Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma
Abstract A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine‐specific demethylase 5D (KDM5D) copy number los...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
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| Series: | The Journal of Pathology: Clinical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cjp2.350 |
| _version_ | 1797372469350236160 |
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| author | Ayako Ura Takuo Hayashi Kazumasa Komura Masaki Hosoya Kazuya Takamochi Eiichi Sato Satomi Saito Susumu Wakai Takafumi Handa Tsuyoshi Saito Shunsuke Kato Kenji Suzuki Takashi Yao the Tokyo Metropolitan Innovative Oncology Research Group (TMIG) |
| author_facet | Ayako Ura Takuo Hayashi Kazumasa Komura Masaki Hosoya Kazuya Takamochi Eiichi Sato Satomi Saito Susumu Wakai Takafumi Handa Tsuyoshi Saito Shunsuke Kato Kenji Suzuki Takashi Yao the Tokyo Metropolitan Innovative Oncology Research Group (TMIG) |
| author_sort | Ayako Ura |
| collection | DOAJ |
| description | Abstract A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine‐specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia‐telangiectasia and Rad3‐related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome‐wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with ‘cell cycle’, whereas downregulated genes in tumors with KDM5D copy number loss were associated with ‘immune response’. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor‐infiltrating CD8+/T‐bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild‐type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be ‘cold tumors’, which are characterized by the paucity of tumor T‐cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors. |
| first_indexed | 2024-03-08T18:36:11Z |
| format | Article |
| id | doaj.art-d74d3a6bf28241e39e1c5855f8cdaf80 |
| institution | Directory Open Access Journal |
| issn | 2056-4538 |
| language | English |
| last_indexed | 2024-03-08T18:36:11Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | The Journal of Pathology: Clinical Research |
| spelling | doaj.art-d74d3a6bf28241e39e1c5855f8cdaf802023-12-29T12:56:36ZengWileyThe Journal of Pathology: Clinical Research2056-45382024-01-01101n/an/a10.1002/cjp2.350Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinomaAyako Ura0Takuo Hayashi1Kazumasa Komura2Masaki Hosoya3Kazuya Takamochi4Eiichi Sato5Satomi Saito6Susumu Wakai7Takafumi Handa8Tsuyoshi Saito9Shunsuke Kato10Kenji Suzuki11Takashi Yao12the Tokyo Metropolitan Innovative Oncology Research Group (TMIG)Department of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Urology Osaka Medical and Pharmaceutical University Osaka JapanDepartment of Clinical Oncology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of General Thoracic Surgery Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Pathology Institute of Medical Science (Medical Research Center), Tokyo Medical University Tokyo JapanDepartment of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanDivision of Clinical Laboratory National Center for Global Health and Medicine Tokyo JapanDepartment of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Clinical Oncology Juntendo University Graduate School of Medicine Tokyo JapanDepartment of General Thoracic Surgery Juntendo University Graduate School of Medicine Tokyo JapanDepartment of Human Pathology Juntendo University Graduate School of Medicine Tokyo JapanAbstract A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine‐specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia‐telangiectasia and Rad3‐related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome‐wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with ‘cell cycle’, whereas downregulated genes in tumors with KDM5D copy number loss were associated with ‘immune response’. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor‐infiltrating CD8+/T‐bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild‐type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be ‘cold tumors’, which are characterized by the paucity of tumor T‐cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.https://doi.org/10.1002/cjp2.350ataxia‐telangiectasia and Rad3‐related kinaseDNA damage responseKDM5Dsquamous cell carcinoma |
| spellingShingle | Ayako Ura Takuo Hayashi Kazumasa Komura Masaki Hosoya Kazuya Takamochi Eiichi Sato Satomi Saito Susumu Wakai Takafumi Handa Tsuyoshi Saito Shunsuke Kato Kenji Suzuki Takashi Yao the Tokyo Metropolitan Innovative Oncology Research Group (TMIG) Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma The Journal of Pathology: Clinical Research ataxia‐telangiectasia and Rad3‐related kinase DNA damage response KDM5D squamous cell carcinoma |
| title | Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| title_full | Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| title_fullStr | Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| title_full_unstemmed | Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| title_short | Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| title_sort | copy number loss of kdm5d may be a predictive biomarker for atr inhibitor treatment in male patients with pulmonary squamous cell carcinoma |
| topic | ataxia‐telangiectasia and Rad3‐related kinase DNA damage response KDM5D squamous cell carcinoma |
| url | https://doi.org/10.1002/cjp2.350 |
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