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1.  Genome-wide association study identifies five new breast cancer susceptibility loci 
Nature genetics  2010;42(6):504-507.
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 × 10−7 to P = 3.2 × 10−15). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 × 10−6), 8q24 (rs1562430, P = 5.8 × 10−7) and LSP1 (rs909116, P = 7.3 × 10−7) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
doi:10.1038/ng.586
PMCID: PMC3632836  PMID: 20453838
2.  Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers 
Im, Kate M. | Kirchhoff, Tomas | Wang, Xianshu | Green, Todd | Chow, Clement Y. | Vijai, Joseph | Korn, Joshua | Gaudet, Mia M. | Fredericksen, Zachary | Pankratz, V. Shane | Guiducci, Candace | Crenshaw, Andrew | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Mai, Phuong L. | Greene, Mark H. | Piedmonte, Marion | Rubinstein, Wendy S. | Hogervorst, Frans B. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Asperen, Christi J. | Meijers-Heijboer, Hanne E. J. | Van Roozendaal, Cees E. | Caldes, Trinidad | Perez-Segura, Pedro | Jakubowska, Anna | Lubinski, Jan | Huzarski, Tomasz | Blecharz, Paweł | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Barkardottir, Rosa B. | Montagna, Marco | D'Andrea, Emma | Devilee, Peter | Olopade, Olufunmilayo I. | Neuhausen, Susan L. | Peissel, Bernard | Bonanni, Bernardo | Peterlongo, Paolo | Singer, Christian F. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda Ewart | Caligo, Maria Adelaide | Beattie, Mary S. | Chan, Salina | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Phelan, Catherine | Narod, Steven | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary-Beth | Tung, Nadine | Hansen, Thomas v. O. | Osorio, Ana | Benitez, Javier | Durán, Mercedes | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Platte, Radka | Evans, D. Gareth | Eeles, Ros | Izatt, Louise | Paterson, Joan | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Laitman, Yael | Meindl, Alfons | Deissler, Helmut | Varon-Mateeva, Raymonda | Preisler-Adams, Sabine | Kast, Karin | Venat-Bouvet, Laurence | Stoppa-Lyonnet, Dominique | Chenevix-Trench, Georgia | Easton, Douglas F. | Klein, Robert J. | Daly, Mark J. | Friedman, Eitan | Dean, Michael | Clark, Andrew G. | Altshuler, David M. | Antoniou, Antonis C. | Couch, Fergus J. | Offit, Kenneth | Gold, Bert
Human genetics  2011;130(5):685-699.
Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
doi:10.1007/s00439-011-1003-z
PMCID: PMC3196382  PMID: 21597964
3.  How to survive an 11-storey fall 
BMJ Case Reports  2010;2010:bcr0320102850.
Survival from a high fall is rarely possible. We report an unusual case of a patient who fell over 100 ft on to boggy ground and survived. A successful outcome was achieved by the use of aggressive blood product resuscitation and the early application of a pelvic fixator.
doi:10.1136/bcr.03.2010.2850
PMCID: PMC3029988  PMID: 22791478
4.  Utility of admission physiology in the surgical triage of isolated ballistic battlefield torso trauma 
Background:
An assessment of hemodynamic stability is central to surgical decision-making in the management of battlefield ballistic torso trauma (BBTT).
Aims:
To analyse the utility of admission physiological parameters in characterising hemodynamic stability.
Settings and Design:
A retrospective analysis of consecutive admissions, with BBTT, to forward surgical facility in Afghanistan.
Materials and Methods:
The cohorts’ admission physiology, need for operative intervention, and mortality data were collected retrospectively. The cohort was divided into patients requiring surgery for Life-Threatening Torso Hemorrhage (LTTH) and those not requiring immediate surgery (non-LTTH).
Statistical Analysis:
Parameters were compared using two sample t tests, Mann–Whitney, Fisher's exact, and Chi-square tests. Receiver operator characteristic curves were used to identify significant parameters and determine optimum cut-off values.
Results:
A total of 103 patients with isolated BBTT were identified: 44 in the LTTH group and 59 in the non-LTTH group. The mean New Injury Severity Score ± Standard Deviation (NISS±SD) was 28±14 and 13±12, respectively. The heart rate, systolic blood pressure (SBP), pulse pressure, shock index (SI=heart rate/SBP) and base excess were analysed. SI correlated best with the need for surgical torso hemorrhage control, P<0.05. An optimal cut-off of 0.9 was identified, producing a positive and negative predictive value of 81% and 82%, respectively.
Conclusions:
Shock index (SI) is a useful parameter for helping military surgeons triage BBTT, identifying patients requiring operative torso hemorrhage control. SI performance requires a normal physiological response to hypovolemia, and thus should always be considered in clinical context.
doi:10.4103/0974-2700.99690
PMCID: PMC3440889  PMID: 22988401
Battlefield torso trauma; shock index; trauma surgery; triage
5.  A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population 
Antoniou, Antonis C | Wang, Xianshu | Fredericksen, Zachary S | McGuffog, Lesley | Tarrell, Robert | Sinilnikova, Olga M | Healey, Sue | Morrison, Jonathan | Kartsonaki, Christiana | Lesnick, Timothy | Ghoussaini, Maya | Barrowdale, Daniel | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Eccles, Diana | Evans, D Gareth | Eeles, Ros | Izatt, Louise | Chu, Carol | Douglas, Fiona | Paterson, Joan | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Mazoyer, Sylvie | Giraud, Sophie | Lasset, Christine | Remenieras, Audrey | Caron, Olivier | Hardouin, Agnès | Berthet, Pascaline | Hogervorst, Frans B L | Rookus, Matti A | Jager, Agnes | van den Ouweland, Ans | Hoogerbrugge, Nicoline | van der Luijt, Rob B | Meijers-Heijboer, Hanne | García, Encarna B Gómez | Devilee, Peter | Vreeswijk, Maaike P G | Lubinski, Jan | Jakubowska, Anna | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Cybulski, Cezary | Spurdle, Amanda B | Holland, Helene | Goldgar, David E | John, Esther M | Hopper, John L | Southey, Melissa | Buys, Saundra S | Daly, Mary B | Terry, Mary-Beth | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Preisler-Adams, Sabine | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Domchek, Susan M | Nathanson, Katherine L | Rebbeck, Timothy | Blum, Joanne L | Piedmonte, Marion | Rodriguez, Gustavo C | Wakeley, Katie | Boggess, John F | Basil, Jack | Blank, Stephanie V | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Andrulis, Irene L | Glendon, Gord | Ozcelik, Hilmi | Kirchhoff, Tomas | Vijai, Joseph | Gaudet, Mia M | Altshuler, David | Guiducci, Candace | Loman, Niklas | Harbst, Katja | Rantala, Johanna | Ehrencrona, Hans | Gerdes, Anne-Marie | Thomassen, Mads | Sunde, Lone | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Viel, Alessandra | Radice, Paolo | Caldes, Trinidad | de la Hoya, Miguel | Singer, Christian F | Fink-Retter, Anneliese | Greene, Mark H | Mai, Phuong L | Loud, Jennifer T | Guidugli, Lucia | Lindor, Noralane M | Hansen, Thomas V O | Nielsen, Finn C | Blanco, Ignacio | Lazaro, Conxi | Garber, Judy | Ramus, Susan J | Gayther, Simon A | Phelan, Catherine | Narod, Stephen | Szabo, Csilla I | Benitez, Javier | Osorio, Ana | Nevanlinna, Heli | Heikkinen, Tuomas | Caligo, Maria A | Beattie, Mary S | Hamann, Ute | Godwin, Andrew K | Montagna, Marco | Casella, Cinzia | Neuhausen, Susan L | Karlan, Beth Y | Tung, Nadine | Toland, Amanda E | Weitzel, Jeffrey | Olopade, Olofunmilayo | Simard, Jacques | Soucy, Penny | Rubinstein, Wendy S | Arason, Adalgeir | Rennert, Gad | Martin, Nicholas G | Montgomery, Grant W | Chang-Claude, Jenny | Flesch-Janys, Dieter | Brauch, Hiltrud | Severi, Gianluca | Baglietto, Laura | Cox, Angela | Cross, Simon S | Miron, Penelope | Gerty, Sue M | Tapper, William | Yannoukakos, Drakoulis | Fountzilas, George | Fasching, Peter A | Beckmann, Matthias W | Silva, Isabel dos Santos | Peto, Julian | Lambrechts, Diether | Paridaens, Robert | Rüdiger, Thomas | Försti, Asta | Winqvist, Robert | Pylkäs, Katri | Diasio, Robert B | Lee, Adam M | Eckel-Passow, Jeanette | Vachon, Celine | Blows, Fiona | Driver, Kristy | Dunning, Alison | Pharoah, Paul P D | Offit, Kenneth | Pankratz, V Shane | Hakonarson, Hakon | Chenevix-Trench, Georgia | Easton, Douglas F | Couch, Fergus J
Nature genetics  2010;42(10):885-892.
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7).
doi:10.1038/ng.669
PMCID: PMC3130795  PMID: 20852631
6.  Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark H. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth
PLoS Genetics  2010;6(11):10.1371/annotation/59ea8540-4e63-4f4a-a79e-f68765fdeac7.
doi:10.1371/annotation/59ea8540-4e63-4f4a-a79e-f68765fdeac7
PMCID: PMC2988688
7.  Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark I. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth
PLoS Genetics  2010;6(11):10.1371/annotation/b28cf02d-7196-4a16-8b36-6562a0b84f75.
doi:10.1371/annotation/b28cf02d-7196-4a16-8b36-6562a0b84f75
PMCID: PMC2999983
8.  Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark I. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth | Ford, James M.
PLoS Genetics  2010;6(10):e1001183.
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
Author Summary
The risk of breast cancer associated with BRCA2 mutations varies widely. To determine whether common genetic variants modify the penetrance of BRCA2 mutations, we conducted the first genome-wide association study of breast cancer among women with BRCA2 mutations using a two-stage approach. The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population, including FGFR2 (rs2981575), modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance. However, the ZNF365 locus has recently independently been associated with breast cancer risk in sporadic tumors, highlighting the potential significance of this zinc finger-containing gene in breast cancer pathogenesis. Our results indicate that it is unlikely that other common variants have a strong modifying effect on BRCA2 penetrance.
doi:10.1371/journal.pgen.1001183
PMCID: PMC2965747  PMID: 21060860
9.  A genome-wide association study of testicular germ cell tumor 
Nature genetics  2009;41(7):807-810.
We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19–1.58), P = 3 × 10−13), chromosome 6 (OR = 1.50 (95% = CI = 1.28–1.75), P = 10−13) and chromosome 12 (OR = 2.55 (95% CI = 2.05–3.19), P = 10−31). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.
doi:10.1038/ng.394
PMCID: PMC2871592  PMID: 19483681
10.  Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 
Ahmed, Shahana | Thomas, Gilles | Ghoussaini, Maya | Healey, Catherine S | Humphreys, Manjeet K | Platte, Radka | Morrison, Jonathan | Maranian, Melanie | Pooley, Karen A | Luben, Robert | Eccles, Diana | Evans, D Gareth | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Peto, Julian | Stratton, Michael R | Rahman, Nazneen | Jacobs, Kevin | Prentice, Ross | Anderson, Garnet L | Rajkovic, Aleksandar | Curb, J David | Ziegler, Regina G | Berg, Christine D | Buys, Saundra S | McCarty, Catherine A | Feigelson, Heather Spencer | Calle, Eugenia E | Thun, Michael J | Diver, W Ryan | Bojesen, Stig | Nordestgaard, Børge G | Flyger, Henrik | Dörk, Thilo | Schürmann, Peter | Hillemanns, Peter | Karstens, Johann H | Bogdanova, Natalia V | Antonenkova, Natalia N | Zalutsky, Iosif V | Bermisheva, Marina | Fedorova, Sardana | Khusnutdinova, Elza | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Ahn, Sei-Hyun | Devilee, Peter | van Asperen, Christi J | Tollenaar, R A E M | Seynaeve, Caroline | Garcia-Closas, Montserrat | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Hopper, John L | Southey, Melissa C | Smith, Letitia | Spurdle, Amanda B | Schmidt, Marjanka K | Broeks, Annegien | van Hien, Richard R | Cornelissen, Sten | Milne, Roger L | Ribas, Gloria | González-Neira, Anna | Benitez, Javier | Schmutzler, Rita K | Burwinkel, Barbara | Bartram, Claus R | Meindl, Alfons | Brauch, Hiltrud | Justenhoven, Christina | Hamann, Ute | Chang-Claude, Jenny | Hein, Rebecca | Wang-Gohrke, Shan | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Hankinson, Susan E | Cox, David G | Kraft, Peter | Vatten, Lars J | Hveem, Kristian | Kumle, Merethe | Sigurdson, Alice | Doody, Michele | Bhatti, Parveen | Alexander, Bruce H | Hooning, Maartje J | van den Ouweland, Ans M W | Oldenburg, Rogier A | Schutte, Mieke | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Yuqing | Cox, Angela | Elliott, Graeme | Brock, Ian | Reed, Malcolm W R | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Giu-Cheng | Chen, Shou-Tung | Anton-Culver, Hoda | Ziogas, Argyrios | Andrulis, Irene L | Knight, Julia A | kConFab | Beesley, Jonathan | Goode, Ellen L | Couch, Fergus | Chenevix-Trench, Georgia | Hoover, Robert N | Ponder, Bruce A J | Hunter, David J | Pharoah, Paul D P | Dunning, Alison M | Chanock, Stephen J | Easton, Douglas F
Nature genetics  2009;41(5):585-590.
Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10−23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10−8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
doi:10.1038/ng.354
PMCID: PMC2748125  PMID: 19330027
11.  Five Polymorphisms and Breast Cancer Risk: Results from the Breast Cancer Association Consortium 
Gaudet, Mia M. | Milne, Roger L. | Cox, Angela | Camp, Nicola J. | Goode, Ellen L. | Humphreys, Manjeet K. | Dunning, Alison M. | Morrison, Jonathan | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Chang-Claude, Jenny | Flesch-Janys, Dieter | Abbas, Sascha | Salazar, Ramona | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Lindblom, Annika | Margolin, Sara | Heikkinen, Tuomas | Kämpjärvi, Kati | Aaltonen, Kirsimari | Nevanlinna, Heli | Bogdanova, Natalia | Coinac, Irina | Schürmann, Peter | Dörk, Thilo | Bartram, Claus R. | Schmutzler, Rita K. | Tchatchou, Sandrine | Burwinkel, Barbara | Brauch, Hiltrud | Torres, Diana | Hamann, Ute | Justenhoven, Christina | Ribas, Gloria | Arias, José I. | Benitez, Javier | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik L. | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Fasching, Peter A. | Beckmann, Matthias W. | Strick, Reiner | Ekici, Arif B. | Broeks, Annegien | Schmidt, Marjanka K. | van Leeuwen, Flora E. | Van’t Veer, Laura J. | Southey, Melissa C. | Hopper, John L. | Apicella, Carmel | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Kristensen, Vessela | Alnæs, Grethe Grenaker | Hunter, David J. | Kraft, Peter | Cox, David G. | Hankinson, Susan E. | Seynaeve, Caroline | Vreeswijk, Maaike P.G. | Tollenaar, Rob A.E.M. | Devilee, Peter | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Czene, Kamila | Hall, Per | Li, Yuqing | Liu, Jianjun | Balasubramanian, Sabapathy | Rafii, Saeed | Reed, Malcolm W.R. | Pooley, Karen A. | Conroy, Don | Baynes, Caroline | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Shen, Chen-Yang | Wang, Hui-Chun | Yu, Jyh-Cherng | Wu, Pei-Ei | Anton-Culver, Hoda | Ziogoas, Argyrios | Egan, Kathleen | Newcomb, Polly | Titus-Ernstoff, Linda | Dietz, Amy Trentham | Sigurdson, Alice J. | Alexander, Bruce H. | Bhatti, Parveen | Allen-Brady, Kristina | Cannon-Albright, Lisa A. | Wong, Jathine | Chenevix-Trench, Georgia | Spurdle, Amanda B. | Beesley, Jonathan | Pharoah, Paul D.P. | Easton, Doug F. | Garcia-Closas, Montserrat
Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97–1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95–1.06), 5.0%; CASP10 1.02 (0.98–1.07), 6.5%; PGR 1.02 (0.99–1.06), 15.3%; and BID 0.98 (0.86–1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.
doi:10.1158/1055-9965.EPI-08-0745
PMCID: PMC2737177  PMID: 19423537
12.  Genome-wide association study identifies novel breast cancer susceptibility loci 
Easton, Douglas F. | Pooley, Karen A. | Dunning, Alison M. | Pharoah, Paul D. P. | Thompson, Deborah | Ballinger, Dennis G. | Struewing, Jeffery P. | Morrison, Jonathan | Field, Helen | Luben, Robert | Wareham, Nicholas | Ahmed, Shahana | Healey, Catherine S. | Bowman, Richard | Meyer, Kerstin B. | Haiman, Christopher A. | Kolonel, Laurence K. | Henderson, Brian E. | Marchand, Loic Le | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Odefrey, Fabrice | Shen, Chen-Yang | Wu, Pei-Ei | Wang, Hui-Chun | Eccles, Diana | Evans, D. Gareth | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Seal, Sheila | Stratton, Michael R. | Rahman, Nazneen | Chenevix-Trench, Georgia | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Garcia-Closas, Montserrat | Brinton, Louise | Chanock, Stephen | Lissowska, Jolanta | Peplonska, Beata | Nevanlinna, Heli | Fagerholm, Rainer | Eerola, Hannaleena | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Hall, Per | Wedren, Sara | Liu, Jianjun | Low, Yen-Ling | Bogdanova, Natalia | Schürmann, Peter | Dörk, Thilo | Tollenaar, Rob A. E. M. | Jacobi, Catharina E. | Devilee, Peter | Klijn, Jan G. M. | Sigurdson, Alice J. | Doody, Michele M. | Alexander, Bruce H. | Zhang, Jinghui | Cox, Angela | Brock, Ian W. | MacPherson, Gordon | Reed, Malcolm W. R. | Couch, Fergus J. | Goode, Ellen L. | Olson, Janet E. | Meijers-Heijboer, Hanne | van den Ouweland, Ans | Uitterlinden, André | Rivadeneira, Fernando | Milne, Roger L. | Ribas, Gloria | Gonzalez-Neira, Anna | Benitez, Javier | Hopper, John L. | McCredie, Margaret | Southey, Melissa | Giles, Graham G. | Schroen, Chris | Justenhoven, Christina | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana | Day, Nicholas E. | Cox, David R. | Ponder, Bruce A. J. | Luccarini, Craig | Conroy, Don | Shah, Mitul | Munday, Hannah | Jordan, Clare | Perkins, Barbara | West, Judy | Redman, Karen | Driver, Kristy | Aghmesheh, Morteza | Amor, David | Andrews, Lesley | Antill, Yoland | Armes, Jane | Armitage, Shane | Arnold, Leanne | Balleine, Rosemary | Begley, Glenn | Beilby, John | Bennett, Ian | Bennett, Barbara | Berry, Geoffrey | Blackburn, Anneke | Brennan, Meagan | Brown, Melissa | Buckley, Michael | Burke, Jo | Butow, Phyllis | Byron, Keith | Callen, David | Campbell, Ian | Chenevix-Trench, Georgia | Clarke, Christine | Colley, Alison | Cotton, Dick | Cui, Jisheng | Culling, Bronwyn | Cummings, Margaret | Dawson, Sarah-Jane | Dixon, Joanne | Dobrovic, Alexander | Dudding, Tracy | Edkins, Ted | Eisenbruch, Maurice | Farshid, Gelareh | Fawcett, Susan | Field, Michael | Firgaira, Frank | Fleming, Jean | Forbes, John | Friedlander, Michael | Gaff, Clara | Gardner, Mac | Gattas, Mike | George, Peter | Giles, Graham | Gill, Grantley | Goldblatt, Jack | Greening, Sian | Grist, Scott | Haan, Eric | Harris, Marion | Hart, Stewart | Hayward, Nick | Hopper, John | Humphrey, Evelyn | Jenkins, Mark | Jones, Alison | Kefford, Rick | Kirk, Judy | Kollias, James | Kovalenko, Sergey | Lakhani, Sunil | Leary, Jennifer | Lim, Jacqueline | Lindeman, Geoff | Lipton, Lara | Lobb, Liz | Maclurcan, Mariette | Mann, Graham | Marsh, Deborah | McCredie, Margaret | McKay, Michael | McLachlan, Sue Anne | Meiser, Bettina | Milne, Roger | Mitchell, Gillian | Newman, Beth | O'Loughlin, Imelda | Osborne, Richard | Peters, Lester | Phillips, Kelly | Price, Melanie | Reeve, Jeanne | Reeve, Tony | Richards, Robert | Rinehart, Gina | Robinson, Bridget | Rudzki, Barney | Salisbury, Elizabeth | Sambrook, Joe | Saunders, Christobel | Scott, Clare | Scott, Elizabeth | Scott, Rodney | Seshadri, Ram | Shelling, Andrew | Southey, Melissa | Spurdle, Amanda | Suthers, Graeme | Taylor, Donna | Tennant, Christopher | Thorne, Heather | Townshend, Sharron | Tucker, Kathy | Tyler, Janet | Venter, Deon | Visvader, Jane | Walpole, Ian | Ward, Robin | Waring, Paul | Warner, Bev | Warren, Graham | Watson, Elizabeth | Williams, Rachael | Wilson, Judy | Winship, Ingrid | Young, Mary Ann | Bowtell, David | Green, Adele | deFazio, Anna | Chenevix-Trench, Georgia | Gertig, Dorota | Webb, Penny
Nature  2007;447(7148):1087-1093.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
doi:10.1038/nature05887
PMCID: PMC2714974  PMID: 17529967
13.  Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert 
Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case–control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.
doi:10.1093/jnci/djn190
PMCID: PMC2902819  PMID: 18577746
14.  Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design 
BMC Bioinformatics  2009;10:180.
Background
In moderate-throughput SNP genotyping there was a gap in the workflow, between choosing a set of SNPs and submitting their sequences to proprietary assay design software, which was not met by existing software. Retrieval and formatting of sequences flanking each SNP, prior to assay design, becomes rate-limiting for more than about ten SNPs, especially if annotated for repetitive regions and adjacent variations. We routinely process up to 50 SNPs at once.
Implementation
We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design.
Conclusion
The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5).
Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation.
Seq4SNPs is available as a service at and , currently for human SNPs, but easily extended to include any species in dbSNP.
doi:10.1186/1471-2105-10-180
PMCID: PMC2711078  PMID: 19523221
15.  A high resolution HLA and SNP haplotype map for disease association studies in the extended human MHC 
Nature genetics  2006;38(10):1166-1172.
The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and play an essential role in self/non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune disease1. Yet identification of causal variants is problematic due to linkage disequilibrium (LD) that extends across multiple HLA and non-HLA genes in the MHC2,3. We therefore set out to characterize the LD patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common single nucleotide polymorphisms (SNPs) and deletion/insertion polymorphisms (DIPs) across four population samples. The analysis provides informative tag SNPs that capture some of the variation in the MHC region and that could be used in initial disease association studies, and provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.
doi:10.1038/ng1885
PMCID: PMC2670196  PMID: 16998491
16.  Identification of new genetic risk factors for prostate cancer 
Asian Journal of Andrology  2008;11(1):49-55.
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
doi:10.1038/aja.2008.18
PMCID: PMC3735221  PMID: 19050691
prostate cancer; genetics; susceptibility loci; SNPs; relative risks
17.  Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics 
Garcia-Closas, Montserrat | Hall, Per | Nevanlinna, Heli | Pooley, Karen | Morrison, Jonathan | Richesson, Douglas A. | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Arias, Jose I. | Milne, Roger L. | Ribas, Gloria | González-Neira, Anna | Benítez, Javier | Zamora, Pilar | Brauch, Hiltrud | Justenhoven, Christina | Hamann, Ute | Ko, Yon-Dschun | Bruening, Thomas | Haas, Susanne | Dörk, Thilo | Schürmann, Peter | Hillemanns, Peter | Bogdanova, Natalia | Bremer, Michael | Karstens, Johann Hinrich | Fagerholm, Rainer | Aaltonen, Kirsimari | Aittomäki, Kristiina | von Smitten, Karl | Blomqvist, Carl | Mannermaa, Arto | Uusitupa, Matti | Eskelinen, Matti | Tengström, Maria | Kosma, Veli-Matti | Kataja, Vesa | Chenevix-Trench, Georgia | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing |  Australian Ovarian Cancer Management Group,  |  The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,  | Devilee, Peter | van Asperen, Christi J. | Jacobi, Catharina E. | Tollenaar, Rob A. E. M. | Huijts, Petra E.A. | Klijn, Jan G. M. | Chang-Claude, Jenny | Kropp, Silke | Slanger, Tracy | Flesch-Janys, Dieter | Mutschelknauss, Elke | Salazar, Ramona | Wang-Gohrke, Shan | Couch, Fergus | Goode, Ellen L. | Olson, Janet E. | Vachon, Celine | Fredericksen, Zachary S. | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | Hopper, John L. | English, Dallas R. | Southey, Melissa C. | Haiman, Christopher A. | Henderson, Brian E. | Kolonel, Laurence N. | Le Marchand, Loic | Stram, Daniel O. | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Tamimi, Rulla | Kraft, Peter | Sherman, Mark E. | Chanock, Stephen J. | Lissowska, Jolanta | Brinton, Louise A. | Peplonska, Beata | Klijn, Jan G. M. | Hooning, Maartje J. | Meijers-Heijboer, Han | Collee, J. Margriet | van den Ouweland, Ans | Uitterlinden, Andre G. | Liu, Jianjun | Lin, Low Yen | Yuqing, Li | Humphreys, Keith | Czene, Kamila | Cox, Angela | Balasubramanian, Sabapathy P. | Cross, Simon S. | Reed, Malcolm W. R. | Blows, Fiona | Driver, Kristy | Dunning, Alison | Tyrer, Jonathan | Ponder, Bruce A. J. | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gabrieau, Valerie | Sigurdson, Alice | Doody, Michele | Struewing, Jeffrey P. | Alexander, Bruce | Easton, Douglas F. | Pharoah, Paul D. | Leal, Suzanne M.
PLoS Genetics  2008;4(4):e1000054.
A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10−13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10−5, 10−8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10−4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
Author Summary
This report from the Breast Cancer Association Consortium evaluates whether common variants in five recently identified breast cancer susceptibility loci (FGFR2, TNRC9, MAP3K1, 8q24, and LSP1) influence the clinical presentation of breast cancer and survival after diagnosis. We studied these susceptibility loci in relation to clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls of European or Asian origin from 20 studies. The association, with overall survival, was evaluated in 13,527 cases from 13 studies. The most notable findings were that the genetic variants in the fibroblast growth factor receptor 2 (FGFR2) gene and the 8q24 region were more strongly related to ER-positive than ER-negative disease, and to low rather than high grade tumors. The loci did not significantly influence survival after accounting for known prognostic factors. Analyses indicated that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative diseases are biologically distinct tumors. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
doi:10.1371/journal.pgen.1000054
PMCID: PMC2291027  PMID: 18437204

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