Cargando…

Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy

ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Yu-Chu, Lee, Ka-Wo, Tsai, Yi-Shan, Lu, Hsing-Han, Chen, Si-Yun, Hsieh, Hsin-Ying, Lin, Chang-Shen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151497/
https://www.ncbi.nlm.nih.gov/pubmed/34068585
http://dx.doi.org/10.3390/jpm11050389
_version_ 1783698397018980352
author Wang, Yu-Chu
Lee, Ka-Wo
Tsai, Yi-Shan
Lu, Hsing-Han
Chen, Si-Yun
Hsieh, Hsin-Ying
Lin, Chang-Shen
author_facet Wang, Yu-Chu
Lee, Ka-Wo
Tsai, Yi-Shan
Lu, Hsing-Han
Chen, Si-Yun
Hsieh, Hsin-Ying
Lin, Chang-Shen
author_sort Wang, Yu-Chu
collection PubMed
description ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.
format Online
Article
Text
id pubmed-8151497
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81514972021-05-27 Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy Wang, Yu-Chu Lee, Ka-Wo Tsai, Yi-Shan Lu, Hsing-Han Chen, Si-Yun Hsieh, Hsin-Ying Lin, Chang-Shen J Pers Med Article ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy. MDPI 2021-05-10 /pmc/articles/PMC8151497/ /pubmed/34068585 http://dx.doi.org/10.3390/jpm11050389 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Yu-Chu
Lee, Ka-Wo
Tsai, Yi-Shan
Lu, Hsing-Han
Chen, Si-Yun
Hsieh, Hsin-Ying
Lin, Chang-Shen
Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title_full Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title_fullStr Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title_full_unstemmed Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title_short Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy
title_sort downregulation of atm and brca1 predicts poor outcome in head and neck cancer: implications for atm-targeted therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151497/
https://www.ncbi.nlm.nih.gov/pubmed/34068585
http://dx.doi.org/10.3390/jpm11050389
work_keys_str_mv AT wangyuchu downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT leekawo downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT tsaiyishan downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT luhsinghan downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT chensiyun downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT hsiehhsinying downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy
AT linchangshen downregulationofatmandbrca1predictspooroutcomeinheadandneckcancerimplicationsforatmtargetedtherapy