Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Neuro Oncol. 2018 Nov 12;20(12):1625-1633. doi: 10.1093/neuonc/noy119.
The genomic characterization of sporadically arising gliomas has delineated molecularly and clinically distinct subclasses of disease. However, less is known about the molecular nature of gliomas that are familial in origin. We performed molecular subtyping of 163 tumor specimens from individuals with a family history of glioma and integrated germline and somatic genomic data to characterize the pathogenesis of 20 tumors in additional detail.
Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tumor sections to determine molecular subtypes of glioma. For 20 cases, tumor DNA was exome sequenced on an Illumina HiSeq 2000 platform and copy number profiling was performed on the Illumina HumanOmniExpress BeadChip. Genotypes at glioma risk polymorphisms were determined from germline DNA profiled on the Illumina Infinium OncoArray and deleterious germline mutations were identified from germline sequencing data.
All 3 molecular subtypes of sporadic glioma were represented in the overall case series, including molecular glioblastoma (n = 102), oligodendroglioma (n = 21), and astrocytoma (n = 20). Detailed profiling of 20 of these cases showed characteristic subtype-specific alterations at frequencies comparable to sporadic glioma cases. All 20 cases had alterations in genes regulating telomere length. Frequencies of common glioma risk alleles were similar to those among sporadic cases, and correlations between risk alleles and same-gene somatic mutations were not observed.
This study illustrates that the molecular characteristics of familial tumors profiled largely recapitulate what is known about sporadic glioma and that both germline and somatic molecular features target common core pathways involved in gliomagenesis.
散发性脑胶质瘤的基因组特征已经明确了在分子和临床方面具有明显不同的疾病亚类。然而，对于起源于家族的脑胶质瘤的分子性质知之甚少。我们对有脑胶质瘤家族史的 163 例肿瘤标本进行了分子分型，并整合了种系和体细胞基因组数据，以更详细地描述 20 例肿瘤的发病机制。
对福尔马林固定、石蜡包埋的肿瘤切片进行免疫组织化学分析，以确定脑胶质瘤的分子亚型。对于 20 例病例，使用 Illumina HiSeq 2000 平台对肿瘤 DNA 进行外显子组测序，并在 Illumina HumanOmniExpress BeadChip 上进行拷贝数谱分析。从 Illumina Infinium OncoArray 上 profiling 的种系 DNA 确定胶质瘤风险多态性的基因型，并从种系测序数据中确定有害的种系突变。
所有 3 种散发性脑胶质瘤的分子亚型在整个病例系列中均有代表，包括分子胶质母细胞瘤（n = 102）、少突胶质细胞瘤（n = 21）和星形细胞瘤（n = 20）。对其中 20 例病例的详细分析显示，具有特征性的亚类特异性改变，其频率与散发性脑胶质瘤病例相当。所有 20 例病例均存在调节端粒长度的基因改变。常见胶质瘤风险等位基因的频率与散发性病例相似，并且未观察到风险等位基因与同基因体细胞突变之间的相关性。
本研究表明，所分析的家族性肿瘤的分子特征在很大程度上再现了散发性脑胶质瘤的特征，并且种系和体细胞分子特征都针对涉及胶质瘤发生的共同核心途径。
