Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.

中文翻译：

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原发性松果体实质性肿瘤的分子亚组揭示了与临床参数和遗传改变相关的不同亚型。

松果体区域的肿瘤包括具有不同临床和组织病理学特征的几种不同实体。尽管某些实体主要影响成年人，但成母细胞瘤（PB）构成了儿童期恶性程度很高的恶性肿瘤，预后较差。PB主要散发，但也可能在癌症易感综合征（包括DICER1和RB1种系突变）的背景下发生。通过这项研究，我们调查了松果体肿瘤的临床病理亚组，并进一步表征了它们的生物学特征。我们在195个松果体区域肿瘤和20个正常松果体对照中进行了全基因组DNA甲基化分析。从DNA甲基化数据获得拷贝数概况；对93个肿瘤添加了基因组测序，对22个肿瘤样品的miRNA测序进一步补充了分析。基于DNA甲基化分析的无监督聚类分离了已知的亚组，如松细胞瘤，中间分化的松果体实质肿瘤，松果体区和PB的乳头状瘤，以及这些组中的其他不同亚型，包括核心PB亚组中的三个亚型。新型的分子亚群Pin-RB包括三侧视网膜母细胞瘤以及具有RB1改变的零星松果体肿瘤，并显示与视网膜母细胞瘤的相似性。不同的临床协会将第二个新的分子亚组PB-MYC与其他PB病例区分开来。在三种核心PB亚型的病例中，约有三分之二发现了miRNA加工途径内的改变（影响DROSHA，DGCR8或DICER1）。甲基化分析揭示了松果体肿瘤的生物学上不同的组，具有特定的临床和分子特征。我们的发现为PB和其他松果体肿瘤的进一步临床以及分子和功能表征，包括miRNA加工缺陷在肿瘤发生中的作用提供了基础。