Sir Peter MacCallum Department of Oncology - Research Publications

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    Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)
    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, 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 ; 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, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; 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 ; Lubinski, 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 ; 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 ; Terry, MB ; 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, JM ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 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, 2022-03)
    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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    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)
    BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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    Rare germline copy number variants (CNVs) and breast cancer risk
    Dennis, J ; Tyrer, JP ; Walker, LC ; Michailidou, K ; Dorling, L ; Bolla, MK ; Wang, Q ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Freeman, LEB ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brenner, H ; Castelao, JE ; Chang-Claude, J ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Devilee, P ; Dork, T ; Dossus, L ; Eliassen, AH ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Fletcher, O ; Flyger, H ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Giles, GG ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hall, P ; Hollestelle, A ; Hoppe, R ; Hopper, JL ; Howell, A ; Jager, A ; Jakubowska, A ; John, EM ; Johnson, N ; Jones, ME ; Jung, A ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kubelka-Sabit, K ; Kurian, AW ; Lacey, J ; Lambrechts, D ; Larson, NL ; Linet, M ; Ogrodniczak, A ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Mavroudis, D ; Milne, RL ; Muranen, TA ; Murphy, RA ; Nevanlinna, H ; Olson, JE ; Olsson, H ; Park-Simon, T-W ; Perou, CM ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shibli, R ; Smeets, A ; Soucy, P ; Southey, MC ; Swerdlow, AJ ; Tamimi, RM ; Taylor, JA ; Teras, LR ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; Wendt, C ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Ziogas, A ; Simard, J ; Dunning, AM ; Pharoah, PDP ; Easton, DF (NATURE PORTFOLIO, 2022-01-18)
    Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
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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, 2021-10-12)
    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, 2021-02-16)
    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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    Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
    Jim, HSL ; Lin, H-Y ; Tyrer, JP ; Lawrenson, K ; Dennis, J ; Chornokur, G ; Chen, Z ; Chen, AY ; Permuth-Wey, J ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Bruinsma, F ; Bandera, EV ; Bean, YT ; Beckmann, MW ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bunker, CH ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; du Bois, A ; Despierre, E ; Sieh, W ; Doherty, JA ; Dörk, T ; Dürst, M ; Easton, DF ; Eccles, DM ; Edwards, RP ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goodman, MT ; Gronwald, J ; Harter, P ; Hasmad, HN ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Iversen, ES ; Jakubowska, A ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kellar, M ; Kiemeney, LA ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Vierkant, RA ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lim, BK ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; McNeish, I ; Menon, U ; Milne, RL ; Modugno, F ; Thomsen, L ; Moysich, KB ; Ness, RB ; Nevanlinna, H ; Eilber, U ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Palmieri Weber, R ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Schernhammer, E ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Sucheston-Campbell, L ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Tangen, IL ; Tworoger, SS ; van Altena, AM ; Vergote, I ; Walsh, CS ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Wu, AH ; Wu, X ; Woo, Y-L ; Yang, H ; Zheng, W ; Ziogas, A ; Amankwah, E ; Berchuck, A ; Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, ; Schildkraut, JM ; Kelemen, LE ; Ramus, SJ ; Monteiro, ANA ; Goode, EL ; Narod, SA ; Gayther, SA ; Pharoah, PDP ; Sellers, TA ; Phelan, CM (ClinMed International Library, 2015)
    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
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    Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
    Chornokur, G ; Lin, H-Y ; Tyrer, JP ; Lawrenson, K ; Dennis, J ; Amankwah, EK ; Qu, X ; Tsai, Y-Y ; Jim, HSL ; Chen, Z ; Chen, AY ; Permuth-Wey, J ; Aben, KKH ; Anton-Culver, H ; Antonenkova, N ; Bruinsma, F ; Bandera, EV ; Bean, YT ; Beckmann, MW ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bunker, CH ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; du Bois, A ; Despierre, E ; Dicks, E ; Doherty, JA ; Dork, T ; Durst, M ; Easton, DF ; Eccles, DM ; Edwards, RP ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goodman, MT ; Gronwald, J ; Harrington, P ; Harter, P ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Jakubowska, A ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kelemen, LE ; Kellar, M ; Kiemeney, LA ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lim, BK ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; McNeish, I ; Menon, U ; Milne, RL ; Modugno, F ; Moysich, KB ; Ness, RB ; Nevanlinna, H ; Eilber, U ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Weber, RP ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schernhammer, E ; Schwaab, I ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Sieh, W ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Sucheston, L ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Thomsen, L ; Tangen, IL ; Tworoger, SS ; van Altena, AM ; Vierkant, RA ; Vergote, I ; Walsh, CS ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Wu, AH ; Wu, X ; Woo, Y-L ; Yang, H ; Zheng, W ; Ziogas, A ; Hasmad, HN ; Berchuck, A ; Iversen, ES ; Schildkraut, JM ; Ramus, SJ ; Goode, EL ; Monteiro, ANA ; Gayther, SA ; Narod, SA ; Pharoah, PP ; Sellers, TA ; Phelan, CM ; Agoulnik, IU (PUBLIC LIBRARY SCIENCE, 2015-06-19)
    BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
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    PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
    Southey, MC ; Goldgar, DE ; Winqvist, R ; Pylkas, K ; Couch, F ; Tischkowitz, M ; Foulkes, WD ; Dennis, J ; Michailidou, K ; van Rensburg, EJ ; Heikkinen, T ; Nevanlinna, H ; Hopper, JL ; Doerk, T ; Claes, KBM ; Reis-Filho, J ; Teo, ZL ; Radice, P ; Catucci, I ; Peterlongo, P ; Tsimiklis, H ; Odefrey, FA ; Dowty, JG ; Schmidt, MK ; Broeks, A ; Hogervorst, FB ; Verhoef, S ; Carpenter, J ; Clarke, C ; Scott, RJ ; Fasching, PA ; Haeberle, L ; Ekici, AB ; Beckmann, MW ; Peto, J ; dos-Santos-Silva, I ; Fletcher, O ; Johnson, N ; Bolla, MK ; Sawyer, EJ ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Marme, F ; Burwinkel, B ; Yang, R ; Guenel, P ; Therese, T ; Menegaux, F ; Sanchez, M ; Bojesen, S ; Nielsen, SF ; Flyger, H ; Benitez, J ; Pilar Zamora, M ; Arias Perez, JI ; Menendez, P ; Anton-Culver, H ; Neuhausen, S ; Ziogas, A ; Clarke, CA ; Brenner, H ; Arndt, V ; Stegmaier, C ; Brauch, H ; Bruening, T ; Ko, Y-D ; Muranen, TA ; Aittomaki, K ; Blomqvist, C ; Bogdanova, NV ; Antonenkova, NN ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Spurdle, AB ; Wauters, E ; Smeets, D ; Beuselinck, B ; Floris, G ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Olson, JE ; Vachon, C ; Pankratz, VS ; McLean, C ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Kristensen, V ; Alnaes, GG ; Zheng, W ; Hunter, DJ ; Lindstrom, S ; Hankinson, SE ; Kraft, P ; Andrulis, I ; Knight, JA ; Glendon, G ; Mulligan, AM ; Jukkola-Vuorinen, A ; Grip, M ; Kauppila, S ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; Hollestelle, A ; Garcia-Closas, M ; Figueroa, J ; Chanock, SJ ; Lissowska, J ; Czene, K ; Darabi, H ; Eriksson, M ; Eccles, DM ; Rafiq, S ; Tapper, WJ ; Gerty, SM ; Hooning, MJ ; Martens, JWM ; Collee, JM ; Tilanus-Linthorst, M ; Hall, P ; Li, J ; Brand, JS ; Humphreys, K ; Cox, A ; Reed, MWR ; Luccarini, C ; Baynes, C ; Dunning, AM ; Hamann, U ; Torres, D ; Ulmer, HU ; Ruediger, T ; Jakubowska, A ; Lubinski, J ; Jaworska, K ; Durda, K ; Slager, S ; Toland, AE ; Ambrosone, CB ; Yannoukakos, D ; Swerdlow, A ; Ashworth, A ; Orr, N ; Jones, M ; Gonzalez-Neira, A ; Pita, G ; Rosario Alonso, M ; Alvarez, N ; Herrero, D ; Tessier, DC ; Vincent, D ; Bacot, F ; Simard, J ; Dumont, M ; Soucy, P ; Eeles, R ; Muir, K ; Wiklund, F ; Gronberg, H ; Schleutker, J ; Nordestgaard, BG ; Weischer, M ; Travis, RC ; Neal, D ; Donovan, JL ; Hamdy, FC ; Khaw, K-T ; Stanford, JL ; Blot, WJ ; Thibodeau, S ; Schaid, DJ ; Kelley, JL ; Maier, C ; Kibel, AS ; Cybulski, C ; Cannon-Albright, L ; Butterbach, K ; Park, J ; Kaneva, R ; Batra, J ; Teixeira, MR ; Kote-Jarai, Z ; Al Olama, AA ; Benlloch, S ; Renner, SP ; Hartmann, A ; Hein, A ; Ruebner, M ; Lambrechts, D ; Van Nieuwenhuysen, E ; Vergote, I ; Lambretchs, S ; Doherty, JA ; Rossing, MA ; Nickels, S ; Eilber, U ; Wang-Gohrke, S ; Odunsi, K ; Sucheston-Campbell, LE ; Friel, G ; Lurie, G ; Killeen, JL ; Wilkens, LR ; Goodman, MT ; Runnebaum, I ; Hillemanns, PA ; Pelttari, LM ; Butzow, R ; Modugno, F ; Edwards, RP ; Ness, RB ; Moysich, KB ; du Bois, A ; Heitz, F ; Harter, P ; Kommoss, S ; Karlan, BY ; Walsh, C ; Lester, J ; Jensen, A ; Kjaer, SK ; Hogdall, E ; Peissel, B ; Bonanni, B ; Bernard, L ; Goode, EL ; Fridley, BL ; Vierkant, RA ; Cunningham, JM ; Larson, MC ; Fogarty, ZC ; Kalli, KR ; Liang, D ; Lu, KH ; Hildebrandt, MAT ; Wu, X ; Levine, DA ; Dao, F ; Bisogna, M ; Berchuck, A ; Iversen, ES ; Marks, JR ; Akushevich, L ; Cramer, DW ; Schildkraut, J ; Terry, KL ; Poole, EM ; Stampfer, M ; Tworoger, SS ; Bandera, EV ; Orlow, I ; Olson, SH ; Bjorge, L ; Salvesen, HB ; van Altena, AM ; Aben, KKH ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bean, Y ; Brooks-Wilson, A ; Kelemen, LE ; Cook, LS ; Le, ND ; Grski, B ; Gronwald, J ; Menkiszak, J ; Hogdall, CK ; Lundvall, L ; Nedergaard, L ; Engelholm, SA ; Dicks, E ; Tyrer, J ; Campbell, I ; McNeish, I ; Paul, J ; Siddiqui, N ; Glasspool, R ; Whittemore, AS ; Rothstein, JH ; McGuire, V ; Sieh, W ; Cai, H ; Shu, X-O ; Teten, RT ; Sutphen, R ; McLaughlin, JR ; Narod, SA ; Phelan, CM ; Monteiro, AN ; Fenstermacher, D ; Lin, H-Y ; Permuth, JB ; Sellers, TA ; Chen, YA ; Tsai, Y-Y ; Chen, Z ; Gentry-Maharaj, A ; Gayther, SA ; Ramus, SJ ; Menon, U ; Wu, AH ; Pearce, CL ; Van den Berg, D ; Pike, MC ; Dansonka-Mieszkowska, A ; Plisiecka-Halasa, J ; Moes-Sosnowska, J ; Kupryjanczyk, J ; Pharoah, PDP ; Song, H ; Winship, I ; Chenevix-Trench, G ; Giles, GG ; Tavtigian, SV ; Easton, DF ; Milne, RL (BMJ PUBLISHING GROUP, 2016-12)
    BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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    Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study
    Dixon-Suen, SC ; Nagle, CM ; Thrift, AP ; Pharoah, PDP ; Ewing, A ; Pearce, CL ; Zheng, W ; Chenevix-Trench, G ; Fasching, PA ; Beckmann, MW ; Lambrechts, D ; Vergote, I ; Lambrechts, S ; Van Nieuwenhuysen, E ; Rossing, MA ; Doherty, JA ; Wicklund, KG ; Chang-Claude, J ; Jung, AY ; Moysich, KB ; Odunsi, K ; Goodman, MT ; Wilkens, LR ; Thompson, PJ ; Shvetsov, YB ; Doerk, T ; Park-Simon, T-W ; Hillemanns, P ; Bogdanova, N ; Butzow, R ; Nevanlinna, H ; Pelttari, LM ; Leminen, A ; Modugno, F ; Ness, RB ; Edwards, RP ; Kelley, JL ; Heitz, F ; du Bois, A ; Harter, P ; Schwaab, I ; Karlan, BY ; Lester, J ; Orsulic, S ; Rimel, BJ ; Kjaer, SK ; Hogdall, E ; Jensen, A ; Goode, EL ; Fridley, BL ; Cunningham, JM ; Winham, SJ ; Giles, GG ; Bruinsma, F ; Milne, RL ; Southey, MC ; Hildebrandt, MAT ; Wu, X ; Lu, KH ; Liang, D ; Levine, DA ; Bisogna, M ; Schildkraut, JM ; Berchuck, A ; Cramer, DW ; Terry, KL ; Bandera, EV ; Olson, SH ; Salvesen, HB ; Thomsen, LCV ; Kopperud, RK ; Bjorge, L ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bruegl, A ; Cook, LS ; Le, ND ; Swenerton, KD ; Brooks-Wilson, A ; Kelemen, LE ; Lubinski, J ; Huzarski, T ; Gronwald, J ; Menkiszak, J ; Wentzensen, N ; Brinton, L ; Yang, H ; Lissowska, J ; Hogdall, CK ; Lundvall, L ; Song, H ; Tyrer, JP ; Campbell, I ; Eccles, D ; Paul, J ; Glasspool, R ; Siddiqui, N ; Whittemore, AS ; Sieh, W ; McGuire, V ; Rothstein, JH ; Narod, SA ; Phelan, C ; Risch, HA ; McLaughlin, JR ; Anton-Culver, H ; Ziogas, A ; Menon, U ; Gayther, SA ; Ramus, SJ ; Gentry-Maharaj, A ; Wu, AH ; Pike, MC ; Tseng, C-C ; Kupryjanczyk, J ; Dansonka-Mieszkowska, A ; Budzilowska, A ; Rzepecka, IK ; Webb, PM (NATURE PUBLISHING GROUP, 2018-04)
    BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.