Sir Peter MacCallum Department of Oncology - Research Publications

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    Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmaña, J ; Bandera, EV ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, NV ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; GEMO Study Collaborators, ; GC-HBOC Study Collaborators, ; EMBRACE Collaborators, ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dörk, T ; du Bois, A ; Dürst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; OPAL Study Group, ; AOCS Group, ; Hahnen, E ; Haiman, CA ; Håkansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Høgdall, E ; Høgdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; KConFab Investigators, ; HEBON Investigators, ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Lubiński, J ; Mai, PL ; Manoukian, S ; Marks, JR ; Matsuno, RK ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, OI ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamariña, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; OCAC Consortium, ; CIMBA Consortium, ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Van Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (Springer Science and Business Media LLC, 2022-05)
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    Polygenic risk modeling for prediction of epithelial ovarian cancer risk
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, E ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, N ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, R ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Group, OS ; AOCSGroup, ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Mai, PL ; Manoukian, S ; Marks, JR ; KimMatsuno, R ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, O ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; BethTerry, M ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-01-14)
    Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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    Mendelian randomisation study of smoking exposure in relation to breast cancer risk
    Park, HA ; Neumeyer, S ; Michailidou, K ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baten, A ; Freeman, LEB ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brucker, SY ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dos-Santos-Silva, I ; Dwek, M ; Eccles, DM ; Eliassen, AH ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Flyger, H ; Fritschi, L ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Grip, M ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Han, S ; Harkness, EF ; Hart, SN ; He, W ; Heemskerk-Gerritsen, BAM ; Hopper, JL ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Jung, A ; Kaaks, R ; Kapoor, PM ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Kurian, AW ; Lacey, J ; Lambrechts, D ; LeMarchand, L ; Lo, W-Y ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; ElenaMartinez, M ; Mavroudis, D ; Meindl, A ; Menon, U ; Milne, RL ; Muranen, TA ; Nevanlinna, H ; Newman, WG ; Nordestgaard, BG ; Offit, K ; Olshan, AF ; Olsson, H ; Park-Simon, T-W ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Presneau, N ; Radice, P ; Rennert, G ; Rennert, HS ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Schoemaker, MJ ; Schwentner, L ; Scott, C ; Shah, M ; Shu, X-O ; Simard, J ; Smeets, A ; Southey, MC ; Spinelli, JJ ; Stevens, V ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Vijai, J ; Wang, S ; Wendt, C ; Winqvist, R ; Wolk, A ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Zheng, W ; Kraft, P ; Chang-Claude, J (SPRINGERNATURE, 2021-08-02)
    BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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    CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
    Johnson, N ; Maguire, S ; Morra, A ; Kapoor, PM ; Tomczyk, K ; Jones, ME ; Schoemaker, MJ ; Gilham, C ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baynes, C ; Freeman, LEB ; Beckmann, MW ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Doerk, T ; Eliassen, AH ; Engel, C ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Flyger, H ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Closas, M ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hart, SN ; Hooning, MJ ; Hopper, JL ; Howell, A ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Le Marchand, L ; Linet, M ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Martens, JWM ; Mavroudis, D ; Mayes, R ; Meindl, A ; Milne, RL ; Neuhausen, SL ; Nevanlinna, H ; Newman, WG ; Nielsen, SF ; Nordestgaard, BG ; Obi, N ; Olshan, AF ; Olson, JE ; Olsson, H ; Orban, E ; Park-Simon, T-W ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Rennert, HS ; Ruddy, KJ ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Scott, C ; Shu, X-O ; Simard, J ; Smichkoska, S ; Sohn, C ; Southey, MC ; Spinelli, JJ ; Stone, J ; Tamimi, RM ; Taylor, JA ; Tollenaar, RAEM ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Wang, SS ; Weinberg, CR ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Howie, AF ; Peto, J ; dos-Santos-Silva, I ; Swerdlow, AJ ; Chang-Claude, J ; Schmidt, MK ; Orr, N ; Fletcher, O (SPRINGERNATURE, 2021-01-26)
    BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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    Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
    Lawrenson, K ; Li, Q ; Kar, S ; Seo, J-H ; Tyrer, J ; Spindler, TJ ; Lee, J ; Chen, Y ; Karst, A ; Drapkin, R ; Aben, KKH ; Anton-Culver, H ; Antonenkova, N ; Baker, H ; Bandera, EV ; Bean, Y ; Beckmann, MW ; Berchuck, A ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bruinsma, F ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Chenevix-Trench, G ; Chen, A ; Chen, Z ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; Dennis, J ; Dicks, E ; Doherty, JA ; Doerk, T ; Du Bois, A ; Duerst, M ; Eccles, D ; Easton, DT ; Edwards, RP ; Eilber, U ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goode, EL ; Goodman, MT ; Grownwald, J ; Harrington, P ; Harter, P ; Hasmad, HN ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, E ; Hogdall, C ; Hosono, S ; Iversen, ES ; Jakubowska, A ; James, P ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kjaer, SK ; Kelemen, LE ; Kellar, M ; Kelley, JL ; Kiemeney, LA ; Krakstad, C ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Nevanlinna, H ; McNeish, I ; Menon, U ; Modugno, F ; Moysich, KB ; Narod, SA ; Nedergaard, L ; Ness, RB ; Azmi, MAN ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Weber, RP ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Permuth-Wey, J ; Phelan, CM ; Pike, MC ; Poole, EM ; Ramus, SJ ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schildkraut, JM ; Schwaab, I ; Sellers, TA ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Sieh, W ; Song, H ; Southey, MC ; Sucheston, L ; Tangen, IL ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Timorek, A ; Tsai, Y-Y ; Tworoger, SS ; Van Altena, AM ; Van Nieuwenhuysen, E ; Vergote, I ; Vierkant, RA ; Wang-Gohrke, S ; Walsh, C ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Woo, Y-L ; Wu, X ; Wu, AH ; Yang, H ; Zheng, W ; Ziogas, A ; Monteiro, A ; Pharoah, PD ; Gayther, SA ; Freedman, ML ; Grp, AOCS ; Bowtell, D ; Webb, PM ; Defazio, A (NATURE RESEARCH, 2015-09-01)
    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
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    Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
    Fachal, L ; Aschard, H ; Beesley, J ; Barnes, DR ; Allen, J ; Kar, S ; Pooley, KA ; Dennis, J ; Michailidou, K ; Turman, C ; Soucy, P ; Lemacon, A ; Lush, M ; Tyrer, JP ; Ghoussaini, M ; Marjaneh, MM ; Jiang, X ; Agata, S ; Aittomaki, K ; Rosario Alonso, M ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auber, B ; Auer, PL ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, AM ; Blomqvist, C ; Blot, W ; Bogdanova, N ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borg, A ; Bosse, K ; Brauch, H ; Brenner, H ; Briceno, I ; Brock, IW ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Cai, Q ; Caldes, T ; Caligo, MA ; Camp, NJ ; Campbell, I ; Canzian, F ; Carroll, JS ; Carter, BD ; Castelao, JE ; Chiquette, J ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Collee, JM ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; Devilee, P ; Diez, O ; Ding, YC ; Dite, GS ; Domchek, SM ; Doerk, T ; dos-Santos-Silva, I ; Droit, A ; Dubois, S ; Dumont, M ; Duran, M ; Durcan, L ; Dwek, M ; Eccles, DM ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fletcher, O ; Floris, G ; Flyger, H ; Foretova, L ; Foulkes, WD ; Friedman, E ; Fritschi, L ; Frost, D ; Gabrielson, M ; Gago-Dominguez, M ; Gambino, G ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Georgoulias, V ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Tibiletti, MG ; Greene, MH ; Grip, M ; Gronwald, J ; Grundy, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hartman, M ; He, W ; Healey, CS ; Heemskerk-Gerritsen, BAM ; Heyworth, J ; Hillemanns, P ; Hogervorst, FBL ; Hollestelle, A ; Hooning, MJ ; Hopper, JL ; Howell, A ; Huang, G ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Iwasaki, M ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, PA ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Jones, ME ; Jukkola-Vuorinen, A ; Jung, A ; Kaaks, R ; Kang, D ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Kerin, MJ ; Khusnutdinova, E ; Kiiski, J ; Kirk, J ; Kitahara, CM ; Ko, Y-D ; Konstantopoulou, I ; Kosma, V-M ; Koutros, S ; Kubelka-Sabit, K ; Kwong, A ; Kyriacou, K ; Laitman, Y ; Lambrechts, D ; Lee, E ; Leslie, G ; Lester, J ; Lesueur, F ; Lindblom, A ; Lo, W-Y ; Long, J ; Lophatananon, A ; Loud, JT ; Lubinski, J ; MacInnis, RJ ; Maishman, T ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matsuo, K ; Maurer, T ; Mavroudis, D ; Mayes, R ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Miller, A ; Miller, N ; Montagna, M ; Moreno, F ; Muir, K ; Mulligan, AM ; Munoz-Garzon, VM ; Muranen, TA ; Narod, SA ; Nassir, R ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Nielsen, FC ; Nikitina-Zake, L ; Norman, A ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Osorio, A ; Pankratz, VS ; Papp, J ; Park, SK ; Park-Simon, T-W ; Parsons, MT ; Paul, J ; Pedersen, IS ; Peissel, B ; Peshkin, B ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Presneau, N ; Prokofyeva, D ; Angel Pujana, M ; Pylkas, K ; Radice, P ; Ramus, SJ ; Rantala, J ; Rau-Murthy, R ; Rennert, G ; Risch, HA ; Robson, M ; Romero, A ; Rossing, M ; Saloustros, E ; Sanchez-Herrero, E ; Sandler, DP ; Santamarina, M ; Saunders, C ; Sawyer, EJ ; Scheuner, MT ; Schmidt, DF ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Scott, C ; Scott, RJ ; Senter, L ; Seynaeve, CM ; Shah, M ; Sharma, P ; Shen, C-Y ; Shu, X-O ; Singer, CF ; Slavin, TP ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Stoppa-Lyonnet, D ; Sutter, C ; Swerdlow, AJ ; Tamimi, RM ; Tan, YY ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Tengstroem, M ; Teo, SH ; Terry, MB ; Teul, A ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Torres-Mejia, G ; Troester, MA ; Truong, T ; Tung, N ; Tzardi, M ; Ulmer, H-U ; Vachon, CM ; van Asperen, CJ ; van der Kolk, LE ; van Rensburg, EJ ; Vega, A ; Viel, A ; Vijai, J ; Vogel, MJ ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Wu, AH ; Yannoukakos, D ; Zhang, Y ; Zheng, W ; Hunter, D ; Pharoah, PDP ; Chang-Claude, J ; Garcia-Closas, M ; Schmidt, MK ; Milne, RL ; Kristensen, VN ; French, JD ; Edwards, SL ; Antoniou, AC ; Chenevix-Trench, G ; Simard, J ; Easton, DF ; Kraft, P ; Dunning, AM ; Mari, V ; Berthet, P ; Castera, L ; Vaur, D ; Lallaoui, H ; Bignon, Y-J ; Uhrhammer, N ; Bonadona, V ; Lasset, C ; Revillion, F ; Vennin, P ; Muller, D ; Gomes, DM ; Ingster, O ; Coupier, I ; Pujol, P ; Collonge-Rame, M-A ; Mortemousque, I ; Bera, O ; Rose, M ; Baurand, A ; Bertolone, G ; Faivre, L ; Dreyfus, H ; Leroux, D ; Venat-Bouvet, L ; Bezieau, S ; Delnatte, C ; Chiesa, J ; Gilbert-Dussardier, B ; Gesta, P ; Prieur, FP ; Bronner, M ; Sokolowska, J ; Coulet, F ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Fert-Ferrer, S ; Jiao, Y ; Lesueur, FL ; Barouk-Simonet, E ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Toulas, C ; Reimineras, A ; Sobol, H ; Bressac-de Paillerets, B ; Cabaret, O ; Caron, O ; Guillaud-Bataille, M ; Rouleau, E ; Belotti, M ; Buecher, B ; Caputo, S ; Colas, C ; De Pauw, A ; Fourme, E ; Gauthier-Villars, M ; Golmard, L ; Moncoutier, V ; Saule, C ; Donaldson, A ; Murray, A ; Brady, A ; Brewer, C ; Pottinger, C ; Miller, C ; Gallagher, D ; Gregory, H ; Cook, J ; Eason, J ; Adlard, J ; Barwell, J ; Ong, K-R ; Snape, K ; Walker, L ; Izatt, L ; Side, L ; Rogers, MT ; Porteous, ME ; Ahmed, M ; Morrison, PJ ; Brennan, P ; Eeles, R ; Davidson, R ; Sexton, A ; Christian, A ; Trainer, A ; Spigelman, A ; Fellows, A ; Shelling, A ; De Fazio, A ; Blackburn, A ; Crook, A ; Meiser, B ; Patterson, B ; Clarke, C ; Hunt, C ; Scott, C ; Amor, D ; Marsh, D ; Edkins, E ; Salisbury, E ; Haan, E ; Neidermayr, E ; Macrea, F ; Farshid, G ; Lindeman, G ; Trench, G ; Mann, G ; Giles, G ; Gill, G ; Thorne, H ; Hickie, I ; Winship, I ; Flanagan, J ; Kollias, J ; Visvader, J ; Taylor, J ; Burke, J ; Saunus, J ; Forbes, J ; Hopper, J ; French, J ; Tucker, K ; Wu, K ; Phillips, K ; Lipton, L ; Andrews, L ; Lobb, L ; Walker, L ; Kentwell, M ; Spurdle, M ; Cummings, M ; Gleeson, M ; Harris, M ; Jenkins, M ; Young, MA ; Delatycki, M ; Wallis, M ; Burgess, M ; Price, M ; Brown, M ; Southey, M ; Bogwitz, M ; Field, M ; Friedlander, M ; Gattas, M ; Saleh, M ; Hayward, N ; Pachter, N ; Cohen, P ; Duijf, P ; James, P ; Simpson, P ; Fong, P ; Butow, P ; Williams, R ; Kefford, R ; Scott, R ; Milne, R ; Balleine, R ; Dawson, S ; Lok, S ; O'Connell, S ; Greening, S ; Nightingale, S ; Edwards, S ; Fox, S ; Mclachlan, S-A ; Lakhani, S ; Antill, Y ; Aalfs, C ; Meijers-Heijboer, H ; van Engelen, K ; Gille, H ; Boere, I ; Collee, M ; van Deurzen, C ; Hooning, M ; Obdeijn, I-M ; van den Ouweland, A ; Seynaeve, C ; Siesling, S ; Verloop, J ; van Asperen, C ; van Cronenburg, T ; Blok, R ; de Boer, M ; Garcia, EG ; Adank, M ; Hogervorst, F ; Jenner, D ; van Leeuwen, F ; Rookus, M ; Russell, N ; Schmidt, M ; van den Belt-Dusebout, S ; Kets, C ; Mensenkamp, A ; de Bock, T ; van Der Hout, A ; Mourits, M ; Oosterwijk, J ; Ausems, M ; Koudijs, M ; Marsh, D ; Baxter, R ; Yip, D ; Carpenter, J ; Davis, A ; Pathmanathan, N ; Simpson, P ; Graham, D ; Sachchithananthan, M (NATURE RESEARCH, 2020-01-07)
    Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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    Transcriptome-wide association study of breast cancer risk by estrogen-receptor status
    Feng, H ; Gusev, A ; Pasaniuc, B ; Wu, L ; Long, J ; Abu-full, Z ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Antoniou, AC ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Auer, PL ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barnes, DR ; Barrowdale, D ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, A ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borg, A ; Brauch, H ; Brenner, H ; Briceno, I ; Broeks, A ; Bruening, T ; Burwinkel, B ; Cai, Q ; Caldes, T ; Caligo, MA ; Campbell, I ; Canisius, S ; Campa, D ; Carter, BD ; Carter, J ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; De Leeneer, K ; Dennis, J ; Devilee, P ; Diez, O ; Domchek, SM ; Doerk, T ; dos-Santos-Silva, I ; Dunning, AM ; Dwek, M ; Eccles, DM ; Ejlertsen, B ; Ellberg, C ; Engel, C ; Eriksson, M ; Fasching, PA ; Fletcher, O ; Flyger, H ; Fostira, F ; Friedman, E ; Fritschi, L ; Frost, D ; Gabrielson, M ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Hake, C ; He, W ; Heyworth, J ; Hogervorst, FBL ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Huang, G ; Hulick, PJ ; Humphreys, K ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Joseph, V ; Jung, A ; Karlan, BY ; Khusnutdinova, E ; Kiiski, J ; Konstantopoulou, I ; Kristensen, VN ; Laitman, Y ; Lambrechts, D ; Lazaro, C ; Leroux, D ; Leslie, G ; Lester, J ; Lesueur, F ; Lindor, N ; Lindstrom, S ; Lo, W-Y ; Loud, JT ; Lubinski, J ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martens, JWM ; Martinez, ME ; Matricardi, L ; Maurer, T ; Mavroudis, D ; McGuffog, L ; Meindl, A ; Menon, U ; Michailidou, K ; Kapoor, PM ; Miller, A ; Montagna, M ; Moreno, F ; Moserle, L ; Mulligan, AM ; Muranen, TA ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Nevelsteen, I ; Nielsen, FC ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Osorio, A ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Pedersen, IS ; Peixoto, A ; Peterlongo, P ; Peto, J ; Pharoah, PDP ; Phillips, K-A ; Plaseska-Karanfilska, D ; Poppe, B ; Pradhan, N ; Prajzendanc, K ; Presneau, N ; Punie, K ; Pylkas, K ; Radice, P ; Rantala, J ; Rashid, MU ; Rennert, G ; Risch, HA ; Robson, M ; Romero, A ; Saloustros, E ; Sandler, DP ; Santos, C ; Sawyer, EJ ; Schmidt, MK ; Schmidt, DF ; Schmutzler, RK ; Schoemaker, MJ ; Scott, RJ ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Skytte, A-B ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Swerdlow, AJ ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomassen, M ; Thoene, K ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Torres, D ; Truong, T ; Tung, N ; Vachon, CM ; van Asperen, CJ ; van den Ouweland, AMW ; van Rensburg, EJ ; Vega, A ; Viel, A ; Vieiro-Balo, P ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wendt, C ; Winqvist, R ; Yang, XR ; Yannoukakos, D ; Ziogas, A ; Milne, RL ; Easton, DF ; Chenevix-Trench, G ; Zheng, W ; Kraft, P ; Jiang, X (WILEY, 2020-03-01)
    Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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    Development and validation of a targeted gene sequencing panel for application to disparate cancers
    McCabe, MJ ; Gauthier, M-EA ; Chan, C-L ; Thompson, TJ ; De Sousa, SMC ; Puttick, C ; Grady, JP ; Gayevskiy, V ; Tao, J ; Ying, K ; Cipponi, A ; Deng, N ; Swarbrick, A ; Thomas, ML ; kConFab, ; Lord, RV ; Johns, AL ; Kohonen-Corish, M ; O'Toole, SA ; Clark, J ; Mueller, SA ; Gupta, R ; McCormack, AI ; Dinger, ME ; Cowley, MJ (Nature Publishing Group, 2019-11-19)
    Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
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    Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
    Ferreira, MA ; Gamazon, ER ; Al-Ejeh, F ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Azzollini, J ; Balmana, J ; Barnes, DR ; Barrowdale, D ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bolla, MK ; Borg, A ; Brauch, H ; Brenner, H ; Broeks, A ; Burwinkel, B ; Caldes, T ; Caligo, MA ; Campa, D ; Campbell, I ; Canzian, F ; Carter, J ; Carter, BD ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; de la Hoya, M ; Dennis, J ; Devilee, P ; Diez, O ; Doerk, T ; Dunning, AM ; Dwek, M ; Eccles, DM ; Ejlertsen, B ; Ellberg, C ; Engel, C ; Eriksson, M ; Fasching, PA ; Fletcher, O ; Flyger, H ; Friedman, E ; Frost, D ; Gabrielson, M ; Gago-Dominguez, M ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; He, W ; Heyworth, J ; Hogervorst, FBL ; Hollestelle, A ; Hoover, RN ; Hopper, JL ; Hulick, PJ ; Humphreys, K ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, PA ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Joseph, V ; Karlan, BY ; Khusnutdinova, E ; Kiiski, J ; Ko, Y-D ; Jones, ME ; Konstantopoulou, I ; Kristensen, VN ; Laitman, Y ; Lambrechts, D ; Lazaro, C ; Leslie, G ; Lester, J ; Lesueur, F ; Lindstrom, S ; Long, J ; Loud, JT ; Lubinski, J ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Maurer, T ; Mavroudis, D ; McGuffog, L ; Meindl, A ; Menon, U ; Michailidou, K ; Miller, A ; Montagna, M ; Moreno, F ; Moserle, L ; Mulligan, AM ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Nevelsteen, I ; Nielsen, FC ; Nikitina-Zake, L ; Nussbaum, RL ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Osorio, A ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Pedersen, IS ; Peixoto, A ; Peterlongo, P ; Pharoah, PDP ; Plaseska-Karanfilska, D ; Poppe, B ; Presneau, N ; Radice, P ; Rantala, J ; Rennert, G ; Risch, HA ; Saloustros, E ; Sanden, K ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Swerdlow, AJ ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomassen, M ; Thoene, K ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Torres, D ; Truong, T ; Tung, N ; Vachon, CM ; van Asperen, CJ ; van den Ouweland, AMW ; van Rensburg, EJ ; Vega, A ; Viel, A ; Wang, Q ; Wappenschmidt, B ; Weitzel, JN ; Wendt, C ; Winqvist, R ; Yang, XR ; Yannoukakos, D ; Ziogas, A ; Kraft, P ; Antoniou, AC ; Zheng, W ; Easton, DF ; Milne, RL ; Beesley, J ; Chenevix-Trench, G ; Arnold, N ; Auber, B ; Bogdanova-Markov, N ; Borde, J ; Caliebe, A ; Ditsch, N ; Dworniczak, B ; Engert, S ; Faust, U ; Gehrig, A ; Hahnen, E ; Hauke, J ; Hentschel, J ; Herold, N ; Honisch, E ; Just, W ; Kast, K ; Larsen, M ; Lemke, J ; Huu, PN ; Niederacher, D ; Ott, C-E ; Platzer, K ; Pohl-Rescigno, E ; Ramser, J ; Rhiem, K ; Steinemann, D ; Sutter, C ; Varon-Mateeva, R ; Wang-Gohrke, S ; Weber, BHF ; Prieur, F ; Pujol, P ; Sagne, C ; Sevenet, N ; Sobol, H ; Sokolowska, J ; Stoppa-Lyonnet, D ; Venat-Bouvet, L ; Adlard, J ; Ahmed, M ; Barwell, J ; Brady, A ; Brewer, C ; Cook, J ; Davidson, R ; Donaldson, A ; Eason, J ; Eeles, R ; Evans, DG ; Gregory, H ; Hanson, H ; Henderson, A ; Hodgson, S ; Izatt, L ; Kennedy, MJ ; Lalloo, F ; Miller, C ; Morrison, PJ ; Ong, K-R ; Perkins, J ; Porteous, ME ; Rogers, MT ; Side, LE ; Snape, K ; Walker, L ; Harrington, PA ; Heemskerk-Gerritsen, BAM ; Rookus, MA ; Seynaeve, CM ; van der Baan, FH ; van der Hout, AH ; van der Kolk, LE ; van der Luijt, RB ; van Deurzen, CHM ; van Doorn, HC ; van Engelen, K ; van Hest, L ; van Os, TAM ; Verhoef, S ; Vogel, MJ ; Wijnen, JT ; Miron, A ; Kapuscinski, M ; Bane, A ; Ross, E ; Buys, SS ; Conner, TA ; Balleine, R ; Baxter, R ; Braye, S ; Carpenter, J ; Dahlstrom, J ; Forbes, J ; Lee, SC ; Marsh, D ; Morey, A ; Pathmanathan, N ; Simpson, P ; Spigelman, A ; Wilcken, N ; Yip, D (NATURE PUBLISHING GROUP, 2019-04-15)
    Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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    The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
    Figlioli, G ; Bogliolo, M ; Catucci, I ; Caleca, L ; Viz Lasheras, S ; Pujol, R ; Kiiski, J ; Muranen, TA ; Barnes, DR ; Dennis, J ; Michailidou, K ; Bolla, MK ; Leslie, G ; Aalfs, CM ; Adank, MA ; Adlard, J ; Agata, S ; Cadoo, K ; Agnarsson, BA ; Ahearn, T ; Aittomaki, K ; Ambrosone, CB ; Andrews, L ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Arnold, N ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Auber, B ; Auvinen, P ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Barwell, J ; Freeman, LEB ; Beauparlant, CJ ; Beckmann, MW ; Behrens, S ; Benitez, J ; Berger, R ; Bermisheva, M ; Blanco, AM ; Blomqvist, C ; Bogdanova, N ; Bojesen, A ; Bojesen, SE ; Bonanni, B ; Borg, A ; Brady, AF ; Brauch, H ; Brenner, H ; Bruening, T ; Burwinkel, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campa, D ; Campbell, IG ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Claes, KBM ; Clarke, CL ; Collavoli, A ; Conner, TA ; Cox, DG ; Cybulski, C ; Czene, K ; Daly, MB ; 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Lambrechts, D ; Lazaro, C ; Le Marchand, L ; Lester, J ; Lesueur, F ; Lilyquist, J ; Loud, JT ; Lu, KH ; Luben, RN ; Lubinski, J ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martens, JWM ; Maurer, T ; Mavroudis, D ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Montagna, M ; Nathanson, KL ; Neuhausen, SL ; Newman, WG ; Nguyen-Dumont, T ; Nielsen, FC ; Nielsen, S ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Olshan, AF ; Olson, JE ; Olsson, H ; Osorio, A ; Ottini, L ; Peissel, B ; Peixoto, A ; Peto, J ; Plaseska-Karanfilska, D ; Pocza, T ; Presneau, N ; Angel Pujana, M ; Punie, K ; Rack, B ; Rantala, J ; Rashid, MU ; Rau-Murthy, R ; Rennert, G ; Lejbkowicz, F ; Rhenius, V ; Romero, A ; Rookus, MA ; Ross, EA ; Rossing, M ; Rudaitis, V ; Ruebner, M ; Saloustros, E ; Sanden, K ; Santamarina, M ; Scheuner, MT ; Schmutzler, RK ; Schneider, M ; Scott, C ; Senter, L ; Shah, M ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Sohn, C ; Soucy, P ; Southey, MC ; Spinelli, JJ ; 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Molina-Gomes, D ; Ingster, O ; Manouvrier-Hanu, S ; Lejeune, S ; Aghmesheh, M ; Greening, S ; Amor, D ; Gattas, M ; Botes, L ; Buckley, M ; Friedlander, M ; Koehler, J ; Meiser, B ; Saleh, M ; Salisbury, E ; Trainer, A ; Tucker, K ; Antill, Y ; Dobrovic, A ; Fellows, A ; Fox, S ; Harris, M ; Nightingale, S ; Phillips, K ; Sambrook, J ; Thorne, H ; Armitage, S ; Arnold, L ; Kefford, R ; Kirk, J ; Rickard, E ; Bastick, P ; Beesley, J ; Hayward, N ; Spurdle, A ; Walker, L ; Beilby, J ; Saunders, C ; Bennett, I ; Blackburn, A ; Bogwitz, M ; Gaff, C ; Lindeman, G ; Pachter, N ; Scott, C ; Sexton, A ; Visvader, J ; Taylor, J ; Winship, I ; Brennan, M ; Brown, M ; French, J ; Edwards, S ; Burgess, M ; Burke, J ; Patterson, B ; Butow, P ; Culling, B ; Caldon, L ; Callen, D ; Chauhan, D ; Eisenbruch, M ; Heiniger, L ; Chauhan, M ; Christian, A ; Dixon, J ; Kidd, A ; Cohen, P ; Colley, A ; Fenton, G ; Crook, A ; Dickson, R ; Field, M ; Cui, J ; Cummings, M ; Dawson, S-J ; DeFazio, A ; Delatycki, M ; Dudding, T ; Edkins, T ; Farshid, G ; Flanagan, J ; Fong, P ; Forrest, L ; Gallego-Ortega, D ; George, P ; Gill, G ; Kollias, J ; Haan, E ; Hart, S ; Jenkins, M ; Hunt, C ; Lakhani, S ; Lipton, L ; Lobb, L ; Mann, G ; McLachlan, SA ; O'Connell, S ; O'Sullivan, S ; Pieper, E ; Robinson, B ; Saunus, J ; Scott, E ; Shelling, A ; Williams, R ; Young, MA (Springer Nature, 2019-11-01)
    Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.