Using evolutionary constraint to define novel candidate driver genes in medulloblastoma

Area of Science:

• Genomics and Bioinformatics
• Cancer Research
• Evolutionary Biology

Background:

• Cancer genomics research has historically overlooked noncoding mutations, limiting our understanding of regulatory genetic alterations.
• Noncoding mutations in conserved genomic regions are hypothesized to play a significant role in cancer development.
• Distinguishing between mutations in malignant and benign tumors can provide insights into distinct oncogenic pathways.

Purpose of the Study:

• To systematically identify functional, regulatory noncoding mutations using evolutionary constraint.
• To compare the landscape of noncoding constraint mutations (NCCMs) between malignant medulloblastoma (MB) and benign pilocytic astrocytoma (PA).
• To explore the potential of identified NCCMs as biomarkers for patient stratification and personalized cancer treatment.

Main Methods:

• Utilized whole-genome sequencing data from the International Cancer Genome Consortium.
• Integrated evolutionary constraint data from 240 mammalian species to pinpoint conserved, potentially functional noncoding regions.
• Analyzed and compared NCCM frequencies in MB and PA, focusing on specific gene loci and their association with clinical features.

Main Results:

• Identified a significant difference in NCCM frequencies between MB and PA, with MB exhibiting a higher burden.
• In PA, NCCMs were predominantly found at the BRAF locus, consistent with its known mutation frequency.
• In MB, over 500 genes showed high NCCM levels, with specific loci like HOXB associated with early-onset disease and WASF-2/AHDC1/FGR linked to adult-onset MB. One NCCM at the FGR locus increased SRC kinase expression and drug sensitivity.

Conclusions:

• Noncoding constraint mutations are crucial for understanding cancer genomics, particularly in distinguishing tumor types.
• NCCMs highlight distinct molecular pathways and age-related differences in medulloblastoma pathogenesis.
• Identified NCCMs represent promising candidate driver mutations for improved medulloblastoma patient stratification and targeted therapy development.