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

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doi:10.1158/1055-9965.EPI-20-1817

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

· 2021-06-23

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

Links

DOI PubMed

Journal

Cancer Epidemiology, Biomarkers & Prevention

Funding

Cancer Research UK

C536/A6689

NCI NIH HHS

R01 CA058598

Cancer Research UK

C12292/A11174

NCI NIH HHS

P50 CA105009

Cancer Research UK

C1287/A 10710

NCI NIH HHS

U19 CA148537

NCI NIH HHS

R01 CA076016

NCI NIH HHS

R01 CA248288

NCI NIH HHS

U19 CA148112

NCI NIH HHS

R01 CA149429

NCI NIH HHS

U19 CA148065

Cancer Research UK

C1281/A12014

NCATS NIH HHS

UL1 TR001881

NCI NIH HHS

R01 CA126841

Cancer Research UK

16561

Cancer Research UK

C536/A13086

NCI NIH HHS

P50 CA159981

NCRR NIH HHS

M01 RR000056

NCI NIH HHS

R01 CA095023

Cancer Research UK

C5047/A10692

NCATS NIH HHS

UL1 TR000124

NCI NIH HHS

K07 CA080668

Cancer Research UK

C5047/A8384

NCI NIH HHS

P30 CA008748

NCI NIH HHS

R01 CA128978

NCI NIH HHS

R01 CA054419

NCI NIH HHS

R01 CA122443

NCI NIH HHS

P30 CA015083

Cancer Research UK

C5047/A15007

Cancer Research UK

C1287/A10118

NCI NIH HHS

P50 CA136393

U.S. National Institutes of Health 2

CA1×01HG007491-01

U.S. National Institutes of Health 2

U19-CA148112

U.S. National Institutes of Health 2

R01-CA149429

U.S. National Institutes of Health 2

R01-CA058598

Canadian Institutes of Health 3 Research

Ovarian Cancer Research Fund