Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma
Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD) is the most frequent copy‐number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, an...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13206 |
| _version_ | 1818027484802711552 |
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| author | Yuan Peng Yonghong Chen Mengmeng Song Xiaoyue Zhang Pansong Li Xian Yu Yusheng Huang Ni Zhang Liyan Ji Lei Xia Xuefeng Xia Xin Yi Benxu Tan Zhenzhou Yang |
| author_facet | Yuan Peng Yonghong Chen Mengmeng Song Xiaoyue Zhang Pansong Li Xian Yu Yusheng Huang Ni Zhang Liyan Ji Lei Xia Xuefeng Xia Xin Yi Benxu Tan Zhenzhou Yang |
| author_sort | Yuan Peng |
| collection | DOAJ |
| description | Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD) is the most frequent copy‐number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK‐IMPACT clinical cohort. CDKN2A/BHD was present in 19.1% of the TCGA‐LUAD cohort and in 5.7% of the MSK‐IMPACT cohort. CDKN2A/BHD patients had shorter disease‐free survival and overall survival compared with CDKN2A/BWT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/BHD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/BHD. In contrast, homozygous deletion of type I interferons (IFN‐IHD) frequently co‐occurred with CDKN2A/BHD. CDKN2A/B and IFN‐I are co‐located in the same p21.3 region of chromosome 9. The co‐occurrence of CDKN2A/BHD and IFN‐IHD was not related to whole‐genome doubling, chromosome instability, or aneuploidy. Patients with co‐occurring CDKN2A/BHD and IFN‐IHD had shorter disease‐free survival and overall survival compared with CDKN2A/BWT patients. CDKN2A/BHDIFN‐IHD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN‐I depletion. |
| first_indexed | 2024-12-10T04:48:38Z |
| format | Article |
| id | doaj.art-3963b9d702484a52ad201983fc590f70 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-10T04:48:38Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-3963b9d702484a52ad201983fc590f702022-12-22T02:01:41ZengWileyMolecular Oncology1574-78911878-02612022-04-011681746176010.1002/1878-0261.13206Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinomaYuan Peng0Yonghong Chen1Mengmeng Song2Xiaoyue Zhang3Pansong Li4Xian Yu5Yusheng Huang6Ni Zhang7Liyan Ji8Lei Xia9Xuefeng Xia10Xin Yi11Benxu Tan12Zhenzhou Yang13Department of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaGeneplus‐Beijing Institute Beijing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaGeneplus‐Beijing Institute Beijing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaGeneplus‐Beijing Institute Beijing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaGeneplus‐Beijing Institute Beijing ChinaGeneplus‐Beijing Institute Beijing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaDepartment of Cancer Center Second Affiliated Hospital Chongqing Medical University Chongqing ChinaHomozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD) is the most frequent copy‐number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK‐IMPACT clinical cohort. CDKN2A/BHD was present in 19.1% of the TCGA‐LUAD cohort and in 5.7% of the MSK‐IMPACT cohort. CDKN2A/BHD patients had shorter disease‐free survival and overall survival compared with CDKN2A/BWT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/BHD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/BHD. In contrast, homozygous deletion of type I interferons (IFN‐IHD) frequently co‐occurred with CDKN2A/BHD. CDKN2A/B and IFN‐I are co‐located in the same p21.3 region of chromosome 9. The co‐occurrence of CDKN2A/BHD and IFN‐IHD was not related to whole‐genome doubling, chromosome instability, or aneuploidy. Patients with co‐occurring CDKN2A/BHD and IFN‐IHD had shorter disease‐free survival and overall survival compared with CDKN2A/BWT patients. CDKN2A/BHDIFN‐IHD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN‐I depletion.https://doi.org/10.1002/1878-0261.13206CDKN2A/Bhomozygous deletiontumor immune microenvironmenttype I interferons |
| spellingShingle | Yuan Peng Yonghong Chen Mengmeng Song Xiaoyue Zhang Pansong Li Xian Yu Yusheng Huang Ni Zhang Liyan Ji Lei Xia Xuefeng Xia Xin Yi Benxu Tan Zhenzhou Yang Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma Molecular Oncology CDKN2A/B homozygous deletion tumor immune microenvironment type I interferons |
| title | Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| title_full | Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| title_fullStr | Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| title_full_unstemmed | Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| title_short | Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| title_sort | co occurrence of cdkn2a b and ifn i homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma |
| topic | CDKN2A/B homozygous deletion tumor immune microenvironment type I interferons |
| url | https://doi.org/10.1002/1878-0261.13206 |
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