Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer

Rosario I Corona,Forough Abassi,Jessica Reddy,Paulette Y Mhawech-Fauceglia,Ji-Heui Seo,Marcos A S Fonseca,Alexander Gusev,Xianzhi Lin,David G Huntsman,Dennis J Hazelett,Benjamin P Berman,Matthew L Freedman,Beth Y Karlan,Yvonne G Lin,Sohrab P Shah,Kate Lawrenson,Simon A Gayther

doi:10.1038/s41467-020-15951-0

Abstract

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.

Highlights

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown
The number of peaks identified plateaued at 16 tumors, suggesting we have identified the majority of active regulatory elements (RE) in OCs
Different cancers have been defined by the spectrum of proteincoding mutations and target genes that drive disease pathogenesis; but little is known about the functional role of non-coding somatic mutations in cancer development which likely drive the underlying mechanisms of gene regulation through epigenomic perturbation

Summary

Introduction

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. H3K27ac ChIP-seq and RNA-seq, and integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4). The collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during. 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 11 McGraw/Patterson Center for Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. OC are rarer and include clear cell and endometrioid OCs (CCOC and EnOC), which are strongly associated with the benign precursor lesion endometriosis[5], and mucinous OC (MOC), which may derive from appendiceal tissues or primordial germ cells[6]

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Conclusion