Citations 2
Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer
Quinn, Michael C. , McCue, Karen, Shi, Wei , Johnatty, Sharon E. , Beesley, Jonathan, Civitarese, Andrew, O’Mara, Tracy A. , Glubb, Dylan M. , Armasu, Sebastian M. , Ong, Jue‐Sheng , Lu, Yi , Gao, Bo , Patch, Ann‐Marie , Fasching, Peter A. , Beckmann, Matthias W. , Lambrechts, Diether , Vergote, Ignace , Beeghly‐Fadiel, Alicia, García, María J. , Goodman, Marc T. , Dörk, Thilo , Moysich, Kirsten B. , Pfisterer, Jacobus , Bauman, Klaus, Lester, Jenny , Cunningham, Julie M. , McCauley, Bryan M. , Høgdall, Claus , Schildkraut, Joellen M. , Riggan, Marjorie J. , Terry, Kathryn L. , Webb, Penelope M. , May, Taymaa, Ene, Gabrielle, Huntsman, David G., Woo, Michelle, Carney, Michael E. , Fereday, Sián , Kennedy, Catherine J. , Edwards, Stacey L. , DeFazio, Anna , Goode, Ellen L. , MacGregor, Stuart , Chenevix‐Trench, Georgia , Lambrechts, Diether , Quinn, Michael C J , Ong, Jue-Sheng , Gharahkhani, Puya , Lu, Yi , Fasching, Peter A , Lambrechts, Diether , Vergote, Ignace , Dörk, Thilo , Dürst, Matthias , Modugno, Francesmary , Bois, Andreas du , Karlan, Beth Y , Cunningham, Julie M , Kjaer, Susanne K , Webb, Penelope M , Friedlander, Michael , Glasspool, Rosalind , Hinsley, Samantha , Heitz, Florian , Kennedy, Catherine J , Winham, Stacey J , Fazio, Anna de , Pharoah, Paul D P , MacGregor, Stuart , Lambrechts, Diether , Moysich, Kirsten , O'Mara, Tracy A , Chenevix-Trench, Georgia , Høgdall, Claus K , Fereday, Sian , Goodman, Marc T , Beesley, Jonathan, Tyrer, Jonathan P. , Gharahkhani, Puya , Edwards, Digna R. Velez , Beeghly‐Fadiel, Alicia , Benı́tez, Javier , Modugno, Francesmary , Karlan, Beth Y. , Larson, Melissa C. , Kjær, Susanne K. , Jensen, Allan , Høgdall, Estrid , Berchuck, Andrew , Cramer, Daniel W. , Bjørge, Line , Friedländer, Michael , Pejovic, Tanja B. , Moffitt, Melissa , Glasspool, Rosalind , Heitz, Florian , Winham, Stacey J. , Pharoah, Paul D.P.
Cancer Epidemiology, Biomarkers & Prevention | June 23, 2021 | Volume: 30 | Issue: 9 | Pages: 1669-1680
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
Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
Talhouk, Aline , Wang, Chen , Budden, Timothy , Kommoss, Stefan , Leong, Huei San, Intermaggio, Maria P., Nazeran, Tayyebeh M., Volchek, Mila, Elatre, Wafaa, Chow, Veronica, Sudderuddin, Hanwei , Mackenzie, Robertson, Leong, Samuel C.Y., Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, AOCS, Alsop, Jennifer , Banerjee, Susana , Bodelón, Clara , Brand, Alison H. , Brinton, Louise A. , Carney, Michael E. , Chiew, Yoke-Eng , Cushing‐Haugen, Kara L. , Ennis, Darren , Fereday, Sián , Fortner, Renée T. , Greene, Casey S. , Hendley, Joy , Hernandez, Brenda Y. , Herpel, Esther , Jimenez‐Liñan, Mercedes , Karpinskyj, Chloe , Keeney, Gary L., Kennedy, Catherine J. , Köbel, Martin , Koziak, Jennifer M. , Lester, Jenny , Lewsley, Liz-Anne , Lissowska, Jolanta , Luk, Hugh, Mahner, Sven� , McNeish, Iain A. , Menkiszak, Janusz , Nevins, Nikilyn, Osório, Ana , Oszurek, Oleg, Pearce, Celeste Leigh , Pike, Malcolm C. , Piskorz, Anna , Rhenius, Valerie , Rodríguez‐Antona, Cristina , Sharma, Raghwa , Silva, Dilrini De , Singh, Naveena , Sinn, Hans‐Peter , Slamon, Dennis J. , Song, Honglin , Steed, Helen , Stronach, Euan A. , Thompson, Pamela J., Tołoczko, Aleksandra, Trabert, Britton , Traficante, Nadia , Tseng, Chiu-Chen , Widschwendter, Martin , Winterhoff, Boris , Beeghly‐Fadiel, Alicia, Brown, Robert , Chang‐Claude, Jenny , Chenevix‐Trench, Georgia , DeFazio, Anna , Fasching, Peter A. , García, María J. , Gayther, Simon A. , Goodman, Marc T. , Henderson, Michelle J. , Kelemen, Linda E. , Menon, Usha , Oršulić, Sandra , Wentzensen, Nicolas , Wu, Anna H. , Schildkraut, Joellen M. , Rossing, Mary Anne, Konecny, Gottfried E. , Huntsman, David G. , Huang, Ruby Yun‐Ju , Goode, Ellen L. , Ramus, Susan J. , Bowtell, David D.L. , Anglesio, Michael S. , George, Joshy , Wang, Chen , Tan, Tuan Zea , Behrens, Sabine , Bodelon, Clara , Brinton, Louise A , Fortner, Renée T , García-Donas, Jesús , Gentry‐Maharaj, Aleksandra , Glasspool, Rosalind , Greene, Casey S , Haluska, Paul , Harris, Holly R , Kaufmann, Scott H , Kennedy, Catherine J , Köbel, Martin , Koziak, Jennifer M , Lissowska, Jolanta , McNeish, Iain A , Menkiszak, Janusz , Hinsley, Samantha , Pike, Malcolm C , Rodríguez-Antona, Cristina , Sinn, Peter , Trabert, B , Widschwendter, Martin , Winham, Stacey J , Brenton, James D , Brown, Robert , Chang-Claude, Jenny , Fazio, Anna de , Fasching, Peter A , Kelemen, Linda E , Menon, Usha , Pharoah, Paul D P , Ramus, Susan J , Doherty, Jennifer A , Anglesio, Michael S , Chenevix-Trench, Georgia , Brand, Alison H , Ennis, Darren P , Traficante, Nadia , Bowtell, David D , Fereday, Sian , Hernandez, Brenda Y , Steed, Helen , Goodman, Marc T , Nevins, Nikilyn , George, Joshy , Chiu, Derek S , Chen, Stephanie , Gilks, C. Blake , Bentley, Rex C. , Senz, Janine , Lum, Amy M. , Group, AOCS, Behrens, Sabine , Cybulski, Cezary , García-Donás, Jesús , Glasspool, Rosalind , Goranova, Teodora , Harris, Holly R. , Kaufmann, Scott H. , Larson, Melissa C. , Lubiński, Jan , Macintyre, Geoff , Palacios, José , Ray-Coquard, Isabelle L. , Sherman, Mark E. , Wilkens, Lynne R. , Winham, Stacey J. , Beeghly‐Fadiel, Alicia , Benı́tez, Javier , Berchuck, Andrew , Brenton, James D. , Gronwald, Jacek , Karlan, Beth Y. , Pharoah, Paul D.P. , Doherty, Jennifer A.
Clinical Cancer Research | June 17, 2020 | Volume: 26 | Issue: 20 | Pages: 5411-5423
Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271