Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer,Cancer Epidemiology, Biomarkers & Prevention

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Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer
Cancer Epidemiology, Biomarkers & Prevention ( IF 3.7 ) Pub Date : 2021-09-01 , DOI: 10.1158/1055-9965.epi-20-1817
Michael C J Quinn ₁ , Karen McCue ₁ , Wei Shi ₁ , Sharon E Johnatty ₁ , Jonathan Beesley ₁ , Andrew Civitarese ₁ , Tracy A O'Mara ₁ , Dylan M Glubb ₁ , Jonathan P Tyrer ₂ , Sebastian M Armasu ₃ , Jue-Sheng Ong ₁ , Puya Gharahkhani ₁ , Yi Lu ₁ , Bo Gao _{4,

5} , Ann-Marie Patch ₁ , Peter A Fasching _{6,

7} , Matthias W Beckmann ₇ , Diether Lambrechts _{8,

9} , Ignace Vergote ₁₀ , Digna R Velez Edwards ₁₁ , Alicia Beeghly-Fadiel ₁₂ , Javier Benitez ₁₃ , Maria J Garcia _{13,

14} , Marc T Goodman _{15,

16} , Thilo Dörk ₁₇ , Matthias Dürst ₁₈ , Francesmary Modugno _{19,

20,

21} , Kirsten Moysich ₂₂ , Andreas du Bois _{23,

24} , Jacobus Pfisterer ₂₅ , Klaus Bauman , Beth Y Karlan ₂₆ , Jenny Lester ₂₆ , Julie M Cunningham ₂₇ , Melissa C Larson ₃ , Bryan M McCauley ₃ , Susanne K Kjaer _{28,

29} , Allan Jensen ₃₀ , Claus K Hogdall ₂₈ , Estrid Hogdall _{29,

30} , Joellen M Schildkraut ₃₁ , Marjorie J Riggan ₃₂ , Andrew Berchuck ₃₂ , Daniel W Cramer ₃₃ , Kathryn L Terry _{33,

34} , Line Bjorge _{35,

36} , Penelope M Webb , Michael Friedlander ₃₇ , Tanja Pejovic _{38,

39} , Melissa Moffitt _{38,

39} , Rosalind Glasspool ₄₀ , Taymaa May ₄₁ , Gabrielle E V Ene ₄₁ , David G Huntsman _{42,

43,

44,

45} , Michelle Woo ₄₆ , Michael E Carney ₄₇ , Samantha Hinsley ₄₈ , Florian Heitz _{23,

24,

49} , Sian Fereday ₅₀ , Catherine J Kennedy _{5,

51} , Stacey L Edwards ₁ , Stacey J Winham ₃ , Anna deFazio , Paul D P Pharoah _{2,

52} , Ellen L Goode ₃ , Stuart MacGregor ₁ , Georgia Chenevix-Trench ₁ , , ,

Affiliation

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
Crown Princess Mary Cancer Care Centre, Westmead Hospital, Sydney, New South Wales, Australia.
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
Division of Hematology and Oncology, Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California.
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Department of Obstetrics and Gynecology, Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
Computational Oncology Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Department of Gynecology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania.
Division of Cancer Prevention and Population Sciences, Cancer Pathology & Prevention, Roswell Park Cancer Institute, Buffalo, New York.
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
Gynecologic Oncology Center, Kiel, Germany.
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Lifestyle, Reproduction and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon.
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, United Kingdom.
Division of Gynecologic Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, British Columbia, Canada.
Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
Department of Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada.
Department of Molecular Oncology, The University of British Columbia, Vancouver, British Columbia, Canada.
British Columbia's Ovarian Cancer Research (OVCARE) Program, Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
Cancer Research UK Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, United Kingdom.
Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
Strangeways Research Laboratory, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Worts Causeway, Cambridge, United Kingdom.

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][1] This article is featured in Highlights of This Issue, [p. 1599][2] [1]: /lookup/volpage/30/1604?iss=9 [2]: /lookup/volpage/30/1599?iss=9

中文翻译：

ULK1 附近与卵巢癌无进展生存相关的基因座的鉴定

背景：已发现许多位点与上皮性卵巢癌（EOC）的风险相关。然而，尽管无进展生存期（PFS）存在相当大的差异，但尚未发现基因座与全基因组水平的结果相关。方法：我们对 2,352 名接受细胞减灭手术和标准卡铂/紫杉醇化疗的 EOC 女性进行了 PFS 全基因组关联研究 (GWAS)。结果：我们在 12q24.33 发现了 7 个与 PFS 相关的 SNP (P < 5 × 10–8)，其中最重要的 SNP 是 rs10794418（HR = 1.24；95% CI，1.15–1.34；P = 1.47 × 10–8）。附近基因 ULK1 的高表达与 EOC 中较短的 PFS 以及其他癌症中的不良预后相关。 SNP rs10794418 也与卵巢肿瘤中 ULK1 的表达相关，与较短 PFS 相关的等位基因与较高表达相关，并且在浆液性和子宫内膜样 EOC 细胞系中检测到 ULK1 启动子与相关 SNP 之间的染色质相互作用。 ULK1基因敲除的卵巢癌细胞系在体外对卡铂的敏感性显着增加。结论：12q24.33 的基因座代表了第一个对任何癌症的生存具有重要意义的全基因组基因座之一。 ULK1 是该协会目标的合理候选者。影响：这一发现提供了对与 EOC 结果和潜在治疗方案相关的遗传标记的深入了解。参见 Peres 和 Monteiro 的相关评论，[p. 11]。 1604][1] 本文刊登在本期亮点中，[p. 1604] 1599][2] [1]: /lookup/volpage/30/1604?iss=9 [2]: /lookup/volpage/30/1599?iss=9

更新日期：2021-09-02

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