Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations
Abstract Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association of FAT1 mutations with ICI response a...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-022-00292-6 |
| _version_ | 1797641828243079168 |
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| author | Wenjing Zhang Yunfeng Tang Yuxian Guo Yujia Kong Fuyan Shi Chao Sheng Suzhen Wang Qinghua Wang |
| author_facet | Wenjing Zhang Yunfeng Tang Yuxian Guo Yujia Kong Fuyan Shi Chao Sheng Suzhen Wang Qinghua Wang |
| author_sort | Wenjing Zhang |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association of FAT1 mutations with ICI response and outcome. We collected somatic mutation profiles and clinical information from ICI-treated 631 melanoma and 109 NSCLC samples, respectively. For validation, a pan-cancer cohort with 1661 patients in an immunotherapy setting was also used. Melanoma and NSCLC samples from the Cancer Genome Atlas were used to evaluate the potential immunologic mechanisms of FAT1 mutations. In melanoma, patients with FAT1 mutations had a significantly improved survival outcome than those wild-type patients (HR: 0.67, 95% CI: 0.46–0.97, P = 0.033). An elevated ICI response rate also appeared in FAT1-mutated patients (43.2% vs. 29.2%, P = 0.032). Associations of FAT1 mutations with improved prognosis and ICI response were confirmed in NSCLC patients. In the pan-cancer cohort, the association between FAT1 mutations and favorable ICI outcome was further validated (HR: 0.74, 95% CI: 0.58–0.96, P = 0.022). Genomic and immunologic analysis showed that a high mutational burden, increased infiltration of immune-response cells, decreased infiltration of immune-suppressive cells, interferon and cell cycle-related pathways were enriched in patients with FAT1 mutations. Our study revealed that FAT1 mutations were associated with better immunogenicity and ICI efficacy, which may be considered as a biomarker for selecting patients to receive immunotherapy. |
| first_indexed | 2024-03-11T13:51:20Z |
| format | Article |
| id | doaj.art-8801898229764f608a64e00274266c6d |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-11T13:51:20Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-8801898229764f608a64e00274266c6d2023-11-02T08:34:39ZengNature Portfolionpj Precision Oncology2397-768X2022-06-016111010.1038/s41698-022-00292-6Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutationsWenjing Zhang0Yunfeng Tang1Yuxian Guo2Yujia Kong3Fuyan Shi4Chao Sheng5Suzhen Wang6Qinghua Wang7Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversitySchool of Public Health, Weifang Medical UniversityDepartment of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversityDepartment of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversityDepartment of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversityDepartment of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and HospitalDepartment of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversityDepartment of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical UniversityAbstract Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association of FAT1 mutations with ICI response and outcome. We collected somatic mutation profiles and clinical information from ICI-treated 631 melanoma and 109 NSCLC samples, respectively. For validation, a pan-cancer cohort with 1661 patients in an immunotherapy setting was also used. Melanoma and NSCLC samples from the Cancer Genome Atlas were used to evaluate the potential immunologic mechanisms of FAT1 mutations. In melanoma, patients with FAT1 mutations had a significantly improved survival outcome than those wild-type patients (HR: 0.67, 95% CI: 0.46–0.97, P = 0.033). An elevated ICI response rate also appeared in FAT1-mutated patients (43.2% vs. 29.2%, P = 0.032). Associations of FAT1 mutations with improved prognosis and ICI response were confirmed in NSCLC patients. In the pan-cancer cohort, the association between FAT1 mutations and favorable ICI outcome was further validated (HR: 0.74, 95% CI: 0.58–0.96, P = 0.022). Genomic and immunologic analysis showed that a high mutational burden, increased infiltration of immune-response cells, decreased infiltration of immune-suppressive cells, interferon and cell cycle-related pathways were enriched in patients with FAT1 mutations. Our study revealed that FAT1 mutations were associated with better immunogenicity and ICI efficacy, which may be considered as a biomarker for selecting patients to receive immunotherapy.https://doi.org/10.1038/s41698-022-00292-6 |
| spellingShingle | Wenjing Zhang Yunfeng Tang Yuxian Guo Yujia Kong Fuyan Shi Chao Sheng Suzhen Wang Qinghua Wang Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations npj Precision Oncology |
| title | Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations |
| title_full | Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations |
| title_fullStr | Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations |
| title_full_unstemmed | Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations |
| title_short | Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations |
| title_sort | favorable immune checkpoint inhibitor outcome of patients with melanoma and nsclc harboring fat1 mutations |
| url | https://doi.org/10.1038/s41698-022-00292-6 |
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