Parisa Mazrooei
Cancer can arise from single nucleotide variants (SNVs) in the DNA sequence of cells. Recent decades of studies have provided a rich understanding of the effect of SNVs found within the protein-coding regions of the genome, giving rise to oncogenes and tumor-suppressor gene. In contrast, the effect of SNVs in the non-coding regions of the genome remains poorly characterized. Given that protein-coding regions only account for less than 1.5% of the human genome, understanding the effect of the excess of SNVs within noncoding regions remains a challenge. In this dissertation, I propose two computational frameworks to identify distinct patterns of noncoding SNVs targeting cancer-type specific regulatory elements and transcription factor cistromes. Combining layers of genetics and epigenetics data, I found that noncoding SNVs enrich in cistromes of a core set of oncogenic transcription factors driving cancer specific regulatory programs. I demonstrate the specificity of SNVs enrichment targeting transcription factors in breast and prostate cancer. Extensive experimental evidence in prostate cancer validates the functional impact of somatic SNVs found within regulatory regions of cancer driver transcription factors in prostate tumors. Having shown that noncoding SNVs can target cistrome of specific transcription factors, I next assessed whether SNVs can disrupt complexes of transcription factors. To this end, a computational framework to identify candidate noncoding SNVs targeting complexes of transcription factors is introduced and validated in a dataset of liver cancer. This work provides a systematic approach for investigating the functionality of SNVs within the noncoding genome, their effect on the transactivation potential of underlying regulatory elements and their target transcription factors. Overall, this work provides a blueprint for the functional interpretation of noncoding mutations in genomics tests to identify cancer driver transcription regulators.
Parisa Mazrooei. Role of Noncoding Single Nucleotide Variants on Transcription Factors’ activity in Cancer. 2019-11.
A variant-focused barcoded reporter library tested 710 somatic prostate-cancer SNVs in regulatory elements bound by FOXA1, AR, and/or HOXB13 tumor cistromes. Reference and mutant 87-bp elements were assayed in untreated LNCaP cells with an episomal luc2 reporter, and the processed package summarizes the 13 unique functional SNVs displayed in the study’s MPRA result figure.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
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