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Using evolutionary constraint to define novel candidate driver genes in medulloblastoma.

Ananya Roy1, Sharadha Sakthikumar2,3, Sergey V Kozyrev2

  • 1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|August 7, 2023
PubMed
Summary

Researchers identified regulatory noncoding mutations in cancer genomes by analyzing conserved regions. These noncoding constraint mutations (NCCMs) differ significantly between malignant medulloblastoma and benign pilocytic astrocytoma, revealing new therapeutic targets.

Keywords:
cancerevolutionary constraintmedulloblastomapilocytic astrocytomaregulatory mutations

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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.