Lancet Oncol：脑瘤治疗的新遗传标记物

近日，英国诺丁汉大学研究人员发现脑癌3套遗传标记物，可能为致命的脑瘤诊断带来新的希望。

这项最新研究由Richard Grundy教授率领，发表在权威杂志Lancet Oncology最新一期上。

尽管需要新的、更有效的治疗手段，早些年也已经开展了一系列研究，但取得的成绩并不如人意。这项诺丁汉大学完成的研究旨在筛选出可用来提高癌症治疗功效和开展治疗的分子标记物。

诺丁汉大学与加拿大多伦多病童医院合作共收集到142例中枢神经系统PNET的样品。Richard Grundy教授说：我们先前的研究使得我们意识到需要国际努力才能带来足够数量样本，才能使我们更好地了解这种疾病。

通过研究肿瘤的基因，他们发现该类型肿瘤有三个子类型具有明显的遗传异常，这些基因的异常可导致患者出现不同的结果。

他们发现通过在两个遗传标记物（LIN28和OLIG2）表达上的差异，每个基因组都有自己的基因特征。

当与临床因素包括年龄、生存期和转移相比时，他们发现第1肿瘤组患者往往是最年轻的患者，存活率也最低。而第3组肿瘤患者在诊断时出现转移的发病率时最高的。

最终，研究确定了两个遗传标记物LIN28和OLIG2可能是脑肿瘤患者的诊断和预测的潜在标志物。

这项研究由加拿大健康研究学院、Brainchild/Sick Kids基金会和Samantha Dickson脑肿瘤信托基金资助。

doi:10.1016/S1470-2045(12)70257-7
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Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis

Daniel Picard BSc a *, Suzanne Miller PhD d *, Cynthia E Hawkins MD b, Prof Eric Bouffet MD a, Hazel A Rogers PhD d, Tiffany SY Chan BSc a, Seung-Ki Kim MD e, Prof Young-Shin Ra MD f, Jason Fangusaro MD g, Andrey Korshunov MD h, Helen Toledano MD i, Hideo Nakamura MD j, James T Hayden MD k, Jennifer Chan MD l, Lucie Lafay-Cousin MD m, Pingzhao Hu PhD c, Xing Fan MD n, Prof Karin M Muraszko MD n, Prof Scott L Pomeroy MD o, Ching C Lau MD p, Prof Ho-Keung Ng MD q, Chris Jones PhD r, Timothy Van Meter PhD s, Prof Steven C Clifford PhD k, Prof Charles Eberhart MD t, Amar Gajjar MD u, Stefan M Pfister MD v, Prof Richard G Grundy MD d , Dr Annie Huang MD

Background

Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease.

Methods

We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers.

Findings

We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4—5·2] for group 1 vs 7·9 years [6·0—9·7] for group 2 and 5·9 years [4·9—7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5—1·2] in group 1, 1·8 years [1·4—2·3] in group 2 and 4·3 years [0·8—7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037).

Interpretation

LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials.