Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

Abstract Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Vetera...

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Autores principales:	Kung-Hao Liang, Che-Chang Chang, Kuo-Sheng Wu, Alice L. Yu, Shian-Ying Sung, Yi-Yen Lee, Muh-Lii Liang, Hsin-Hung Chen, Jun-Jeng Fen, Meng-En Chao, Yi-Ting Liao, Tai-Tong Wong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e96f9cecc0bb4657ab6c77263ba10107
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spelling	oai:doaj.org-article:e96f9cecc0bb4657ab6c77263ba101072021-12-05T12:15:37ZNotch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis10.1038/s41598-021-02651-y2045-2322https://doaj.org/article/e96f9cecc0bb4657ab6c77263ba101072021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02651-yhttps://doaj.org/toc/2045-2322Abstract Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients’ subsequent tumor recurrence (Hazard Ratio [HR] 1.645, confidence interval [CI] 1.337–2.025, P < 0.001) and mortality (HR 2.720, CI 1.798–4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292–1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762–4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis.Kung-Hao LiangChe-Chang ChangKuo-Sheng WuAlice L. YuShian-Ying SungYi-Yen LeeMuh-Lii LiangHsin-Hung ChenJun-Jeng FenMeng-En ChaoYi-Ting LiaoTai-Tong WongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kung-Hao Liang Che-Chang Chang Kuo-Sheng Wu Alice L. Yu Shian-Ying Sung Yi-Yen Lee Muh-Lii Liang Hsin-Hung Chen Jun-Jeng Fen Meng-En Chao Yi-Ting Liao Tai-Tong Wong Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
description	Abstract Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients’ subsequent tumor recurrence (Hazard Ratio [HR] 1.645, confidence interval [CI] 1.337–2.025, P < 0.001) and mortality (HR 2.720, CI 1.798–4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292–1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762–4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis.
format	article
author	Kung-Hao Liang Che-Chang Chang Kuo-Sheng Wu Alice L. Yu Shian-Ying Sung Yi-Yen Lee Muh-Lii Liang Hsin-Hung Chen Jun-Jeng Fen Meng-En Chao Yi-Ting Liao Tai-Tong Wong
author_facet	Kung-Hao Liang Che-Chang Chang Kuo-Sheng Wu Alice L. Yu Shian-Ying Sung Yi-Yen Lee Muh-Lii Liang Hsin-Hung Chen Jun-Jeng Fen Meng-En Chao Yi-Ting Liao Tai-Tong Wong
author_sort	Kung-Hao Liang
title	Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
title_short	Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
title_full	Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
title_fullStr	Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
title_full_unstemmed	Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
title_sort	notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e96f9cecc0bb4657ab6c77263ba10107
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Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

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