Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy
Abstract Background Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-023-03122-2 |
| _version_ | 1797556309285928960 |
|---|---|
| author | Yang Li Yang Liu Keyan Yang Ling Jin Jing Yang Shuang Huang Ying Liu Bo Hu Rong Liu Wei Liu Ansheng Liu Qinlong Zheng Yonghong Zhang |
| author_facet | Yang Li Yang Liu Keyan Yang Ling Jin Jing Yang Shuang Huang Ying Liu Bo Hu Rong Liu Wei Liu Ansheng Liu Qinlong Zheng Yonghong Zhang |
| author_sort | Yang Li |
| collection | DOAJ |
| description | Abstract Background Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. Methods 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher’s exact test were applied to test for group differences. Results A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. Conclusion These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations. |
| first_indexed | 2024-03-10T17:00:02Z |
| format | Article |
| id | doaj.art-90779d56bb0c4be9b8ed964e25f114c6 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-10T17:00:02Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-90779d56bb0c4be9b8ed964e25f114c62023-11-20T10:59:43ZengBMCCancer Cell International1475-28672023-11-0123111210.1186/s12935-023-03122-2Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapyYang Li0Yang Liu1Keyan Yang2Ling Jin3Jing Yang4Shuang Huang5Ying Liu6Bo Hu7Rong Liu8Wei Liu9Ansheng Liu10Qinlong Zheng11Yonghong Zhang12Molecular diagnostics laboratory, Beijing GoBroad Boren HospitalDepartment of Pediatric Lymphoma, Beijing GoBroad Boren HospitalMolecular diagnostics laboratory, Beijing GoBroad Boren HospitalDepartment of Hematology/Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical UniversityDepartment of Hematology/Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical UniversityDepartment of Hematology/Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical UniversityDepartment of Pediatric Lymphoma, Beijing GoBroad Boren HospitalDepartment of Pediatric Lymphoma, Beijing GoBroad Boren HospitalDepartment of Hematology/Oncology, Capital institute of pediatricDepartment of Hematology/Oncology, Zhengzhou Children’s HospitalDepartment of Hematology/Oncology, Xian Children’s HospitalMolecular diagnostics laboratory, Beijing GoBroad Boren HospitalDepartment of Pediatric Lymphoma, Beijing GoBroad Boren HospitalAbstract Background Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. Methods 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher’s exact test were applied to test for group differences. Results A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. Conclusion These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations.https://doi.org/10.1186/s12935-023-03122-2Pediatric B-cell non-hodgkin LymphomasCAR-T cell therapiesGene mutations |
| spellingShingle | Yang Li Yang Liu Keyan Yang Ling Jin Jing Yang Shuang Huang Ying Liu Bo Hu Rong Liu Wei Liu Ansheng Liu Qinlong Zheng Yonghong Zhang Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy Cancer Cell International Pediatric B-cell non-hodgkin Lymphomas CAR-T cell therapies Gene mutations |
| title | Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy |
| title_full | Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy |
| title_fullStr | Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy |
| title_full_unstemmed | Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy |
| title_short | Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy |
| title_sort | impact of arid1a and tp53 mutations in pediatric refractory or relapsed mature b cell lymphoma treated with car t cell therapy |
| topic | Pediatric B-cell non-hodgkin Lymphomas CAR-T cell therapies Gene mutations |
| url | https://doi.org/10.1186/s12935-023-03122-2 |
| work_keys_str_mv | AT yangli impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT yangliu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT keyanyang impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT lingjin impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT jingyang impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT shuanghuang impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT yingliu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT bohu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT rongliu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT weiliu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT anshengliu impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT qinlongzheng impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy AT yonghongzhang impactofarid1aandtp53mutationsinpediatricrefractoryorrelapsedmaturebcelllymphomatreatedwithcartcelltherapy |