Florey Department of Neuroscience and Mental Health - Research Publications

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    Differences between pure desmoplastic melanoma and superficial spreading melanoma in terms of survival, distribution and other clinicopathologic features
    Howard, MD ; Wee, E ; Wolfe, R ; McLean, CA ; Kelly, JW ; Pan, Y (WILEY, 2019-10)
    BACKGROUND: Pure desmoplastic melanoma (pDM) is an uncommon subtype of malignant melanoma with comparative high rates of local recurrence and low rates of sentinel lymph node positivity. The melanoma-specific survival (MSS) of pDM compared to other melanoma subtypes is unclear, with conflicting reports and lack of multivariable analyses. OBJECTIVES: We aimed to describe clinicopathological characteristics of a cohort of patients with pDM and to compare the MSS of pDM with superficial spreading melanoma (SSM). METHODS: A prospective cohort study was performed of all primary invasive cutaneous pDM with known tumour location and thickness reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 119 primary cutaneous invasive pDMs from 3570 total invasive cutaneous melanomas were included. Compared to 2272 SSMs, and due largely to their greater average thickness, patients with pDM had worse MSS (unadjusted hazard ratio, HR, 2.56, 95% confidence interval, CI, 1.56-4.22). After adjustment for clinicopathologic factors (including thickness, ulceration, mitotic rate, age and sex), there was evidence that patients with pDM had an improved MSS (adjusted HR, 0.49; 95% CI, 0.28-0.87). Median thickness of head and neck pDM was greater than non-head and neck pDM (P < 0.001). There was reduced univariable MSS in head and neck pDM compared to the rest of the body. CONCLUSIONS: Decreased univariable MSS of patients with pDM compared to SSM was explained by the increased frequency of adverse clinicopathologic features at diagnosis, in particular the greater Breslow thickness of pDM. After adjustment, patients with pDM had half the chance of melanoma-specific death compared to SSM. Head and neck pDM were thicker at diagnosis compared to the rest of the body, which may account for its poorer survival compared to the rest of the body.
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    Accuracy of partial biopsies in the management of cutaneous melanoma
    Doolan, BJ ; Robinson, AJ ; Wolfe, R ; Kelly, JW ; McLean, C ; McCormack, C ; Henderson, MA ; Pan, Y (WILEY, 2019-08)
    BACKGROUND: The recommended method for histopathological diagnosis of cutaneous melanoma is excisional biopsy, although partial biopsies (shave and punch) are often used. Following a partial biopsy, treatment guidelines recommend a narrow excisional biopsy to plan definitive management. There is limited evidence on the benefits of direct wide local excision (WLE) following diagnostic partial biopsies. METHODS: Retrospective cohort study of cutaneous melanoma cases, from two tertiary referral centres from January 2013 to December 2015. Demographic and histopathological data, including tumour thickness (T-stage) from initial biopsy and subsequent excisions, were collected. Logistic regression was used to examine histopathological T-staging between biopsy and subsequent excisions (upstaging). RESULTS: 2304 melanomas (2157 patients) were identified; 455 shave, 308 punch, 14 incisional and 1527 excisional biopsies. Out of 1527, 5 (<1%) excisional biopsies were upstaged from original biopsy T-stage to final WLE; compared to 28/455 (6%) for shave, 45/308 (15%) for punch and 2/14 (14%) for incisional biopsies. Histopathology upstaging were increased with punch (OR, 52.1; 95% CI, 20.5-132.4. P < 0.001) and shave biopsy (OR, 20.0; 95% CI, 7.7-52.0. P < 0.001) compared to excisional biopsy. Upstaging rates of 9.4% for desmoplastic (OR, 6.9; 95% CI, 2.4-19.7. P < 0.001) and 21.9% for acral lentiginous (OR, 18.4; 95% CI, 6.9-49.2. P < 0.001) melanomas were elevated compared to 1.4% for superficial spreading melanoma. CONCLUSIONS: In most cases, partial biopsy (particularly shave biopsy) can provide sufficient information to plan for definitive surgical melanoma management. Punch and incisional biopsies have elevated upstaging rates, a consideration in planning therapy. Partial biopsies of desmoplastic or acral lentiginous melanomas have high rates of upstaging and should have a complete excision prior to definitive treatment.
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    Interferon-beta in multiple sclerosis causing thrombotic microangiopathy
    Yam, C ; Fok, A ; Mclean, C ; Butler, E ; Kempster, P (WILEY, 2019-02)
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    Atraumatic splenic rupture following IVIg for parvovirus B19 pure red cell aplasia post renal transplant
    Tiong, M ; Casan, J ; McLean, C (WILEY, 2019-04)
    Parvovirus B19 (PB19) associated pure red cell aplasia (PRCA) is an uncommon but well described complication of immunosuppression post solid organ transplantation. We report a unique case of a renal transplant patient with PB19 associated PRCA who developed a spontaneous splenic rupture after receiving IVIg for persistent anemia. He subsequently required splenectomy. Within the spleen we subsequently identified PB19 affected cells.
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    SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease
    Baldo, B ; Gabery, S ; Soylu-Kucharz, R ; Cheong, RY ; Henningsen, JB ; Englund, E ; McLean, C ; Kirik, D ; Halliday, G ; Petersen, A (WILEY, 2019-06)
    AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
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    Type 4 Luschka duct: a rare anatomical variant to be wary of
    Parkin, CJ ; Buxey, K ; McLean, CA (WILEY, 2019-07)
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    Gastric adenocarcinoma causing biliary obstruction without ductal dilatation: a case report
    Vaz, K ; Luber, RP ; McLean, C ; Gerstenmaier, JF ; Roberts, SK (BMC, 2019-03-09)
    INTRODUCTION: Gastric adenocarcinoma is a known complication of partial gastrectomy. Jaundice from gastric adenocarcinoma usually occurs in the setting of hepatic nodal or parenchymal metastasis. This case demonstrates an unusual level of biliary obstruction from gastric adenocarcinoma. CASE PRESENTATION: An 84-year-old Caucasian man was diagnosed as having a new gastric adenocarcinoma at the level of the gastroenteric anastomosis of a prior Billroth II gastrectomy after presenting with painless jaundice. He had a non-dilated biliary tree on radiographic imaging despite evidence of large bile duct obstruction on liver biopsy. The obstruction was managed with endoscopic wire-guided stenting of the malignant tumor. CONCLUSIONS: The unusual finding of a non-dilated biliary tree in the face of obstructive jaundice is likely to have resulted from the unusual post-surgical anatomy and hence distal level of obstruction. Endoscopic duodenal stenting is a novel method of managing obstructive jaundice in gastric adenocarcinoma.
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    Genome-wide association study of germline variants and breast cancer-specific mortality
    Escala-Garcia, M ; Guo, Q ; Doerk, T ; Canisius, S ; Keeman, R ; Dennis, J ; Beesley, J ; Lecarpentier, J ; Bolla, MK ; Wang, Q ; Abraham, J ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Auer, PL ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bernstein, L ; Blomqvist, C ; Boeckx, B ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brentnall, A ; Brinton, L ; Broberg, P ; Brock, IW ; Brucker, SY ; Burwinkel, B ; Caldas, C ; Caldes, T ; Campa, D ; Canzian, F ; Carracedo, A ; Carter, BD ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Cheng, T-YD ; Chin, S-F ; Clarke, CL ; Cordina-Duverger, E ; Couch, FJ ; Cox, DG ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dunn, JA ; Dunning, AM ; Durcan, L ; Dwek, M ; Earl, HM ; Ekici, AB ; Eliassen, AH ; Ellberg, C ; Engel, C ; Eriksson, M ; Evans, DG ; Figueroa, J ; Flesch-Janys, D ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; Galle, E ; Gapstur, SM ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; George, A ; Georgoulias, V ; Giles, GG ; Glendon, G ; Goldgar, DE ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haeberle, L ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Hankinson, S ; Harkness, EF ; Harrington, PA ; Hart, SN ; Hartikainen, JM ; Hein, A ; Hillemanns, P ; Hiller, L ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Huang, G ; Humphreys, K ; Hunter, DJ ; Janni, W ; John, EM ; Jones, ME ; Jukkola-Vuorinen, A ; Jung, A ; Kaaks, R ; Kabisch, M ; Kaczmarek, K ; Kerin, MJ ; Khan, S ; Khusnutdinova, E ; Kiiski, J ; Kitahara, CM ; Knight, JA ; Ko, Y-D ; Koppert, LB ; Kosma, V-M ; Kraft, P ; Kristensen, VN ; Kruger, U ; Kuehl, T ; Lambrechts, D ; Le Marchand, L ; Lee, E ; Lejbkowicz, F ; Li, L ; Lindblom, A ; Lindstrom, S ; Linet, M ; Lissowska, J ; Lo, W-Y ; Loibl, S ; Lubinski, J ; Lux, MP ; MacInnis, RJ ; Maierthaler, M ; Maishman, T ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Mavroudis, D ; McLean, C ; Meindl, A ; Middha, P ; Miller, N ; Milne, RL ; Moreno, F ; Mulligan, AM ; Mulot, C ; Nassir, R ; Neuhausen, SL ; Newman, WT ; Nielsen, SF ; Nordestgaard, BG ; Norman, A ; Olsson, H ; Orr, N ; Pankratz, VS ; Park-Simon, T-W ; Perez, JIA ; Perez-Barrios, C ; Peterlongo, P ; Petridis, C ; Pinchev, M ; Prajzendanc, K ; Prentice, R ; Presneau, N ; Prokofieva, D ; Pylkas, K ; Rack, B ; Radice, P ; Ramachandran, D ; Rennert, G ; Rennert, HS ; Rhenius, V ; Romero, A ; Roylance, R ; Saloustros, E ; Sawyer, EJ ; Schmidt, DF ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schumacher, F ; Schwentner, L ; Scott, RJ ; Scott, C ; Seynaeve, C ; Shah, M ; Simard, J ; Smeets, A ; Sohn, C ; Southey, MC ; Swerdlow, AJ ; Talhouk, A ; Tamimi, RM ; Tapper, WJ ; Teixeira, MR ; Tengstrom, M ; Terry, MB ; Thoene, K ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Truong, T ; Turman, C ; Turnbull, C ; Ulmer, H-U ; Untch, M ; Vachon, C ; van Asperen, CJ ; van den Ouweland, AMW ; van Veen, EM ; Wendt, C ; Whittemore, AS ; Willett, W ; Winqvist, R ; Wolk, A ; Yang, XR ; Zhang, Y ; Easton, DF ; Fasching, PA ; Nevanlinna, H ; Eccles, DM ; Pharoah, PDP ; Schmidt, MK (NATURE PUBLISHING GROUP, 2019-03-19)
    BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
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    Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
    Mavaddat, N ; Michailidou, K ; Dennis, J ; Lush, M ; Fachal, L ; Lee, A ; Tyrer, JP ; Chen, T-H ; Wang, Q ; Bolla, MK ; Yang, X ; Adank, MA ; Ahearn, T ; Aittomaki, K ; Allen, J ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Auer, PL ; Auvinen, P ; Barrdahl, M ; Freeman, LEB ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bernstein, L ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Bremer, M ; Brenner, H ; Brentnall, A ; Brock, IW ; Brooks-Wilson, A ; Brucker, SY ; Bruening, T ; Burwinkel, B ; Campa, D ; Carter, BD ; Castelao, JE ; Chanock, SJ ; Chlebowski, R ; Christiansen, H ; Clarke, CL ; Collee, JM ; Cordina-Duverger, E ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Doerk, T ; dos-Santos-Silva, I ; Dumont, M ; Durcan, L ; Dwek, M ; Eccles, DM ; Ekici, AB ; Eliassen, AH ; Ellberg, C ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Fletcher, O ; Flyger, H ; Foersti, A ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Georgoulias, V ; Giles, GG ; Gilyazova, IR ; Glendon, G ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Gronwald, J ; Grundy, A ; Guenel, P ; Haeberle, L ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hankinson, SE ; Harkness, EF ; Hart, SN ; He, W ; Hein, A ; Heyworth, J ; Hillemanns, P ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Huang, G ; Humphreys, K ; Hunter, DJ ; Jakimovska, M ; Jakubowska, A ; Janni, W ; John, EM ; Johnson, N ; Jones, ME ; Jukkola-Vuorinen, A ; Jung, A ; Kaaks, R ; Kaczmarek, K ; Kataja, V ; Keeman, R ; Kerin, MJ ; Khusnutdinova, E ; Kiiski, J ; Knight, JA ; Ko, Y-D ; Kosma, V-M ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kuehl, T ; Lambrechts, D ; Le Marchand, L ; Lee, E ; Lejbkowicz, F ; Lilyquist, J ; Lindblom, A ; Lindstrom, S ; Lissowska, J ; Lo, W-Y ; Loibl, S ; Long, J ; Lubinski, J ; Lux, MP ; MacInnis, RJ ; Maishman, T ; Makalic, E ; Kostovska, IM ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Martens, JWM ; Martinez, ME ; Mavroudis, D ; McLean, C ; Meindl, A ; Menon, U ; Middha, P ; Miller, N ; Moreno, F ; Mulligan, AM ; Mulot, C ; Munoz-Garzon, VM ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Newman, WG ; Nielsen, SF ; Nordestgaard, BG ; Norman, A ; Offit, K ; Olson, JE ; Olsson, H ; Orr, N ; Pankratz, VS ; Park-Simon, T-W ; Perez, JIA ; Perez-Barrios, C ; Peterlongo, P ; Peto, J ; Pinchev, M ; Plaseska-Karanfilska, D ; Polley, EC ; Prentice, R ; Presneau, N ; Prokofyeva, D ; Purrington, K ; Pylkas, K ; Rack, B ; Radice, P ; Rau-Murthy, R ; Rennert, G ; Rennert, HS ; Rhenius, V ; Robson, M ; Romero, A ; Ruddy, KJ ; Ruebner, M ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmidt, DF ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schumacher, F ; Schuermann, P ; Schwentner, L ; Scott, C ; Scott, RJ ; Seynaeve, C ; Shah, M ; Sherman, ME ; Shrubsole, MJ ; Shu, X-O ; Slager, S ; Smeets, A ; Sohn, C ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Stegmaier, C ; Stone, J ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Thoene, K ; Tollenaar, RAEM ; Tomlinson, I ; Truong, T ; Tzardi, M ; Ulmer, H-U ; Untch, M ; Vachon, CM ; van Veen, EM ; Vijai, J ; Weinberg, CR ; Wendt, C ; Whittemore, AS ; Wildiers, H ; Willett, W ; Winqvist, R ; Wolk, A ; Yang, XR ; Yannoukakos, D ; Zhang, Y ; Zheng, W ; Ziogas, A ; Clarke, C ; Balleine, R ; Baxter, R ; Braye, S ; Carpenter, J ; Dahlstrom, J ; Forbes, J ; Lee, CS ; Marsh, D ; Morey, A ; Pathmanathan, N ; Scott, R ; Simpson, P ; Spigelman, A ; Wilcken, N ; Yip, D ; Zeps, N ; Sexton, A ; Dobrovic, A ; Christian, A ; Trainer, A ; Fellows, A ; Shelling, A ; De Fazio, A ; Blackburn, A ; Crook, A ; Meiser, B ; Patterson, B ; Clarke, C ; Saunders, C ; Hunt, C ; Scott, C ; Amor, D ; Ortega, DG ; Marsh, D ; Edkins, E ; Salisbury, E ; Haan, E ; Macrea, F ; Farshid, G ; Lindeman, G ; Trench, G ; Mann, G ; Giles, G ; Gill, G ; Thorne, H ; Campbell, I ; Hickie, I ; Caldon, L ; Winship, I ; Cui, J ; Flanagan, J ; Kollias, J ; Visvader, J ; Taylor, J ; Burke, J ; Saunus, J ; Forbs, J ; Hopper, J ; Beesley, J ; Kirk, J ; French, J ; Tucker, K ; Wu, K ; Phillips, K ; Forrest, L ; 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 ; Brown, M ; Southey, M ; Bogwitz, M ; Field, M ; Friedlander, M ; Gattas, M ; Saleh, M ; Aghmesheh, M ; Hayward, N ; Pachter, N ; Cohen, P ; Duijf, P ; James, P ; Simpson, P ; Fong, P ; Butow, P ; Williams, R ; Kefford, R ; Simard, J ; Balleine, R-M ; Dawson, S-J ; Lok, S ; O'connell, S ; Greening, S ; Nightingale, S ; Edwards, S ; Fox, S ; McLachlan, S-A ; Lakhani, S ; Dudding, T ; Antill, Y ; Sahlberg, KK ; Ottestad, L ; Karesen, R ; Schlichting, E ; Holmen, MM ; Sauer, T ; Haakensen, V ; Engebraten, O ; Naume, B ; Fossa, A ; Kiserud, CE ; Reinertsen, K ; Helland, A ; Riis, M ; Geisler, J ; Dunning, AM ; Thompson, DJ ; Chenevix-Trench, G ; Chang-Claude, J ; Schmidt, MK ; Hall, P ; Milne, RL ; Pharoah, PDP ; Antoniou, AC ; Chatterjee, N ; Kraft, P ; Garcia-Closas, M ; Easton, DF (CELL PRESS, 2019-01-03)
    Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.