TY - JOUR
T1 - Identification of a locus near ULK1 associated with progression-free survival in ovarian cancer
AU - AGO Study Group
AU - OPAL Study Group
AU - Australian Ovarian Cancer Study Group
AU - Quinn, Michael C.J.
AU - McCue, Karen
AU - Shi, Wei
AU - Johnatty, Sharon E.
AU - Beesley, Jonathan
AU - Civitarese, Andrew
AU - O'Mara, Tracy A.
AU - Glubb, Dylan M.
AU - Tyrer, Jonathan P.
AU - Armasu, Sebastian M.
AU - Ong, Jue Sheng
AU - Gharahkhani, Puya
AU - Lu, Yi
AU - Gao, Bo
AU - Patch, Ann Marie
AU - Fasching, Peter A.
AU - Beckmann, Matthias W.
AU - Lambrechts, Diether
AU - Vergote, Ignace
AU - Velez Edwards, Digna R.
AU - Beeghly-Fadiel, Alicia
AU - Benitez, Javier
AU - Garcia, Maria J.
AU - Goodman, Marc T.
AU - Dörk, Thilo
AU - Dürst, Matthias
AU - Modugno, Francesmary
AU - Moysich, Kirsten
AU - Du Bois, Andreas
AU - Pfisterer, Jacobus
AU - Bauman, Klaus
AU - Karlan, Beth Y.
AU - Lester, Jenny
AU - Cunningham, Julie M.
AU - Larson, Melissa C.
AU - McCauley, Bryan M.
AU - Kjaer, Susanne K.
AU - Jensen, Allan
AU - Hogdall, Claus K.
AU - Hogdall, Estrid
AU - Schildkraut, Joellen M.
AU - Riggan, Marjorie J.
AU - Berchuck, Andrew
AU - Cramer, Daniel W.
AU - Terry, Kathryn L.
AU - Bjorge, Line
AU - Webb, Penelope M.
AU - Friedlander, Michael
AU - Pejovic, Tanja
AU - Moffitt, Melissa
N1 - Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85114153776
U2 - 10.1158/1055-9965.EPI-20-1817
DO - 10.1158/1055-9965.EPI-20-1817
M3 - Article
C2 - 34162658
SN - 1055-9965
VL - 30
SP - 1669
EP - 1680
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 9
ER -