m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

Abstract Background Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N 6-methyladenos...

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Autores principales:	Zhihui Zhang, Chaoqi Zhang, Yuejun Luo, Peng Wu, Guochao Zhang, Qingpeng Zeng, Lide Wang, Zhaoyang Yang, Liyan Xue, Bo Zheng, Hua Zeng, Fengwei Tan, Qi Xue, Shugeng Gao, Nan Sun, Jie He
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	m6A regulators Small cell lung cancer Chemotherapy Immunotherapy Individualized medicine Medicine R
Acceso en línea:	https://doaj.org/article/dd9d148f1db54179a35633ac8c984e84
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spelling	oai:doaj.org-article:dd9d148f1db54179a35633ac8c984e842021-11-28T12:15:21Zm6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer10.1186/s12916-021-02148-51741-7015https://doaj.org/article/dd9d148f1db54179a35633ac8c984e842021-11-01T00:00:00Zhttps://doi.org/10.1186/s12916-021-02148-5https://doaj.org/toc/1741-7015Abstract Background Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N 6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. Methods We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. Results We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. Conclusions Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.Zhihui ZhangChaoqi ZhangYuejun LuoPeng WuGuochao ZhangQingpeng ZengLide WangZhaoyang YangLiyan XueBo ZhengHua ZengFengwei TanQi XueShugeng GaoNan SunJie HeBMCarticlem6A regulatorsSmall cell lung cancerChemotherapyImmunotherapyIndividualized medicineMedicineRENBMC Medicine, Vol 19, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	m6A regulators Small cell lung cancer Chemotherapy Immunotherapy Individualized medicine Medicine R
spellingShingle	m6A regulators Small cell lung cancer Chemotherapy Immunotherapy Individualized medicine Medicine R Zhihui Zhang Chaoqi Zhang Yuejun Luo Peng Wu Guochao Zhang Qingpeng Zeng Lide Wang Zhaoyang Yang Liyan Xue Bo Zheng Hua Zeng Fengwei Tan Qi Xue Shugeng Gao Nan Sun Jie He m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
description	Abstract Background Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N 6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. Methods We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. Results We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. Conclusions Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.
format	article
author	Zhihui Zhang Chaoqi Zhang Yuejun Luo Peng Wu Guochao Zhang Qingpeng Zeng Lide Wang Zhaoyang Yang Liyan Xue Bo Zheng Hua Zeng Fengwei Tan Qi Xue Shugeng Gao Nan Sun Jie He
author_facet	Zhihui Zhang Chaoqi Zhang Yuejun Luo Peng Wu Guochao Zhang Qingpeng Zeng Lide Wang Zhaoyang Yang Liyan Xue Bo Zheng Hua Zeng Fengwei Tan Qi Xue Shugeng Gao Nan Sun Jie He
author_sort	Zhihui Zhang
title	m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
title_short	m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
title_full	m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
title_fullStr	m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
title_full_unstemmed	m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
title_sort	m6a regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-pd-1 immunotherapy in patients with small-cell lung cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/dd9d148f1db54179a35633ac8c984e84
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m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

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