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Central nervous system (CNS) metastasis is the most common brain tumor type in adults. Compared to their primary tumors, these metastases undergo a variety of genetic changes to be able to survive and thrive in the complex tissue microenvironment of the brain. In clinical settings, the majority of traditional chemotherapies have shown limited efficacy against CNS metastases. However, the discovery of potential driver mutations, and the development of drugs specifically targeting affected signaling pathways, could change the treatment landscape of CNS metastasis. Genetic studies of brain tumors have so far focused mainly on common cancers in western populations. In this study, we performed Next Generation Sequencing (NGS) on 50 pairs of primary tumors, including but not limited to colorectal, breast, renal and thyroid tumors, along with their brain metastatic tumor tissue counterparts, from three different local tertiary centers in Saudi Arabia. We identified potentially clinically relevant mutations in brain metastases that were not detected in corresponding primary tumors, including mutations in the PI3K, CDK, and MAPK pathways. These data highlight the differences between primary cancers and brain metastases and the importance of acquiring and analyzing brain metastatic samples for further clinical management.

Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we show that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.