{"title":"朗格汉斯细胞组织细胞增生症患儿的遗传特征及其预后影响","authors":"Chan-Juan Wang, Lei Cui, Shuang-Shuang Li, Hong-Hao Ma, Dong Wang, Hong-Yun Lian, Yun-Ze Zhao, Li-Ping Zhang, Wei-Jing Li, Qing Zhang, Xiao-Xi Zhao, Ying Yang, Xiao-Tong Huang, Wei Liu, Yi-Zhuo Wang, Wan-Shui Wu, Tian-You Wang, Rui Zhang, Zhi-Gang Li","doi":"10.5858/arpa.2023-0236-OA","DOIUrl":null,"url":null,"abstract":"<p><strong>Context.—: </strong>Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.</p><p><strong>Objective.—: </strong>To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.</p><p><strong>Design.—: </strong>We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.</p><p><strong>Results.—: </strong>A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.</p><p><strong>Conclusions.—: </strong>Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.</p>","PeriodicalId":93883,"journal":{"name":"Archives of pathology & laboratory medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.\",\"authors\":\"Chan-Juan Wang, Lei Cui, Shuang-Shuang Li, Hong-Hao Ma, Dong Wang, Hong-Yun Lian, Yun-Ze Zhao, Li-Ping Zhang, Wei-Jing Li, Qing Zhang, Xiao-Xi Zhao, Ying Yang, Xiao-Tong Huang, Wei Liu, Yi-Zhuo Wang, Wan-Shui Wu, Tian-You Wang, Rui Zhang, Zhi-Gang Li\",\"doi\":\"10.5858/arpa.2023-0236-OA\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Context.—: </strong>Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.</p><p><strong>Objective.—: </strong>To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.</p><p><strong>Design.—: </strong>We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.</p><p><strong>Results.—: </strong>A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.</p><p><strong>Conclusions.—: </strong>Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.</p>\",\"PeriodicalId\":93883,\"journal\":{\"name\":\"Archives of pathology & laboratory medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-05-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of pathology & laboratory medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.5858/arpa.2023-0236-OA\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of pathology & laboratory medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.5858/arpa.2023-0236-OA","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.
Context.—: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.
Objective.—: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.
Design.—: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.
Results.—: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.
Conclusions.—: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.
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