Diether Lambrechts

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Single-cell profiling in ovarian germ cell and sex cord-stromal tumours

The tumour microenvironment of rare ovarian germ cell tumours (OGCT) and sex-cord stromal tumours (SCST) remains unexplored. To better understand their immune and stromal landscape, we constructed a blueprint using single-cell RNA sequencing (scRNA-seq). We performed scRNA-seq of 66, 919 cells from twelve fresh tumour samples: seven adult granulosa cell tumour (aGSCT), one juvenile GSCT (jGSCT), one Sertoli-Leydig (SL) tumour, two immature teratoma (IT) and one dysgerminoma (DG). We characterised immune cell subtypes and fibroblasts based on their specific marker genes. Validation included combined positive score (CPS) of 46 OGCTs and 66 SCSTs, and bulk RNA sequencing (n = 32). Cell clustering and annotation revealed a immune-activated microenvironment in DG, driven by PD-1- exhausted T cells, reflected in high CPS (≥10) and upregulated immune pathways. IT samples displayed no immunoreactive profile, consistent with a negative CPS. aGSCTs exhibited a fibroblast-enriched, immune-desert phenotype, with low T cell infiltration and increased immunosuppressive LYVE1 and CX3CR1+ macrophages, corresponding to negative CPS. We constructed a detailed blueprint of the OGCT and SCSTs microenvironment of, elucidating potential modulators that shape their immune landscape. The immune-suppressive environment in aGSCTs likely limits immunotherapy response, as immunosuppressive macrophages inhibit T cell expansion along with EMT activation and fibroblast predominance.