# MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

## TL;DR

This study shows that the MYC protein controls DNA repair genes in a rare ovarian cancer, SCCOHT, and suggests a link between MYC and SWI/SNF mutations.

## Contribution

The study identifies a MYC-regulated DNA repair gene program in SCCOHT and links it to SWI/SNF dysfunction.

## Key findings

- MYC binds to thousands of active promoters in SCCOHT cells and regulates DNA repair genes.
- A DNA repair gene signature is overexpressed in SCCOHT tumors compared to normal tissue.
- BRG1 reintroduction antagonizes MYC-regulated DNA repair gene expression in SCCOHT cells.

## Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive cancer with limited treatment options. Understanding the underlying biology of SCCOHT is critical to comprehending how this cancer is formed and identifying new ways to treat it. The aim of this study was to explore how MYC—a major oncogenic transcription factor with intimate ties to cancer—influences SCCOHT biology. Using engineered cell lines, we characterize the genes occupied by MYC and identify a cohort of genes activated by MYC that function in DNA repair and genome stability. We also discover a DNA repair gene signature that is overexpressed in SCCOHT tumor samples compared to normal ovary tissue, pointing to MYC as a key regulator of DNA repair gene expression in these cancers.

Background/Objectives: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. Methods: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. Results: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. Conclusions: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.