• Cistrome partitioning reveals convergence of somatic mutations and risk variants on master transcription regulators in primary prostate tumors

      Mazrooei, P; Kron, KJ; Zhu, Y; Zhou, S; Grillo, G; Mehdi, T; Ahmed, M; Severson, TM; Guilhamon, P; Armstrong, NS; et al. (2019)
      Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1, and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variants and somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulate in cistromes of master transcription regulators required for prostate cancer development.
    • Genome-wide germline correlates of the epigenetic landscape of prostate cancer

      Houlahan, KE; Shiah, YJ; Gusev, A; Yuan, J; Ahmed, M; Shetty, A; Ramanand, SG; Yao, CQ; Bell, C; O'Connor, E; et al. (2019)
    • Molecular landmarks of tumor hypoxia across cancer types.

      Bhandari, V; Hoey, C; Liu, LY; Lalonde, E; Ray, J; Livingstone, J; Lesurf, R; Shiah, YJ; Vujcic, T; Huang, X; et al. (2019)
      Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.
    • Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

      Zhou, S; Hawley, JR; Soares, F; Grillo, G; Teng, M; Madani, Tonekaboni SA; Hua, JT; Kron, KJ; Mazrooei, P; Ahmed, M; et al. (2020)
      Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.