The genomic consequences of tumor hypoxia in human cancers

Abstract Introduction: Localized prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumors. Prostate tumor cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumors with low levels of oxygen (hypoxia) have poor clinical outcomes. Methods and Results: To understand the correlates of hypoxia in cancer we conducted a pan-cancer analysis of copy number alterations (CNAs) and single nucleotide variants (SNVs) across 19 cancer types. We measured hypoxia using multiple mRNA-based signatures and discovered numerous CNAs and SNVs enriched or depleted in hypoxic tumors, highlighting the role of hypoxia in shaping the genomic landscape of multiple tumor types. Next, we examined 548 patients with localized prostate cancer and statistically assessed the association of hypoxia with CNAs, SNVs, genomic rearrangements, focal genomic events (i.e. kataegis, chromothripsis), telomere length, clinical indices (i.e. grade, stage) and subclonal architecture. Tumor hypoxia is associated with specific CNAs and SNVs in prostate cancer driver genes. To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumor microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups. Impact: These data suggest that the aggressiveness of cancers is driven by the interplay of the tumor microenvironment and its genomic mutational profile. Citation Format: Vinayak Bhandari, Shadrielle M. Espiritu, Lydia Y. Liu, Emilie Lalonde, Takafumi N. Yamaguchi, Lawrence E. Heisler, Julie Livingstone, Vincent Huang, Yu-Jia Shiah, Veronica Y. Sabelnykova, Fouad Yousif, Melvin L. Chua, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Robert G. Bristow. The genomic consequences of tumor hypoxia in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2432.