TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma
Abstract Background Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical char...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04742-y |
| _version_ | 1797414193861754880 |
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| author | Yiran Zhou Jiabin Jin Yuchen Ji Jiaqiang Zhang Ningzhen Fu Mengmin Chen Jun Wang Kai Qin Yu Jiang Dongfeng Cheng Xiaxing Deng Baiyong Shen |
| author_facet | Yiran Zhou Jiabin Jin Yuchen Ji Jiaqiang Zhang Ningzhen Fu Mengmin Chen Jun Wang Kai Qin Yu Jiang Dongfeng Cheng Xiaxing Deng Baiyong Shen |
| author_sort | Yiran Zhou |
| collection | DOAJ |
| description | Abstract Background Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. Methods We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients’ clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. Results TP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6–7.6] vs. 9.2 [5.2–13.3] months, HR 0.368 [0.200–0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7–30.0] months, HR 0.457 [0.248–0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8–27.7] vs. 23.8 [19.0–28.5] months, HR 1.461 [1.005–2.124], P = 0.047) was observed in TP53missense cases after chemotherapy. Conclusions TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients. |
| first_indexed | 2024-03-09T05:29:32Z |
| format | Article |
| id | doaj.art-a83fd937bfe142fab9a3f42cc7f8612f |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-09T05:29:32Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-a83fd937bfe142fab9a3f42cc7f8612f2023-12-03T12:34:23ZengBMCJournal of Translational Medicine1479-58762023-12-0121111510.1186/s12967-023-04742-yTP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinomaYiran Zhou0Jiabin Jin1Yuchen Ji2Jiaqiang Zhang3Ningzhen Fu4Mengmin Chen5Jun Wang6Kai Qin7Yu Jiang8Dongfeng Cheng9Xiaxing Deng10Baiyong Shen11Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. Methods We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients’ clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. Results TP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6–7.6] vs. 9.2 [5.2–13.3] months, HR 0.368 [0.200–0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7–30.0] months, HR 0.457 [0.248–0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8–27.7] vs. 23.8 [19.0–28.5] months, HR 1.461 [1.005–2.124], P = 0.047) was observed in TP53missense cases after chemotherapy. Conclusions TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.https://doi.org/10.1186/s12967-023-04742-yPancreatic ductal adenocarcinoma (PDAC)TP53 mutation subtypeGain-of-function propertiesSurvival outcomes |
| spellingShingle | Yiran Zhou Jiabin Jin Yuchen Ji Jiaqiang Zhang Ningzhen Fu Mengmin Chen Jun Wang Kai Qin Yu Jiang Dongfeng Cheng Xiaxing Deng Baiyong Shen TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma Journal of Translational Medicine Pancreatic ductal adenocarcinoma (PDAC) TP53 mutation subtype Gain-of-function properties Survival outcomes |
| title | TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma |
| title_full | TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma |
| title_fullStr | TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma |
| title_full_unstemmed | TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma |
| title_short | TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma |
| title_sort | tp53 missense mutation reveals gain of function properties in small sized kras transformed pancreatic ductal adenocarcinoma |
| topic | Pancreatic ductal adenocarcinoma (PDAC) TP53 mutation subtype Gain-of-function properties Survival outcomes |
| url | https://doi.org/10.1186/s12967-023-04742-y |
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