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2.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
doi:10.1371/journal.pgen.1004256
PMCID: PMC3974638  PMID: 24698998
3.  Identification of a recurrent germline PAX5 mutation and susceptibility to pre-B cell acute lymphoblastic leukemia 
Nature genetics  2013;45(10):1226-1231.
doi:10.1038/ng.2754
PMCID: PMC3919799  PMID: 24013638
4.  Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer 
BJU international  2011;109(5):713-719.
Objective
To investigate the relationship between BRCA mutation status and response to taxane-based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non-carriers and docetaxel improves survival in patients with castration-resistant prostate cancer.
Patients and Methods
We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration-resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review.
Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations.
Response to taxane-based therapy was defined by the prostate-specific antigen nadir within 12 weeks of therapy.
Results
In all, 88 men received taxane-based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non-carriers.
Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non-carriers (72%) (absolute difference 15%; 95% confidence interval −23% to 53%; P = 0.4).
Among patients with an initial response, the median change in prostate-specific antigen was similar for BRCA carriers (−63%, interquartile range −71% to −57%) and non-carriers (−60%, interquartile range −78% to −35%) (P = 0.6).
At last follow-up, all seven BRCA carriers and 49 non-carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months.
Conclusion
In this small, hypothesis-generating study approximately half of BRCA carriers had a prostate-specific antigen response to taxane-based chemotherapy, suggesting that it is an active therapy in these individuals.
doi:10.1111/j.1464-410X.2011.10292.x
PMCID: PMC3971723  PMID: 21756279
castration-resistant prostate cancer; BRCA1; BRCA2; taxane; docetaxel; response
5.  Association of a HOXB13 Variant with Breast Cancer 
The New England journal of medicine  2012;367(5):480-481.
doi:10.1056/NEJMc1205138
PMCID: PMC3926433  PMID: 22853031
6.  Genome-wide analysis of the role of copy-number variation in pancreatic cancer risk 
Although family history is a risk factor for pancreatic adenocarcinoma, much of the genetic etiology of this disease remains unknown. While genome-wide association studies have identified some common single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk, these SNPs do not explain all the heritability of this disease. We hypothesized that copy number variation (CNVs) in the genome may play a role in genetic predisposition to pancreatic adenocarcinoma. Here, we report a genome-wide analysis of CNVs in a small hospital-based, European ancestry cohort of pancreatic cancer cases and controls. Germline CNV discovery was performed using the Illumina Human CNV370 platform in 223 pancreatic cancer cases (both sporadic and familial) and 169 controls. Following stringent quality control, we asked if global CNV burden was a risk factor for pancreatic cancer. Finally, we performed in silico CNV genotyping and association testing to discover novel CNV risk loci. When we examined the global CNV burden, we found no strong evidence that CNV burden plays a role in pancreatic cancer risk either overall or specifically in individuals with a family history of the disease. Similarly, we saw no significant evidence that any particular CNV is associated with pancreatic cancer risk. Taken together, these data suggest that CNVs do not contribute substantially to the genetic etiology of pancreatic cancer, though the results are tempered by small sample size and large experimental variability inherent in array-based CNV studies.
doi:10.3389/fgene.2014.00029
PMCID: PMC3923159  PMID: 24592275
pancreatic cancer; copy number variation; cancer risk; SNP microarrays; CNVs
7.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
9.  Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers 
Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [Hazard ratio (HR)=1.55, 95% CI 1.25–1.92, p=6.0×10−5]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers [HR=1.09, 95% CI 0.96–1.24, p=0.18]. No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
doi:10.1007/s10549-012-2255-6
PMCID: PMC3482828  PMID: 23011509
BRCA1; BRCA2; genetic modifier; association study
10.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
11.  A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome 
PLoS Genetics  2013;9(8):e1003695.
Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.
Author Summary
Patients with dyskeratosis congenita (DC), a rare inherited disease, are at very high risk of developing cancer and bone marrow failure. The clinical features of DC include nail abnormalities, skin discoloration, and white spots in the mouth. Patients with Hoyeraal-Hreidarsson syndrome (HH) have symptoms of DC plus cerebellar hypoplasia, immunodeficiency, and poor prenatal growth. DC and HH are caused by defects in telomere biology; improperly maintained telomeres are thought to be a major contributor to carcinogenesis. In half the cases of DC, the causative mutation is unknown. By studying families affected by DC for whom a causative mutation has not yet been identified, we have discovered a homozygous germline mutation in RTEL1, a telomere maintenance gene that, if mutated, can result in HH. The mutations result in the inability of the RTEL1 protein to function properly at the telomere, and underscore its important role in telomere biology.
doi:10.1371/journal.pgen.1003695
PMCID: PMC3757051  PMID: 24009516
12.  Susceptibility Loci Associated with Prostate Cancer Progression and Mortality 
Purpose
Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
Experimental Design
We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and PSA. We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we performed an independent analysis using a high resolution panel of 13 SNPs.
Results
On univariate analysis, 2 SNPs were associated (p<0.05) with biochemical recurrence; 3 SNPs were associated with clinical metastases; and 1 SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis).
Conclusions
We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.
doi:10.1158/1078-0432.CCR-10-0028
PMCID: PMC3732009  PMID: 20460480
Single nucleotide polymorphisms; Prostate cancer; Prognosis
13.  Improved survival for BRCA2-associated serous ovarian cancer compared to both BRCA-negative and BRCA1-associated serous ovarian cancer 
Cancer  2011;118(15):3703-3709.
BACKGROUND
Multiple observational studies have suggested that BRCA-associated ovarian cancers have improved survival compared to BRCA-negative ovarian cancers. Most of these studies, however, have combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. We sought to examine if BRCA1− and BRCA2-associated ovarian cancers were associated with different outcomes.
METHODS
A single-institution retrospective analysis of patients seen between January 1, 1996 and February 1st, 2011 for a new diagnosis of histologically confirmed Stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer and who underwent BRCA mutation testing on one of two IRB approved follow-up studies. Patients tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients referred for genetic testing because of long survival.
RESULTS
Data from 190 patients (143 BRCA−, 30 BRCA1+, 17 BRCA2+) were analyzed. During the study period, 73 deaths were observed (60 BRCA−, 10 BRCA1+, 3 BRCA2+). Median follow-up time for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90·7%, and 100% of BRCA−, BRCA1+, and BRCA2+ patients were alive, respectively. On univariate analysis, age, BRCA2, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of overall survival (OS). On multivariate analysis, BRCA2 status (HR .20; 95% CI, .06–.65; P=.007) but not BRCA1 status (HR .70; 95% CI, .36–1.38; P=.31) predicted for improved OS compared to BRCA-patients. When carriers of BRCA2 mutations were directly compared to carriers of BRCA1 mutations, BRCA2 mutation status appeared to confer an improved OS (HR .29; 95% CI, 0.08–1.05; P=.060), although this finding did not reach significance.
CONCLUSION
Our data suggest that BRCA2 status confers an overall survival advantage compared to both BRCA− and BRCA1 status in high-grade serous ovarian cancer. This finding may have important implications for clinic trial design.
doi:10.1002/cncr.26655
PMCID: PMC3625663  PMID: 22139894
Ovarian cancer; BRCA1; BRCA2; PARP inhibitors
14.  Germline BRCA mutations denote a clinicopathologic subset of prostate cancer 
Purpose
Increased prostate cancer risk has been reported for BRCA mutation carriers but BRCA-associated clinicopathologic features have not been clearly defined.
Experimental Design
We determined BRCA mutation prevalence in 832 Ashkenazi Jewish (AJ) men diagnosed with localized prostate cancer between 1988 and 2007 and 454 AJ controls, and compared clinical outcome measures among 26 BRCA mutation carriers and 806 non-carriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason Score (GS), and logistic regression models to determine associations between carrier status, prostate cancer risk, and GS. Hazard ratios for clinical endpoints were estimated using Cox proportional hazards models.
Results
BRCA2 mutations were associated with a threefold risk of prostate cancer (OR [95% CI]=3.18 [1.52-6.66]; p = 0.002), and presented with more poorly differentiated (GS ≥ 7) tumors(85% vs. 57%, p= 0.0002) compared with non-BRCA associated PC. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, PSA, GS, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence (HR [95% CI] = 2.41[1.23, 4.75] and 4.32 [1.31, 13.62], respectively) and prostate cancer -specific death (HR [95% CI] = 5.48 [2.03, 14.79] and 5.16 [1.09,24.53], respectively) than non-carriers.
Conclusions
BRCA2 mutation-carriers had an increased risk of prostate cancer and a higher histological grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have impact on tailoring clinical management of this subset of hereditary prostate cancer.
doi:10.1158/1078-0432.CCR-09-2871
PMCID: PMC3713614  PMID: 20215531
BRCA1; BRCA2; prostate cancer; clinicopathologic associations
15.  Assessment of SLX4 Mutations in Hereditary Breast Cancers 
PLoS ONE  2013;8(6):e66961.
Background
SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.
Methods and Results
To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65–1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so.
Conclusion
Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.
doi:10.1371/journal.pone.0066961
PMCID: PMC3694110  PMID: 23840564
16.  A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms 
Nature genetics  2009;41(4):455-459.
Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis1–5. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis6–10, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci11. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
doi:10.1038/ng.342
PMCID: PMC3676425  PMID: 19287384
17.  The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers 
Breast Cancer Research and Treatment  2012;132(3):1119-1126.
Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
doi:10.1007/s10549-011-1938-8
PMCID: PMC3352679  PMID: 22212556
Breast cancer; Ovarian cancer-Klotho; BRCA; Modifier gene
18.  Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk 
Couch, Fergus J. | Wang, Xianshu | McGuffog, Lesley | Lee, Andrew | Olswold, Curtis | Kuchenbaecker, Karoline B. | Soucy, Penny | Fredericksen, Zachary | Barrowdale, Daniel | Dennis, Joe | Gaudet, Mia M. | Dicks, Ed | Kosel, Matthew | Healey, Sue | Sinilnikova, Olga M. | Lee, Adam | Bacot, François | Vincent, Daniel | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Jakubowska, Anna | Investigators, kConFab | Radice, Paolo | Schmutzler, Rita Katharina | Domchek, Susan M. | Piedmonte, Marion | Singer, Christian F. | Friedman, Eitan | Thomassen, Mads | Hansen, Thomas V. O. | Neuhausen, Susan L. | Szabo, Csilla I. | Blanco, Ignacio | Greene, Mark H. | Karlan, Beth Y. | Garber, Judy | Phelan, Catherine M. | Weitzel, Jeffrey N. | Montagna, Marco | Olah, Edith | Andrulis, Irene L. | Godwin, Andrew K. | Yannoukakos, Drakoulis | Goldgar, David E. | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | Terry, Mary Beth | Daly, Mary B. | van Rensburg, Elizabeth J. | Hamann, Ute | Ramus, Susan J. | Ewart Toland, Amanda | Caligo, Maria A. | Olopade, Olufunmilayo I. | Tung, Nadine | Claes, Kathleen | Beattie, Mary S. | Southey, Melissa C. | Imyanitov, Evgeny N. | Tischkowitz, Marc | Janavicius, Ramunas | John, Esther M. | Kwong, Ava | Diez, Orland | Balmaña, Judith | Barkardottir, Rosa B. | Arun, Banu K. | Rennert, Gad | Teo, Soo-Hwang | Ganz, Patricia A. | Campbell, Ian | van der Hout, Annemarie H. | van Deurzen, Carolien H. M. | Seynaeve, Caroline | Gómez Garcia, Encarna B. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E. J. | Gille, Johannes J. P. | Ausems, Margreet G. E. M. | Blok, Marinus J. | Ligtenberg, Marjolijn J. L. | Rookus, Matti A. | Devilee, Peter | Verhoef, Senno | van Os, Theo A. M. | Wijnen, Juul T. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Izatt, Louise | Eeles, Rosalind A. | Adlard, Julian | Eccles, Diana M. | Cook, Jackie | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley | Morrison, Patrick J. | Side, Lucy E. | Donaldson, Alan | Houghton, Catherine | Rogers, Mark T. | Dorkins, Huw | Eason, Jacqueline | Gregory, Helen | McCann, Emma | Murray, Alex | Calender, Alain | Hardouin, Agnès | Berthet, Pascaline | Delnatte, Capucine | Nogues, Catherine | Lasset, Christine | Houdayer, Claude | Leroux, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Sobol, Hagay | Coupier, Isabelle | Venat-Bouvet, Laurence | Castera, Laurent | Gauthier-Villars, Marion | Léoné, Mélanie | Pujol, Pascal | Mazoyer, Sylvie | Bignon, Yves-Jean | Złowocka-Perłowska, Elżbieta | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska, Katarzyna | Huzarski, Tomasz | Spurdle, Amanda B. | Viel, Alessandra | Peissel, Bernard | Bonanni, Bernardo | Melloni, Giulia | Ottini, Laura | Papi, Laura | Varesco, Liliana | Tibiletti, Maria Grazia | Peterlongo, Paolo | Volorio, Sara | Manoukian, Siranoush | Pensotti, Valeria | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Gadzicki, Dorothea | Gehrig, Andrea | Kast, Karin | Rhiem, Kerstin | Meindl, Alfons | Niederacher, Dieter | Ditsch, Nina | Plendl, Hansjoerg | Preisler-Adams, Sabine | Engert, Stefanie | Sutter, Christian | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Weber, Bernhard H. F. | Arver, Brita | Stenmark-Askmalm, Marie | Loman, Niklas | Rosenquist, Richard | Einbeigi, Zakaria | Nathanson, Katherine L. | Rebbeck, Timothy R. | Blank, Stephanie V. | Cohn, David E. | Rodriguez, Gustavo C. | Small, Laurie | Friedlander, Michael | Bae-Jump, Victoria L. | Fink-Retter, Anneliese | Rappaport, Christine | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Lindor, Noralane M. | Kaufman, Bella | Shimon Paluch, Shani | Laitman, Yael | Skytte, Anne-Bine | Gerdes, Anne-Marie | Pedersen, Inge Sokilde | Moeller, Sanne Traasdahl | Kruse, Torben A. | Jensen, Uffe Birk | Vijai, Joseph | Sarrel, Kara | Robson, Mark | Kauff, Noah | Mulligan, Anna Marie | Glendon, Gord | Ozcelik, Hilmi | Ejlertsen, Bent | Nielsen, Finn C. | Jønson, Lars | Andersen, Mette K. | Ding, Yuan Chun | Steele, Linda | Foretova, Lenka | Teulé, Alex | Lazaro, Conxi | Brunet, Joan | Pujana, Miquel Angel | Mai, Phuong L. | Loud, Jennifer T. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Narod, Steven A. | Herzog, Josef | Sand, Sharon R. | Tognazzo, Silvia | Agata, Simona | Vaszko, Tibor | Weaver, Joellen | Stavropoulou, Alexandra V. | Buys, Saundra S. | Romero, Atocha | de la Hoya, Miguel | Aittomäki, Kristiina | Muranen, Taru A. | Duran, Mercedes | Chung, Wendy K. | Lasa, Adriana | Dorfling, Cecilia M. | Miron, Alexander | Benitez, Javier | Senter, Leigha | Huo, Dezheng | Chan, Salina B. | Sokolenko, Anna P. | Chiquette, Jocelyne | Tihomirova, Laima | Friebel, Tara M. | Agnarsson, Bjarni A. | Lu, Karen H. | Lejbkowicz, Flavio | James, Paul A. | Hall, Per | Dunning, Alison M. | Tessier, Daniel | Cunningham, Julie | Slager, Susan L. | Wang, Chen | Hart, Steven | Stevens, Kristen | Simard, Jacques | Pastinen, Tomi | Pankratz, Vernon S. | Offit, Kenneth | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C.
PLoS Genetics  2013;9(3):e1003212.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Author Summary
BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
doi:10.1371/journal.pgen.1003212
PMCID: PMC3609646  PMID: 23544013
19.  Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk 
Gaudet, Mia M. | Kuchenbaecker, Karoline B. | Vijai, Joseph | Klein, Robert J. | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Dunning, Alison M. | Lee, Andrew | Dennis, Joe | Healey, Sue | Dicks, Ed | Soucy, Penny | Sinilnikova, Olga M. | Pankratz, Vernon S. | Wang, Xianshu | Eldridge, Ronald C. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Schmutzler, Rita K. | Nathanson, Katherine L. | Piedmonte, Marion | Singer, Christian F. | Thomassen, Mads | Hansen, Thomas v. O. | Neuhausen, Susan L. | Blanco, Ignacio | Greene, Mark H. | Garber, Judith | Weitzel, Jeffrey N. | Andrulis, Irene L. | Goldgar, David E. | D'Andrea, Emma | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | van Rensburg, Elizabeth J. | Arason, Adalgeir | Rennert, Gad | van den Ouweland, Ans M. W. | van der Hout, Annemarie H. | Kets, Carolien M. | Aalfs, Cora M. | Wijnen, Juul T. | Ausems, Margreet G. E. M. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Jacobs, Chris | Adlard, Julian | Tischkowitz, Marc | Porteous, Mary E. | Damiola, Francesca | Golmard, Lisa | Barjhoux, Laure | Longy, Michel | Belotti, Muriel | Ferrer, Sandra Fert | Mazoyer, Sylvie | Spurdle, Amanda B. | Manoukian, Siranoush | Barile, Monica | Genuardi, Maurizio | Arnold, Norbert | Meindl, Alfons | Sutter, Christian | Wappenschmidt, Barbara | Domchek, Susan M. | Pfeiler, Georg | Friedman, Eitan | Jensen, Uffe Birk | Robson, Mark | Shah, Sohela | Lazaro, Conxi | Mai, Phuong L. | Benitez, Javier | Southey, Melissa C. | Schmidt, Marjanka K. | Fasching, Peter A. | Peto, Julian | Humphreys, Manjeet K. | Wang, Qin | Michailidou, Kyriaki | Sawyer, Elinor J. | Burwinkel, Barbara | Guénel, Pascal | Bojesen, Stig E. | Milne, Roger L. | Brenner, Hermann | Lochmann, Magdalena | Aittomäki, Kristiina | Dörk, Thilo | Margolin, Sara | Mannermaa, Arto | Lambrechts, Diether | Chang-Claude, Jenny | Radice, Paolo | Giles, Graham G. | Haiman, Christopher A. | Winqvist, Robert | Devillee, Peter | García-Closas, Montserrat | Schoof, Nils | Hooning, Maartje J. | Cox, Angela | Pharoah, Paul D. P. | Jakubowska, Anna | Orr, Nick | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Hall, Per | Couch, Fergus J. | Simard, Jacques | Altshuler, David | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Offit, Kenneth
PLoS Genetics  2013;9(3):e1003173.
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Author Summary
Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.
doi:10.1371/journal.pgen.1003173
PMCID: PMC3609647  PMID: 23544012
20.  Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors 
Nickels, Stefan | Truong, Thérèse | Hein, Rebecca | Stevens, Kristen | Buck, Katharina | Behrens, Sabine | Eilber, Ursula | Schmidt, Martina | Häberle, Lothar | Vrieling, Alina | Gaudet, Mia | Figueroa, Jonine | Schoof, Nils | Spurdle, Amanda B. | Rudolph, Anja | Fasching, Peter A. | Hopper, John L. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Beckmann, Matthias W. | Ekici, Arif B. | Fletcher, Olivia | Gibson, Lorna | dos Santos Silva, Isabel | Peto, Julian | Humphreys, Manjeet K. | Wang, Jean | Cordina-Duverger, Emilie | Menegaux, Florence | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Harth, Volker | The GENICA Network,  | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | kConFab,  | Group, AOCS Management | Lambrechts, Diether | Smeets, Dominiek | Neven, Patrick | Paridaens, Robert | Flesch-Janys, Dieter | Obi, Nadia | Wang-Gohrke, Shan | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine M. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Offit, Kenneth | John, Esther M. | Miron, Alexander | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Chanock, Stephen J. | Lissowska, Jolanta | Liu, Jianjun | Cox, Angela | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Dunning, Alison M. | Shah, Mitul | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen | Cahoon, Elizabeth K. | Rajaraman, Preetha | Sigurdson, Alice J. | Doody, Michele M. | Guénel, Pascal | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Hall, Per | Easton, Doug F. | Garcia-Closas, Montserrat | Milne, Roger L. | Chang-Claude, Jenny
PLoS Genetics  2013;9(3):e1003284.
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
doi:10.1371/journal.pgen.1003284
PMCID: PMC3609648  PMID: 23544014
21.  Genetics, Genomics and Cancer Risk Assessment: State of the art and future directions in the era of personalized medicine 
CA: a cancer journal for clinicians  2011;10.3322/caac.20128.
Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently-discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease-risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine.
doi:10.3322/caac.20128
PMCID: PMC3346864  PMID: 21858794
Genomics; genetic cancer risk assessment; genetic counseling; prevention; genetics; hereditary cancer
22.  A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers 
Ding, Yuan C. | McGuffog, Lesley | Healey, Sue | Friedman, Eitan | Laitman, Yael | Shani-Shimon–Paluch,  | Kaufman, Bella | Liljegren, Annelie | Lindblom, Annika | Olsson, Håkan | Kristoffersson, Ulf | Stenmark-Askmalm, Marie | Melin, Beatrice | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Huzarski, Tomasz | Cybulski, Cezary | Byrski, Tomasz | Osorio, Ana | Cajal, Teresa Ramóny | Stavropoulou, Alexandra V | Benítez, Javier | Hamann, Ute | Rookus, Matti | Aalfs, Cora M. | de Lange, Judith L. | Meijers-Heijboer, Hanne E.J. | Oosterwijk, Jan C. | van Asperen, Christi J. | García, Encarna B. Gómez | Hoogerbrugge, Nicoline | Jager, Agnes | van der Luijt, Rob B. | Easton, Douglas F. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Cole, Trevor | Cook, Jackie | Brewer, Carole | Tischkowitz, Marc | Godwin, Andrew K. | Pathak, Harsh | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Barjhoux, Laure | Léoné, Mélanie | Gauthier-Villars, Marion | Caux-Moncoutier, Virginie | de Pauw, Antoine | Hardouin, Agnès | Berthet, Pascaline | Dreyfus, Hélène | Ferrer, Sandra Fert | Collonge-Rame, Marie-Agnès | Sokolowska, Johanna | Buys, Saundra | Daly, Mary | Miron, Alex | Terry, Mary Beth | Chung, Wendy | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Maria, Muy-Kheng Tea | Gschwantler-Kaulich, Daphne | Fink-Retter, Anneliese | Hansen, Thomas v. O. | Ejlertsen, Bent | Johannsson, Oskar Th. | Offit, Kenneth | Sarrel, Kara | Gaudet, Mia M. | Vijai, Joseph | Robson, Mark | Piedmonte, Marion R | Andrews, Lesley | Cohn, David | DeMars, Leslie R. | DiSilvestro, Paul | Rodriguez, Gustavo | Toland, Amanda Ewart | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Ramus, Susan J | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Ganz, Patricia A. | Beattie, Mary S. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Meindl, Alfons | Arnold, Norbert | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorotehea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Nevanlinna, Heli | Aittomäki, Kristiina | Simard, Jacques | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Tomlinson, Gail E. | Weitzel, Jeffrey | Garber, Judy E. | Olopade, Olufunmilayo I. | Rubinstein, Wendy S. | Tung, Nadine | Blum, Joanne L. | Narod, Steven A. | Brummel, Sean | Gillen, Daniel L. | Lindor, Noralane | Fredericksen, Zachary | Pankratz, Vernon S. | Couch, Fergus J. | Radice, Paolo | Peterlongo, Paolo | Greene, Mark H. | Loud, Jennifer T. | Mai, Phuong L. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Gerdes, Anne-Marie | Thomassen, Mads | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A. | Lee, Andrew | Chenevix-Trench, Georgia | Antoniou, Antonis C | Neuhausen, Susan L.
Background
We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.
Methods
IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.
Results
Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03).
Conclusion
The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers.
Impact
These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
doi:10.1158/1055-9965.EPI-12-0229
PMCID: PMC3415567  PMID: 22729394
Breast cancer; Ovarian cancer; BRCA1 and BRCA2 mutation carriers; insulin receptor substrate 1; Insulin-like growth factor /insulin (IGF/INS) signaling
23.  Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies 
PLoS Genetics  2013;9(1):e1003220.
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Author Summary
B-cell lymphomas comprise several diseases representing aberrant proliferations of immune cells at various stages of maturation. It might be expected that dissimilar subtypes of lymphoma will have different etiologic and pathogenic mechanisms, reflecting the distinct histologic and clinical characteristics of these diseases. This study aims to define both shared as well as specific genetic risk factors for lymphoma. Utilizing a genome-wide approach, we discovered novel locations in the genome associated with risk for lymphoid malignancies. Common variants in these regions, on chromosome 11q12.1 and 6p23, were each associated with a modest modification of risk for lymphoma. These regions harbor several genes of biological importance in lymphoid maturation and function. We also further characterized the HLA region at 6p21.32, previously associated with lymphoma risk and thought to be important in immune function. Some of the associated SNP markers were specific for one common subtype of lymphoma, e.g. follicular lymphoma. However, others were associated with combined subsets of disease, suggesting that there are both shared and subtype-specific associations between common genetic variants and human lymphoid cancer. Secondary analyses showed that the two novel regions harbor candidates that are biologically relevant and that regulate cell development and hematopoiesis.
doi:10.1371/journal.pgen.1003220
PMCID: PMC3547842  PMID: 23349640
24.  Functional redundancy of exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A>G p.I2285V variant 
Human mutation  2009;30(11):1543-1550.
Variants of Unknown Significance (VUS) in BRCA1 and BRCA2 are common, and present significant challenges for genetic counseling. We observed that BRCA2: c.6853A>G (p.I2285V) (Brest cancer Information Core [BIC] name: 7081A>G; http://nhgri.nih.gov/bic/) co-occurs in trans with the founder mutation c.5946delT (p.S1982RfsX22) (BIC name: 6174delT), supporting the published classification of p.I2285V as a neutral variant. However, we also noted that when compared with wild-type BRCA2, p.I2285V resulted in increased exclusion of exon 12. Functional assay using allelic complementation in Brca2-null mouse embryonic stem cells revealed that p.I2285V, an allele with exon 12 deleted and wild-type BRCA2 were all phenotypically indistinguishable, as measured by sensitivity to DNA-damaging agents, effect on irradiation-induced Rad51 foci formation, homologous recombination and overall genomic integrity. An allele frequency study showed the p.I2285V variant was identified in 15/722 (2.1%) Ashkenazi Jewish cases and 10/475 (2.1%) ethnically-matched controls, odds ratio: 0.99 (95% confidence interval: 0.44–2.21), P = 0.97. Thus the p.I2285V variant is not associated with an increased risk for breast cancer. Taken together, our clinical and functional studies strongly suggest that exon 12 is functionally redundant and therefore missense variants in this exon are likely to be neutral. Such comprehensive functional studies will be important adjuncts to genetic studies of variants.
doi:10.1002/humu.21101
PMCID: PMC3501199  PMID: 19795481
BRCA2; unclassified variants; co-occurrence; exon splicing enhancer; exon skipping; in-frame deletion; neutral variant; Embryonic Stem (ES) cells
25.  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

Results 1-25 (67)