18), or neither gene, wild type (n = 5). In patients with a final indication for neoadjuvant therapy, the TherapyOPTIMAL was higher in the SC compared with the RC [61/63 (97%) versus 33/42 (79%), p = 0.006], leading to a significantly higher Tumor RegressionMAX in patients treated with TKI (27% vs. 19%, p = 0.015). CONCLUSIONS Pretreatment endosonography-guided biopsy sampling followed by immediate tumor DNA sequencing of KIT and PDGFRA is highly accurate and valuable in guiding neoadjuvant TKI therapy in GIST. This approach minimizes maltreatment with inappropriate regimens and leads to improved tumor size reduction before surgery.
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Affiliation(s)
- Per Hedenström
- Division of Medical Gastroenterology, Department of Internal Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 35, Gothenburg, Sweden. .,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Carola Andersson
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Henrik Sjövall
- Division of Medical Gastroenterology, Department of Internal Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 35, Gothenburg, Sweden.,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fredrik Enlund
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ola Nilsson
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Bengt Nilsson
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Riadh Sadik
- Division of Medical Gastroenterology, Department of Internal Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 35, Gothenburg, Sweden
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Steeghs EMP, Gelderblom H, Ho VKY, Voorham QJM, Willems SM, PATH consortium, Grünberg K, Ligtenberg MJL. Nationwide evaluation of mutation-tailored treatment of gastrointestinal stromal tumors in daily clinical practice. Gastric Cancer 2021; 24:990-1002. [PMID: 33909171 PMCID: PMC8338807 DOI: 10.1007/s10120-021-01190-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Molecular analysis of KIT and PDGFRA is critical for tyrosine kinase inhibitor treatment selection of gastrointestinal stromal tumors (GISTs) and hence recommended by international guidelines. We performed a nationwide study into the application of predictive mutation testing in GIST patients and its impact on targeted treatment decisions in clinical practice. METHODS Real-world clinical and pathology information was obtained from GIST patients with initial diagnosis in 2017-2018 through database linkage between the Netherlands Cancer Registry and the nationwide Dutch Pathology Registry. RESULTS Predictive mutation analysis was performed in 89% of the patients with high risk or metastatic disease. Molecular testing rates were higher for patients treated in expertise centers (96%) compared to non-expertise centers (75%, P < 0.01). Imatinib therapy was applied in 81% of the patients with high risk or metastatic disease without patient's refusal or adverse characteristics, e.g., comorbidities or resistance mutations. Mutation analysis that was performed in 97% of these imatinib-treated cases, did not guarantee mutation-tailored treatment: 2% of these patients had the PDGFRA p.D842V resistance mutation and 7% initiated imatinib therapy at the normal instead of high dose despite of having a KIT exon 9 mutation. CONCLUSION In conclusion, nationwide real-world data show that over 81% of the eligible high risk or metastatic disease patients receive targeted therapy, which was tailored to the mutation status as recommended in guidelines in 88% of cases. Therefore, still 27% of these GIST patients misses out on mutation-tailored treatment. The reasons for suboptimal uptake of testing and treatment require further study.
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Affiliation(s)
- Elisabeth M. P. Steeghs
- grid.10417.330000 0004 0444 9382Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans Gelderblom
- grid.10419.3d0000000089452978Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Vincent K. Y. Ho
- Departments of Research and Development, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands
| | | | - Stefan M. Willems
- PALGA Foundation, Houten, The Netherlands ,grid.4494.d0000 0000 9558 4598Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Katrien Grünberg
- grid.10417.330000 0004 0444 9382Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marjolijn J. L. Ligtenberg
- grid.10417.330000 0004 0444 9382Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands ,grid.10417.330000 0004 0444 9382Laboratory of Tumor Genetics, Department of Pathology and Human Genetics, Radboud University Medical Center, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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Vanden Bempt I, Vander Borght S, Sciot R, Spans L, Claerhout S, Brems H, Lehnert S, Dehaspe L, Fransis S, Neuville B, Topal B, Schöffski P, Legius E, Debiec-Rychter M. Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor. Genes Chromosomes Cancer 2020; 60:239-249. [PMID: 33258138 DOI: 10.1002/gcc.22923] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/26/2022] Open
Abstract
Mutational analysis guides therapeutic decision making in patients with advanced-stage gastrointestinal stromal tumors (GISTs). We evaluated three targeted next-generation sequencing (NGS) assays, consecutively used over 4 years in our laboratory for mutational analysis of 162 primary GISTs: Agilent GIST MASTR, Illumina TruSight 26 and an in-house developed 96 gene panels. In addition, we investigated the feasibility of a more comprehensive approach by adding targeted RNA sequencing (Archer FusionPlex, 11 genes) in an attempt to reduce the number of Wild Type GISTs. We found KIT or PDGFRA mutations in 149 out of 162 GISTs (92.0%). Challenging KIT exon 11 alterations were initially missed by different assays in seven GISTs and typically represented deletions at the KIT intron 10-exon 11 boundary or large insertions/deletions (>24 base pairs). Comprehensive analysis led to the additional identification of driver alterations in 8/162 GISTs (4.9%): apart from BRAF and SDHA mutations (one case each), we found five GISTs harboring somatic neurofibromatosis type 1 (NF1) alterations (3.1%) and one case with an in-frame TRIM4-BRAF fusion not reported in GIST before. Eventually, no driver alteration was found in two out of 162 GISTs (1.2%) and three samples (1.9%) failed analysis. Our study shows that a comprehensive targeted NGS approach is feasible for routine mutational analysis of GIST, thereby substantially reducing the number of Wild Type GISTs, and highlights the need to optimize assays for challenging KIT exon 11 alterations.
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Affiliation(s)
- Isabelle Vanden Bempt
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sara Vander Borght
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Lien Spans
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sofie Claerhout
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Hilde Brems
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Stefan Lehnert
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Luc Dehaspe
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sabine Fransis
- Department of Pathology, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Bart Neuville
- Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Baki Topal
- Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium.,Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium
| | - Eric Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Maria Debiec-Rychter
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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PDGFRA mutant gastrointestinal stromal tumor with composite sclerosing and inflammatory myofibroblastic tumor-like morphology, a case report. HUMAN PATHOLOGY: CASE REPORTS 2020. [DOI: 10.1016/j.ehpc.2020.200453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Duan Y, Haybaeck J, Yang Z. Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress. Cancers (Basel) 2020; 12:2972. [PMID: 33066449 PMCID: PMC7602170 DOI: 10.3390/cancers12102972] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/03/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
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Affiliation(s)
- Yi Duan
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Zhihui Yang
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
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Liu P, Tan F, Liu H, Ge J, Liu S, Lei T, Zhao X. Skin Metastasis of Gastrointestinal Stromal Tumors: A Case Series and Literature Review. Cancer Manag Res 2020; 12:7681-7690. [PMID: 32904396 PMCID: PMC7455533 DOI: 10.2147/cmar.s261823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/04/2020] [Indexed: 12/12/2022] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) extremely and rarely metastasize to the skin, and such metastases have not been well characterized. Methods Retrospective analysis of clinicopathological data of patients with skin metastasis of a GIST (SM-GIST) admitted to Xiangya Hospital (Changsha, Hunan, China) and literature review were conducted. Results Including our 4 cases, a total of 17 cases have been reported to date. The mean age of the patients was 55.4 years (29~70 years) and there was not sex predominance (male 10 and female 7). Primary tumors were often located in the stomach (n=9), duodenum (n=2) and small bowel (n=2). Meanwhile, SM-GIST mainly occurred in head and face (n=6), extremities (n=6), followed by abdomen wall (n=5), back (n=3) and chest (n=2). Mutation analysis revealed that the frequency of wild-type GIST (WT-GIST), exon 9, 11 and 13 mutations was 6, 1, 4 and 1, respectively. The average time to SM-GIST was 4.22 years, specifically 4.59 years in gastric and 3.8 years in non-gastric. Moreover, for the resection only group (including chemotherapy), such average time was 3.63 years, while for the combined group (resection and tyrosine kinase inhibitors (TKIs)), it was about 4.74 years. The mean survival was approximately 6.2 years. However, after the diagnosis of SM-GIST, survival was only about 1.69 years. Conclusion SM-GIST is a rare malignant condition. Non-gastric GIST, surgery without TKIs, high invasiveness and tumor burden, and molecular subtype (mutation in exon 9, 11 and wild-type) may be conducive to the development of SM-GIST. Additionally, it is also a sign of poor prognosis.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Jie Ge
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Sheng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China
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Shen YY, Ma XL, Wang M, Zhuang C, Ni B, Tu L, Liu Q, Zhao WY, Cao H. Exon 11 homozygous mutations and intron 10/exon 11 junction deletions in the KIT gene are associated with poor prognosis of patients with gastrointestinal stromal tumors. Cancer Med 2020; 9:6485-6496. [PMID: 32697050 PMCID: PMC7520349 DOI: 10.1002/cam4.3212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 04/20/2020] [Accepted: 05/15/2020] [Indexed: 12/23/2022] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) with different types of mutations exhibit different clinical characteristics and prognosis. This study aimed to evaluate the prognostic value of mutations in KIT and PDGFRA in a large‐scale cohort of GIST patients with current therapy including surgery and imatinib. Methods A total of 1163 patients diagnosed with GISTs between January 2006 and December 2018 were enrolled in this study. Mutation analysis was performed for exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA. Mutations were grouped into 12 categories according to the gene, exon, and involved codons; they were analyzed considering the clinical characteristics, disease‐free survival (DFS), and overall survival (OS) of patients with GISTs. Results In low‐risk GISTs, we identified two predictors of worse DFS: tumor origin in the rectum and KIT exon 11 deletion involving two or more codons. In high‐risk GISTs treated with R0 resection and imatinib, patients with KIT exon 11 homozygous mutations and KIT intron 10/exon 11 junction deletions demonstrated the highest recurrence rate, indicating that these mutations can be independent prognostic factors of DFS. The presence of KIT exon 11 homozygous mutations also independently influenced OS. Conclusion Low‐incidence mutations such as KIT exon 11 homozygous mutations or intron 10/exon 11 junction deletions in GISTs should be carefully evaluated to explore novel treatment strategies, as tumors with these mutations have a high recurrence rate and a very poor prognosis after surgery followed by imatinib adjuvant treatment.
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Affiliation(s)
- Yan-Ying Shen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.,Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Xin-Li Ma
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Chun Zhuang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Bo Ni
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Lin Tu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Wen-Yi Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
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Zhang H, Liu Q. Prognostic Indicators for Gastrointestinal Stromal Tumors: A Review. Transl Oncol 2020; 13:100812. [PMID: 32619820 PMCID: PMC7327422 DOI: 10.1016/j.tranon.2020.100812] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are potentially malignancies that can occur anywhere in the digestive tract. Tyrosine kinase inhibitors (TKIs) such as imatinib have proven effective since the discovery of KIT and PDGFRA. The current version of NCNN, ESMO and EURACAN guidelines recognized that the three main prognostic factors are the mitotic rate, tumor size and tumor site. In addition, tumor rupture is also recognized as an independent risk factor. However, recent evidence shows that various types of gene mutations are associated with prognosis, and influencing factors such as gastrointestinal bleeding and high Ki67 index have been associated with poor prognosis. It shows that the current risk classification is still insufficient and controversial. With the emergence of more and more lack mutation in KIT/PDGFRA GISTs (KIT/PDGFRA wild-type GISTs) or drug resistance genes, primary and secondary drug resistance problems are caused, which makes the treatment of late or metastatic GIST face challenges. Therefore, this article will review the clinicopathological characteristics of GIST, the special molecular subtypes and other factors that may affect prognosis. We will also explore reliable prognostic markers for better postoperative management and improve the prognosis of patients with GIST.
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Affiliation(s)
- Haixin Zhang
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China
| | - Qi Liu
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China.
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35
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Smrke A, Gennatas S, Huang P, Jones RL. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. Future Oncol 2020; 16:1639-1646. [PMID: 32517495 DOI: 10.2217/fon-2020-0348] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal stromal tumors (GIST) can be molecularly classified based on different subtypes including mutations in KIT and PDGFRA. Patients with PDGFRA mutations are an important subgroup that commonly arise in the stomach and are associated with a more indolent disease course. Importantly, the most common PDGFRA molecular subtype, the D842V mutation in exon 18 of the gene which alters the activation loop, is imatinib insensitive in in vitro studies. Poor responses to imatinib have been seen clinically compared with PDGFRA exon 18 non-D842V-mutated GIST. Avapritinib (BLU-285) is a potent KIT and PDGFRA-specific tyrosine kinase inhibitor which has shown >90% response rates in patients with PDGFRA exon 18 D842V-mutated GIST. Results from the Phase I trial of avapritinib have indicated that this drug should be the standard of care for patients with PDGFRA exon 18 D842V-mutated GIST.
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Affiliation(s)
- Alannah Smrke
- Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London, SW36JJ, UK
| | - Spyridon Gennatas
- Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London, SW36JJ, UK
| | - Paul Huang
- Department of Pathology, Molecular & Systems Oncology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
| | - Robin L Jones
- Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London, SW36JJ, UK.,Department of Pathology, Molecular & Systems Oncology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
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36
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Indio V, Ravegnini G, Astolfi A, Urbini M, Saponara M, De Leo A, Gruppioni E, Tarantino G, Angelini S, Pession A, Pantaleo MA, Nannini M. Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation. Front Immunol 2020; 11:851. [PMID: 32670260 PMCID: PMC7326057 DOI: 10.3389/fimmu.2020.00851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/14/2020] [Indexed: 12/18/2022] Open
Abstract
Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5-7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.
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Affiliation(s)
- Valentina Indio
- "Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Milena Urbini
- "Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.,Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Maristella Saponara
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Antonio De Leo
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Elisa Gruppioni
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giuseppe Tarantino
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Andrea Pession
- "Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- "Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.,Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Margherita Nannini
- Medical Oncology Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy
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37
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Kalfusova A, Linke Z, Kalinova M, Krskova L, Hilska I, Szabova J, Vicha A, Kodet R. Gastrointestinal stromal tumors – Summary of mutational status of the primary/secondary KIT/PDGFRA mutations, BRAF mutations and SDH defects. Pathol Res Pract 2019; 215:152708. [DOI: 10.1016/j.prp.2019.152708] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/18/2019] [Accepted: 10/19/2019] [Indexed: 02/08/2023]
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38
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Hemming ML, Heinrich MC, Bauer S, George S. Translational insights into gastrointestinal stromal tumor and current clinical advances. Ann Oncol 2019; 29:2037-2045. [PMID: 30101284 DOI: 10.1093/annonc/mdy309] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.
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Affiliation(s)
- M L Hemming
- Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - M C Heinrich
- VA Health Care System and Knight Cancer Institute, Oregon Health and Science University, Oregon, USA
| | - S Bauer
- Sarcoma Center, Western German Cancer Center and German Cancer Consortium (DKTK), Essen, Germany
| | - S George
- Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
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39
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Li Y, Teng Y, Wei X, Tian Z, Cao Y, Liu X, Duan X. A rare simultaneous coexistence of epithelioid gastrointestinal stromal tumors and schwannoma in the stomach: a case report. Diagn Pathol 2019; 14:116. [PMID: 31647020 PMCID: PMC6813059 DOI: 10.1186/s13000-019-0898-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/04/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations. Schwannoma in the stomach, which is an unusual location, is a rare disorder. The simultaneous occurrence of the two diseases is rarer than metachronous occurrences, and its pathological characteristics have not been reported to date. We present a case report on a patient with simultaneous coexistence of gastric schwannoma and GISTs. CASE PRESENTATION A 39-year-old female visited our hospital complaining of intermittent abdominal pain for the previous 3 months. CT revealed a 3.4 cm slight homogeneous enhancement in the lesser curvature of the stomach; the mass was nodular soft tissue, which was removed by radical surgery. Two solid tumors with different volumes were located in the stomach. Histologically and immunohistochemically different, the larger tumor consisted of spindle cells surrounded by a peripheral lymphoid cuff, and was positive for S-100. The larger tumor was therefore classified as a gastric schwannoma. The smaller tumor was composed of medium-sized round, oval cells with amphiphilic granular cytoplasm; vacuolization was also observed. The tumor cells were positive for DOG1 and sporadically positive for CD34 and CD117. Hence, the smaller tumor was diagnosed as epithelioid GISTs. Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843-846del4), which was located in exon 18 of PDGFRA. CONCLUSION GISTs combined with gastric schwannoma are a considerably rare subgroup of gastric tumors. Related clinical research is comparatively weak, and the mechanism remains unknown. We reviewed related articles to provide knowledge to improve the correct identification, diagnosis and management of patients with gastric cancer. All pathologists involved in the diagnosis and clinicians involved in the treatment should be aware of this new kind of disease pattern to improve their understanding of the disease.
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Affiliation(s)
- Yuxin Li
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Yongliang Teng
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Xiaofei Wei
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Zhuang Tian
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Yuqing Cao
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Xiaona Liu
- Department of Pathology, the First Hospital of Jilin University, Changchun, China
| | - Xiumei Duan
- Department of Pathology, the First Hospital of Jilin University, Changchun, China.
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40
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Optimal thresholds of risk parameters for gastrointestinal stromal tumors. Eur J Surg Oncol 2019; 46:180-188. [PMID: 31431322 DOI: 10.1016/j.ejso.2019.08.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal neoplasms of the gastrointestinal tract with highly variable potential for relapse. Tumor size and mitotic index (MI) are major risk factors that predict the outcome of GIST patients. Recent risk stratification schemes include some or all of the empirical size thresholds of 2 cm, 5 cm, and 10 cm and MI thresholds of 5 per 50 high-power fields (hpf) and 10 per 50 hpf. However, data that verify these numbers are sparse. METHODS By exhaustive regression tree analysis, maximally selected rank statistics and survival difference analysis with bootstrap sampling on a naive GIST population of 161 patients with a mean follow-up of 44 months, current stratification schemes using tumor size and MI were analyzed herein. RESULTS /Conclusions: Thresholds that optimally stratify the risk of recurrence are observed at tumor sizes of 4-5 cm and 10-11 cm and at mitotic indices of about 5 per 50 hpf and 10 per 50 hpf, respectively. While these data validate the canonical thresholds for size and MI used in risk stratification of GIST, transition regions as well as differences in the implementation of these thresholds between the different classification schemes proposed in the recent years should be considered when classifying GIST.
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41
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Kobayashi M, Inaguma S, Raffeld M, Kato H, Suzuki S, Wakasugi T, Mitsui A, Kuwabara Y, Lasota J, Ikeda H, Miettinen M, Takahashi S. Epithelioid variant of gastrointestinal stromal tumor harboring PDGFRA mutation and MLH1 gene alteration: A case report. Pathol Int 2019; 69:541-546. [PMID: 31273885 DOI: 10.1111/pin.12830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/28/2019] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most important and common mesenchymal tumors of the gastrointestinal tract, especially in the stomach. GISTs are usually driven by activating mutations in either KIT or PDGFRA genes. It is known that activating gene mutations predicts, to a certain extent, not only the morphology of the tumor cells but also a response to treatment with tyrosine kinase inhibitors. Here, we present a case of an epithelioid variant of GIST harboring PDGFRA and MLH1 gene alterations in the stomach of a 55-year-old Japanese woman. The tumor of 98 mm with multiple cysts showed exophytic growth from the gastric fundus. Histopathologically, it consisted of scattered medium-sized epithelioid tumor cells in a loose myxoid background. Based on c-kit and DOG-1 immunoreactivity and a PDGFRA mutation (p.Trp559_Arg560del), the tumor was diagnosed as an epithelioid variant GIST. Interestingly, it had a gene alteration (p.Met524Ile) in the MLH1 gene of unknown pathogenicity. It was assigned to Group 3a (low risk for malignant behavior). After surgery, the patient has been on imatinib therapy and disease-free for 10 months.
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Affiliation(s)
- Mizuho Kobayashi
- Department of Pathology, Nagoya City West Medical Center, Nagoya, Japan.,Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Shingo Inaguma
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Mark Raffeld
- Laboratory of Pathology, National Cancer Institute, Bethesda, USA
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Shugo Suzuki
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Takehiro Wakasugi
- Gastrointestinal Surgery, Nagoya City West Medical Center, Nagoya, Japan
| | - Akira Mitsui
- Gastrointestinal Surgery, Nagoya City West Medical Center, Nagoya, Japan
| | - Yoshiyuki Kuwabara
- Gastrointestinal Surgery, Nagoya City West Medical Center, Nagoya, Japan
| | - Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, USA
| | - Hiroshi Ikeda
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, Bethesda, USA
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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42
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Li GZ, Raut CP. Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies. Onco Targets Ther 2019; 12:5123-5133. [PMID: 31308690 PMCID: PMC6612765 DOI: 10.2147/ott.s180763] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 05/30/2019] [Indexed: 01/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Since the discovery that the KIT and PDGFRA receptor tyrosine kinases are the primary oncogenic drivers in the vast majority of GISTs, targeted therapy with tyrosine kinase inhibitors has been the mainstay of treatment for this disease. Using molecular profiling of tumor specimens, researchers also discovered that KIT and PDGFRA mutations are non-random and occur in specific regions of the receptors, and furthermore, that particular genotypes predicted response or resistance to targeted therapy. Imatinib, the first tyrosine kinase inhibitor used to treat GIST, remains the first-line therapy in advanced GIST and the only therapy confirmed through clinical trials in the adjuvant or neoadjuvant setting for resectable disease. Resistance to imatinib is well described and is either primary or secondary. Primary resistance is associated with specific tumor genotypes, so genotyping of individual patient tumors helps guide decision-making into whether to offer imatinib and at what dose. Secondary resistance occurs due to the acquisition of secondary mutations during therapy. Currently, the main strategy to combat imatinib resistance is to switch to another tyrosine kinase inhibitor, because imatinib-resistant GIST is usually still oncogenically addicted to KIT/PDGFRA signaling. Surgery can also be used to combat resistant disease in select settings. Unfortunately, progression-free and overall survival remains dismal for patients who develop imatinib-resistant disease, and further research into alternative strategies is still needed.
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Affiliation(s)
- George Z Li
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Chandrajit P Raut
- Center for Sarcoma and Bone Oncology, Dana Farber Cancer Center, Boston, MA, USA
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43
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Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, Loo JK, Goldfeder RL, Chibon F, Rossi F, Zeng S, DeMatteo RP. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Invest 2019; 129:1863-1877. [PMID: 30762585 PMCID: PMC6486334 DOI: 10.1172/jci124108] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.
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Affiliation(s)
| | - Timothy G. Bowler
- Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Mengyuan Liu
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | | | - Nesteene J. Param
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Rachel L. Goldfeder
- Genome Technologies, The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Frederic Chibon
- INSERM U1037, Cancer Research Center of Toulouse, Toulouse, France
| | - Ferdinand Rossi
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Ronald P. DeMatteo
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Kaneva K, Yeo KK, Hawes D, Ji J, Biegel JA, Nelson MD, Bluml S, Krieger MD, Erdreich-Epstein A. Rare Pediatric Invasive Gliofibroma Has BRAFV600E Mutation and Transiently Responds to Targeted Therapy Before Progressive Clonal Evolution. JCO Precis Oncol 2019; 3. [PMID: 31179415 DOI: 10.1200/po.18.00138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Kristiyana Kaneva
- Division of Hematology, Oncology, and Blood and Marrow Transplant Program, Children's Center for Cancer and Blood Diseases, Department of Pediatrics, Children's Hospital Los Angeles
| | - Kee Kiat Yeo
- Division of Hematology, Oncology, and Blood and Marrow Transplant Program, Children's Center for Cancer and Blood Diseases, Department of Pediatrics, Children's Hospital Los Angeles
| | - Debra Hawes
- Department of Pathology, University of Southern California, Los Angeles, CA
| | - Jianling Ji
- Department of Pathology, University of Southern California, Los Angeles, CA
| | - Jaclyn A Biegel
- Department of Pathology, University of Southern California, Los Angeles, CA
| | - Marvin D Nelson
- Department of Radiology, University of Southern California, Los Angeles, CA
| | - Stefan Bluml
- Department of Radiology, University of Southern California, Los Angeles, CA
| | - Mark D Krieger
- Division of Neurosurgery, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Anat Erdreich-Epstein
- Division of Hematology, Oncology, and Blood and Marrow Transplant Program, Children's Center for Cancer and Blood Diseases, Department of Pediatrics, Children's Hospital Los Angeles.,Department of Pathology, University of Southern California, Los Angeles, CA.,Department of Pediatrics, University of Southern California, Los Angeles, CA.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
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45
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Wu W, Yang Y, Lei H. Progress in the application of CRISPR: From gene to base editing. Med Res Rev 2019; 39:665-683. [PMID: 30171624 DOI: 10.1002/med.21537] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 12/26/2022]
Abstract
The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated endonucleases (Cas) has been utilized for genome editing with great accuracy and high efficiency in generating gene knockout, knockin, and point mutations in eukaryotic genomes. However, traditional CRISPR/Cas9 technology introduces double-stranded DNA breaks (DSBs) at a target locus as the first step to make gene corrections, which easily results in undesired mutations. Thus, it is necessary to develop new methods for correcting the unwanted mutations. In this review, we summarize the recent developments and a new approach to genome and base editing by using CRISPR/Cas9. This methodology renders a conversion of one target base into another, for example, C to T (or G to A), and A to G (or T to C) without producing DSBs, requiring a donor DNA template, or generating excessive insertions and deletions. Furthermore, CRISPR/Cas9-derived base editing also improves efficiency in repairing point mutations in the genome.
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Affiliation(s)
- Wenyi Wu
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts
| | - Yanhui Yang
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Hetian Lei
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts
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46
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Gastrointestinal stromal tumor (GIST) in an adolescent. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2018. [DOI: 10.1016/j.epsc.2018.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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47
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Giustiniani MC, Papa V, Martini M, Castri F, Cenci T, Alfieri S, Ricci R. Plexiform architecture in gastrointestinal stromal tumors is not restricted to succinate dehydrogenase-deficient cases. HUMAN PATHOLOGY: CASE REPORTS 2018. [DOI: 10.1016/j.ehpc.2018.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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48
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Ricci R, Giustiniani MC, Gessi M, Lanza P, Castri F, Biondi A, Persiani R, Vecchio FM, Risio M. Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA-mutant GISTs. J Cell Mol Med 2018; 22:4856-4862. [PMID: 30117724 PMCID: PMC6156396 DOI: 10.1111/jcmm.13748] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 05/29/2018] [Indexed: 12/23/2022] Open
Abstract
PDGFRA mutations in the gastrointestinal (GI) tract can cause GI stromal tumour (GIST) and inflammatory fibroid polyp (IFP). Hitherto no cell type has been identified as a physiological counterpart of the latter, while interstitial Cajal cells (ICC) are considered the precursor of the former. However, ICC hyperplasia (ICCH), which strongly supports the ICC role in GIST pathogenesis, has been identified in germline KIT-mutant settings but not in PDGFRA-mutant ones, challenging the precursor role of ICC for PDGFRA-driven GISTs. Telocytes are a recently described interstitial cell type, CD34+/PDGFRA+. Formerly considered fibroblasts, they are found in many organs, including the GI tract where they are thought to be involved in neurotransmission. Alongside IFPs and gastric GISTs, GI wall "fibrosis" has been reported in germline PDGFRA-mutants. Taking the opportunity offered by its presence in a germline PDGFRA-mutant individual, we demonstrate that this lesion is sustained by hyperplastic telocytes, constituting the PDGFRA-mutant counterpart of germline KIT mutation-associated ICCH. Moreover, our findings support a pathogenetic relationship between telocyte hyperplasia and both IFPs and PDGFRA-mutant GISTs. We propose the term "telocytoma" for defining IFP, as it conveys both the pathogenetic (neoplastic) and histotypic ("telocytary") essence of this tumour, unlike IFP, which rather evokes an inflammatory-hyperplastic lesion.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Maria Cristina Giustiniani
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Marco Gessi
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Paola Lanza
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Federica Castri
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Alberto Biondi
- Department of Surgery, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Roberto Persiani
- Department of Surgery, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Fabio M Vecchio
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Mauro Risio
- Department of Pathology, Emeritus, IRCC, Candiolo, Italy
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49
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Noninvasive Detection of ctDNA Reveals Intratumor Heterogeneity and Is Associated with Tumor Burden in Gastrointestinal Stromal Tumor. Mol Cancer Ther 2018; 17:2473-2480. [DOI: 10.1158/1535-7163.mct-18-0174] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/07/2018] [Accepted: 08/03/2018] [Indexed: 11/16/2022]
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50
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Selves J. [Carcinoma of unknown primary. Case no. 4]. Ann Pathol 2018; 38:179-184. [PMID: 29929741 DOI: 10.1016/j.annpat.2018.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Janick Selves
- Département d'anatomie et cytologie pathologiques, institut universitaire du cancer-Oncopole, 1, avenue Irène Joliot-Curie, 31059 Toulouse cedex 9, France
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