Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.
Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.
复制标题
DOI：
10.1016/s1470-2045(17)30243-7
复制
发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Clifford SC
中科院分区：
文献类型：
--
作者：
Schwalbe EC;Lindsey JC;Nakjang S;Crosier S;Smith AJ;Hicks D;Rafiee G;Hill RM;Iliasova A;Stone T;Pizer B;Michalski A;Joshi A;Wharton SB;Jacques TS;Bailey S;Williamson D;Clifford SC
国际共识承认四个髓母细胞瘤分子亚群：WNT(MBWNT)、SHH(MBSHH)、组3(MBGrp3)和组4(MBGrp4)，每个亚组都由其特有的全基因组转录和DNA甲基组图谱定义。这些亚群具有不同的临床病理和分子特征，是目前正在进行临床试验的疾病亚型和最初的亚群导向治疗的基础。然而，在每个亚群中都存在明显的生物学异质性和生存差异，这些问题仍有待解决。我们的目的是调查儿童髓母细胞瘤中是否存在额外的分子亚群，以及这些亚群是否可以用于改善疾病亚型和预后预测。在这项回顾性队列研究中，我们评估了从英国儿童癌症和白血病组织(CCLG)治疗中心(UK)、合作的欧洲机构和UKCCSG-SIOP-PNET3欧洲临床试验收集的428个原发髓母细胞瘤样本。对档案肿瘤样本的独立验证队列(n=276)也进行了分析。我们分析了儿童髓母细胞瘤患者的样本，这些患者确诊时年龄为0-16岁，并进行了中央病理学回顾和全面的临床资料。我们进行了全面的分子图谱分析，包括DNA甲基化微阵列分析，并进行了测试和验证队列的非监督分类发现，以确定一致的主要分子亚群，并表征它们的临床和生物学意义。我们模拟了215名接受过颅脊放射治疗的患者(n=215)的3-16岁患者的存活率。我们鉴定了儿童髓母细胞瘤的7个健壮和可复制的初级分子亚群。MBWNT保持不变，剩下的每个共识小组被一分为二。按年龄分为婴儿期(4·3岁)和儿童期(≥4·3岁)亚组。MBGrp3和MBGrp4分为高危亚组(MBGrp3-HR[n=65]和MBGrp4-HR[n=85])和低危亚组(MBGrp3-LR[n=50]和MBGrp4-LR[n=73])。这些生物学亚群在独立队列中得到了验证。我们确定了预测结果的七个亚组的特征。交叉验证的亚组依赖生存模型结合了这些新的亚组以及次级临床病理和分子特征以及已建立的疾病风险因素，优于现有的疾病风险分层方案。这些亚组依赖模型将患者分为四个临床风险组，用于5年无进展生存：有利风险(215名患者中54[25%]；91%存活率[95%可信区间82-100])；标准风险(50名[23%]患者；81%存活率[70-94])；高风险(82名[38%]患者；42%存活率[31-56])；以及极高风险(29名[13%]患者；28%存活率[14-56])。七个新的、具有临床意义的亚组的发现改善了疾病风险分层，并可能为治疗决策提供信息。这些数据为未来的研究和临床研究提供了新的基础。英国癌症研究基金会、汤姆·格雷厄姆信托基金会、哈里斯之星基金会、行动医学研究基金会、斯帕克斯基金会、JGW Patterson基金会、本能网络(由脑瘤慈善机构、大奥蒙德街儿童慈善机构和英国癌症儿童基金会共同资助)。
International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82–100]); standard risk (50 [23%] patients; 81% survival [70–94]); high-risk (82 [38%] patients; 42% survival [31–56]); and very high-risk (29 [13%] patients; 28% survival [14–56]). The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).