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1.  Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2 
Silvestri, Valentina | Barrowdale, Daniel | Mulligan, Anna Marie | Neuhausen, Susan L. | Fox, Stephen | Karlan, Beth Y. | Mitchell, Gillian | James, Paul | Thull, Darcy L. | Zorn, Kristin K. | Carter, Natalie J. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Ramus, Susan J. | Nussbaum, Robert L. | Olopade, Olufunmilayo I. | Rantala, Johanna | Yoon, Sook-Yee | Caligo, Maria A. | Spugnesi, Laura | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Toland, Amanda Ewart | Senter, Leigha | Andrulis, Irene L. | Glendon, Gord | Hulick, Peter J. | Imyanitov, Evgeny N. | Greene, Mark H. | Mai, Phuong L. | Singer, Christian F. | Rappaport-Fuerhauser, Christine | Kramer, Gero | Vijai, Joseph | Offit, Kenneth | Robson, Mark | Lincoln, Anne | Jacobs, Lauren | Machackova, Eva | Foretova, Lenka | Navratilova, Marie | Vasickova, Petra | Couch, Fergus J. | Hallberg, Emily | Ruddy, Kathryn J. | Sharma, Priyanka | Kim, Sung-Won | Teixeira, Manuel R. | Pinto, Pedro | Montagna, Marco | Matricardi, Laura | Arason, Adalgeir | Johannsson, Oskar Th | Barkardottir, Rosa B. | Jakubowska, Anna | Lubinski, Jan | Izquierdo, Angel | Pujana, Miguel Angel | Balmaña, Judith | Diez, Orland | Ivady, Gabriella | Papp, Janos | Olah, Edith | Kwong, Ava | Nevanlinna, Heli | Aittomäki, Kristiina | Perez Segura, Pedro | Caldes, Trinidad | Van Maerken, Tom | Poppe, Bruce | Claes, Kathleen B. M. | Isaacs, Claudine | Elan, Camille | Lasset, Christine | Stoppa-Lyonnet, Dominique | Barjhoux, Laure | Belotti, Muriel | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Hahnen, Eric | Kast, Karin | Arnold, Norbert | Varon-Mateeva, Raymonda | Wand, Dorothea | Godwin, Andrew K. | Evans, D. Gareth | Frost, Debra | Perkins, Jo | Adlard, Julian | Izatt, Louise | Platte, Radka | Eeles, Ros | Ellis, Steve | Hamann, Ute | Garber, Judy | Fostira, Florentia | Fountzilas, George | Pasini, Barbara | Giannini, Giuseppe | Rizzolo, Piera | Russo, Antonio | Cortesi, Laura | Papi, Laura | Varesco, Liliana | Palli, Domenico | Zanna, Ines | Savarese, Antonella | Radice, Paolo | Manoukian, Siranoush | Peissel, Bernard | Barile, Monica | Bonanni, Bernardo | Viel, Alessandra | Pensotti, Valeria | Tommasi, Stefania | Peterlongo, Paolo | Weitzel, Jeffrey N. | Osorio, Ana | Benitez, Javier | McGuffog, Lesley | Healey, Sue | Gerdes, Anne-Marie | Ejlertsen, Bent | Hansen, Thomas V. O. | Steele, Linda | Ding, Yuan Chun | Tung, Nadine | Janavicius, Ramunas | Goldgar, David E. | Buys, Saundra S. | Daly, Mary B. | Bane, Anita | Terry, Mary Beth | John, Esther M. | Southey, Melissa | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Ottini, Laura
Background
BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).
Methods
We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.
Results
Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12).
Conclusions
On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0671-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0671-y
PMCID: PMC4746828  PMID: 26857456
Male breast cancer; BRCA1/2; Pathology; Histologic grade; Genotype–phenotype correlations
2.  A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis 
PLoS ONE  2016;11(1):e0146435.
We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28–2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews.
doi:10.1371/journal.pone.0146435
PMCID: PMC4709047  PMID: 26751797
3.  Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements 
PLoS ONE  2015;10(9):e0139360.
Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkin’s lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation-defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well.
doi:10.1371/journal.pone.0139360
PMCID: PMC4589387  PMID: 26422229
4.  Identification of six new susceptibility loci for invasive epithelial ovarian cancer 
Kuchenbaecker, Karoline B. | Ramus, Susan J. | Tyrer, Jonathan | Lee, Andrew | Shen, Howard C. | Beesley, Jonathan | Lawrenson, Kate | McGuffog, Lesley | Healey, Sue | Lee, Janet M. | Spindler, Tassja J. | Lin, Yvonne G. | Pejovic, Tanja | Bean, Yukie | Li, Qiyuan | Coetzee, Simon | Hazelett, Dennis | Miron, Alexander | Southey, Melissa | Terry, Mary Beth | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas V. O. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | Barrowdale, Daniel | Dennis, Joe | Benitez, Javier | Osorio, Ana | Garcia, Maria Jose | Komenaka, Ian | Weitzel, Jeffrey N. | Ganschow, Pamela | Peterlongo, Paolo | Bernard, Loris | Viel, Alessandra | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Radice, Paolo | Papi, Laura | Ottini, Laura | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Frost, Debra | Perkins, Jo | Platte, Radka | Ellis, Steve | Godwin, Andrew K. | Schmutzler, Rita Katharina | Meindl, Alfons | Engel, Christoph | Sutter, Christian | Sinilnikova, Olga M. | Damiola, Francesca | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Claes, Kathleen | De Leeneer, Kim | Kirk, Judy | Rodriguez, Gustavo C. | Piedmonte, Marion | O'Malley, David M. | de la Hoya, Miguel | Caldes, Trinidad | Aittomäki, Kristiina | Nevanlinna, Heli | Collée, J. Margriet | Rookus, Matti A. | Oosterwijk, Jan C. | Tihomirova, Laima | Tung, Nadine | Hamann, Ute | Isaacs, Claudine | Tischkowitz, Marc | Imyanitov, Evgeny N. | Caligo, Maria A. | Campbell, Ian | Hogervorst, Frans B.L. | Olah, Edith | Diez, Orland | Blanco, Ignacio | Brunet, Joan | Lazaro, Conxi | Pujana, Miquel Angel | Jakubowska, Anna | Gronwald, Jacek | Lubinski, Jan | Sukiennicki, Grzegorz | Barkardottir, Rosa B. | Plante, Marie | Simard, Jacques | Soucy, Penny | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Pankratz, Vernon S. | Wang, Xianshu | Lindor, Noralane | Szabo, Csilla I. | Kauff, Noah | Vijai, Joseph | Aghajanian, Carol A. | Pfeiler, Georg | Berger, Andreas | Singer, Christian F. | Tea, Muy-Kheng | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Tchatchou, Sandrine | Andrulis, Irene L. | Glendon, Gord | Toland, Amanda Ewart | Jensen, Uffe Birk | Kruse, Torben A. | Thomassen, Mads | Bojesen, Anders | Zidan, Jamal | Friedman, Eitan | Laitman, Yael | Soller, Maria | Liljegren, Annelie | Arver, Brita | Einbeigi, Zakaria | Stenmark-Askmalm, Marie | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Rebbeck, Timothy R. | Nathanson, Katherine L. | Domchek, Susan M. | Lu, Karen H. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Dicks, Ed | Doherty, Jennifer A. | Wicklund, Kristine G. | Rossing, Mary Anne | Rudolph, Anja | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lele, Shashi | Wilkens, Lynne R. | Goodman, Marc T. | Thompson, Pamela J. | Shvetsov, Yurii B. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Pelttari, Liisa M. | Butzow, Ralf | Modugno, Francesmary | Kelley, Joseph L. | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Matsuo, Keitaro | Hosono, Satoyo | Orsulic, Sandra | Jensen, Allan | Kjaer, Susanne Kruger | Hogdall, Estrid | Hasmad, Hanis Nazihah | Noor Azmi, Mat Adenan | Teo, Soo-Hwang | Woo, Yin-Ling | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Bruinsma, Fiona | Giles, Graham G. | Liang, Dong | Hildebrandt, Michelle A.T. | Wu, Xifeng | Levine, Douglas A. | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Concannon, Patrick | Weber, Rachel Palmieri | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Orlow, Irene | Olson, Sara H. | Krakstad, Camilla | Salvesen, Helga B. | Tangen, Ingvild L. | Bjorge, Line | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Kellar, Melissa | Brooks-Wilson, Angela | Kelemen, Linda E. | Cook, Linda S. | Le, Nhu D. | Cybulski, Cezary | Yang, Hannah | Lissowska, Jolanta | Brinton, Louise A. | Wentzensen, Nicolas | Hogdall, Claus | Lundvall, Lene | Nedergaard, Lotte | Baker, Helen | Song, Honglin | Eccles, Diana | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S. | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Ji, Bu-Tian | Zheng, Wei | Shu, Xiao-Ou | Gao, Yu-Tang | Rosen, Barry | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Monteiro, Alvaro N. | Chen, Ann | Lin, Hui-Yi | Permuth-Wey, Jenny | Sellers, Thomas A. | Tsai, Ya-Yu | Chen, Zhihua | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Harrington, Patricia | Lee, Alice W. | Wu, Anna H. | Pearce, Celeste L. | Coetzee, Gerhard A. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Timorek, Agnieszka | Rzepecka, Iwona K. | Kupryjanczyk, Jolanta | Freedman, Matt | Noushmehr, Houtan | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Gayther, Simon | Pharoah, Paul P. | Antoniou, Antonis C. | Chenevix-Trench, Georgia
Nature genetics  2015;47(2):164-171.
doi:10.1038/ng.3185
PMCID: PMC4445140  PMID: 25581431
5.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005–1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers; Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
6.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Bressac-de Paillerets, Brigitte | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers, Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
7.  Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia 
PLoS Genetics  2015;11(6):e1005262.
Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.
Author Summary
Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia. Here we report two unrelated kindreds with inherited mutations in ETV6, the gene encoding the transcription factor ETS variant 6. These families were characterized by a low platelet count (thrombocytopenia) and acute lymphoblastic leukemia (ALL). Sequencing a panel of genes identified germline ETV6 mutations associated with leukemia and thrombocytopenia in multiple individuals tested. In one family, there was a substitution within the DNA binding domain of ETV6, termed L349P, and in the second there were five base pairs missing in ETV6 (N385fs), causing an abnormally truncated protein. We overexpressed the ETV6 mutants in the HeLa cell line and measured protein levels and localization within the cells. Instead of localizing to the nucleus, as expected for a transcription factor, the mutant proteins were found in the cytoplasm. The mutant proteins also showed decreased ability to regulate the expression of other genes typically suppressed by ETV6. These findings suggest that germline ETV6 mutations cause a new type of heritable leukemia. This discovery makes possible the pre-symptomatic diagnosis of leukemia susceptibility in families with germline ETV6 mutations, and also provides new information on the causes of leukemia.
doi:10.1371/journal.pgen.1005262
PMCID: PMC4477877  PMID: 26102509
8.  Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma 
Cerhan, James R | Berndt, Sonja I | Vijai, Joseph | Ghesquières, Hervé | McKay, James | Wang, Sophia S | Wang, Zhaoming | Yeager, Meredith | Conde, Lucia | de Bakker, Paul I W | Nieters, Alexandra | Cox, David | Burdett, Laurie | Monnereau, Alain | Flowers, Christopher R | De Roos, Anneclaire J | Brooks-Wilson, Angela R | Lan, Qing | Severi, Gianluca | Melbye, Mads | Gu, Jian | Jackson, Rebecca D | Kane, Eleanor | Teras, Lauren R | Purdue, Mark P | Vajdic, Claire M | Spinelli, John J | Giles, Graham G | Albanes, Demetrius | Kelly, Rachel S | Zucca, Mariagrazia | Bertrand, Kimberly A | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Hutchinson, Amy | Zhi, Degui | Habermann, Thomas M | Link, Brian K | Novak, Anne J | Dogan, Ahmet | Asmann, Yan W | Liebow, Mark | Thompson, Carrie A | Ansell, Stephen M | Witzig, Thomas E | Weiner, George J | Veron, Amelie S | Zelenika, Diana | Tilly, Hervé | Haioun, Corinne | Molina, Thierry Jo | Hjalgrim, Henrik | Glimelius, Bengt | Adami, Hans-Olov | Bracci, Paige M | Riby, Jacques | Smith, Martyn T | Holly, Elizabeth A | Cozen, Wendy | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Tinker, Lesley F | North, Kari E | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | Staines, Anthony | Lightfoot, Tracy | Crouch, Simon | Smith, Alex | Roman, Eve | Diver, W Ryan | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J | Villano, Danylo J | Zheng, Tongzhang | Zhang, Yawei | Holford, Theodore R | Kricker, Anne | Turner, Jenny | Southey, Melissa C | Clavel, Jacqueline | Virtamo, Jarmo | Weinstein, Stephanie | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Vermeulen, Roel C H | Boeing, Heiner | Tjonneland, Anne | Angelucci, Emanuele | Di Lollo, Simonetta | Rais, Marco | Birmann, Brenda M | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Huang, Jinyan | Ma, Baoshan | Ye, Yuanqing | Chiu, Brian C H | Sampson, Joshua | Liang, Liming | Park, Ju-Hyun | Chung, Charles C | Weisenburger, Dennis D | Chatterjee, Nilanjan | Fraumeni, Joseph F | Slager, Susan L | Wu, Xifeng | de Sanjose, Silvia | Smedby, Karin E | Salles, Gilles | Skibola, Christine F | Rothman, Nathaniel | Chanock, Stephen J
Nature genetics  2014;46(11):1233-1238.
doi:10.1038/ng.3105
PMCID: PMC4213349  PMID: 25261932
9.  An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers 
Blein, Sophie | Bardel, Claire | Danjean, Vincent | McGuffog, Lesley | Healey, Sue | Barrowdale, Daniel | Lee, Andrew | Dennis, Joe | Kuchenbaecker, Karoline B | Soucy, Penny | Terry, Mary Beth | Chung, Wendy K | Goldgar, David E | Buys, Saundra S | Janavicius, Ramunas | Tihomirova, Laima | Tung, Nadine | Dorfling, Cecilia M | van Rensburg, Elizabeth J | Neuhausen, Susan L | Ding, Yuan Chun | Gerdes, Anne-Marie | Ejlertsen, Bent | Nielsen, Finn C | Hansen, Thomas VO | Osorio, Ana | Benitez, Javier | Conejero, Raquel Andrés | Segota, Ena | Weitzel, Jeffrey N | Thelander, Margo | Peterlongo, Paolo | Radice, Paolo | Pensotti, Valeria | Dolcetti, Riccardo | Bonanni, Bernardo | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Manoukian, Siranoush | Varesco, Liliana | Capone, Gabriele L | Papi, Laura | Ottini, Laura | Yannoukakos, Drakoulis | Konstantopoulou, Irene | Garber, Judy | Hamann, Ute | Donaldson, Alan | Brady, Angela | Brewer, Carole | Foo, Claire | Evans, D Gareth | Frost, Debra | Eccles, Diana | Douglas, Fiona | Cook, Jackie | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E | Kennedy, M John | Tischkowitz, Marc | Rogers, Mark T | Porteous, Mary E | Morrison, Patrick J | Platte, Radka | Eeles, Ros | Davidson, Rosemarie | Hodgson, Shirley | Cole, Trevor | Godwin, Andrew K | Isaacs, Claudine | Claes, Kathleen | De Leeneer, Kim | Meindl, Alfons | Gehrig, Andrea | Wappenschmidt, Barbara | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Schmutzler, Rita K | Preisler-Adams, Sabine | Markov, Nadja Bogdanova | Wang-Gohrke, Shan | de Pauw, Antoine | Lefol, Cédrick | Lasset, Christine | Leroux, Dominique | Rouleau, Etienne | Damiola, Francesca | Dreyfus, Hélène | Barjhoux, Laure | Golmard, Lisa | Uhrhammer, Nancy | Bonadona, Valérie | Sornin, Valérie | Bignon, Yves-Jean | Carter, Jonathan | Van Le, Linda | Piedmonte, Marion | DiSilvestro, Paul A | de la Hoya, Miguel | Caldes, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Jager, Agnes | van den Ouweland, Ans MW | Kets, Carolien M | Aalfs, Cora M | van Leeuwen, Flora E | Hogervorst, Frans BL | Meijers-Heijboer, Hanne EJ | Oosterwijk, Jan C | van Roozendaal, Kees EP | Rookus, Matti A | Devilee, Peter | van der Luijt, Rob B | Olah, Edith | Diez, Orland | Teulé, Alex | Lazaro, Conxi | Blanco, Ignacio | Del Valle, Jesús | Jakubowska, Anna | Sukiennicki, Grzegorz | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Agnarsson, Bjarni A | Maugard, Christine | Amadori, Alberto | Montagna, Marco | Teixeira, Manuel R | Spurdle, Amanda B | Foulkes, William | Olswold, Curtis | Lindor, Noralane M | Pankratz, Vernon S | Szabo, Csilla I | Lincoln, Anne | Jacobs, Lauren | Corines, Marina | Robson, Mark | Vijai, Joseph | Berger, Andreas | Fink-Retter, Anneliese | Singer, Christian F | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng | Greene, Mark H | Mai, Phuong L | Rennert, Gad | Imyanitov, Evgeny N | Mulligan, Anna Marie | Glendon, Gord | Andrulis, Irene L | Tchatchou, Sandrine | Toland, Amanda Ewart | Pedersen, Inge Sokilde | Thomassen, Mads | Kruse, Torben A | Jensen, Uffe Birk | Caligo, Maria A | Friedman, Eitan | Zidan, Jamal | Laitman, Yael | Lindblom, Annika | Melin, Beatrice | Arver, Brita | Loman, Niklas | Rosenquist, Richard | Olopade, Olufunmilayo I | Nussbaum, Robert L | Ramus, Susan J | Nathanson, Katherine L | Domchek, Susan M | Rebbeck, Timothy R | Arun, Banu K | Mitchell, Gillian | Karlan, Beth Y | Lester, Jenny | Orsulic, Sandra | Stoppa-Lyonnet, Dominique | Thomas, Gilles | Simard, Jacques | Couch, Fergus J | Offit, Kenneth | Easton, Douglas F | Chenevix-Trench, Georgia | Antoniou, Antonis C | Mazoyer, Sylvie | Phelan, Catherine M | Sinilnikova, Olga M | Cox, David G
Introduction
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0567-2
PMCID: PMC4478717  PMID: 25925750
10.  The Signatures of Autozygosity among Patients with Colorectal Cancer 
Cancer research  2008;68(8):2610-2621.
Previous studies have shown that among populations with a high rate of consanguinity, there is a significant increase in the prevalence of cancer. Single nucleotide polymorphism (SNP) array data (Affymetrix, 50K XbaI) analysis revealed long regions of homozygosity in genomic DNAs taken from tumor and matched normal tissues of colorectal cancer (CRC) patients. The presence of these regions in the genome may indicate levels of consanguinity in the individual’s family lineage. We refer to these autozygous regions as identity-by-descent (IBD) segments. In this study, we compared IBD segments in 74 mostly Caucasian CRC patients (mean age of 66 years) to two control data sets: (a) 146 Caucasian individuals (mean age of 80 years) who participated in an age-related macular degeneration (AMD) study and (b) 118 cancer-free Caucasian individuals from the Framingham Heart Study (mean age of 67 years). Our results show that the percentage of CRC patients with IBD segments (≥4 Mb length and 50 SNPs probed) in the genome is at least twice as high as the AMD or Framingham control groups. Also, the average length of these IBD regions in the CRC patients is more than twice the length of the two control data sets. Compared with control groups, IBD segments are found to be more common among individuals of Jewish background. We believe that these IBD segments within CRC patients are likely to harbor important CRC-related genes with low-penetrance SNPs and/or mutations, and, indeed, two recently identified CRC predisposition SNPs in the 8q24 region were confirmed to be homozygous in one particular patient carrying an IBD segment covering the region.
doi:10.1158/0008-5472.CAN-07-5250
PMCID: PMC4383032  PMID: 18375840
11.  Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants 
Mavaddat, Nasim | Pharoah, Paul D. P. | Michailidou, Kyriaki | Tyrer, Jonathan | Brook, Mark N. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Peto, Julian | dos-Santos-Silva, Isabel | Dudbridge, Frank | Johnson, Nichola | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J. | Figueroa, Jonine | Chanock, Stephen J. | Brinton, Louise | Lissowska, Jolanta | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Pankratz, Vernon S. | Lambrechts, Diether | Wildiers, Hans | Van Ongeval, Chantal | van Limbergen, Erik | Kristensen, Vessela | Grenaker Alnæs, Grethe | Nord, Silje | Borresen-Dale, Anne-Lise | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen M. | Hunter, David J. | Lindstrom, Sara | Tamimi, Rulla M. | Kraft, Peter | Rahman, Nazneen | Turnbull, Clare | Renwick, Anthony | Seal, Sheila | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Bernstein, Leslie | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofyeva, Darya | Takhirova, Zalina | Meindl, Alfons | Schmutzler, Rita K. | Sutter, Christian | Yang, Rongxi | Schürmann, Peter | Bremer, Michael | Christiansen, Hans | Park-Simon, Tjoung-Won | Hillemanns, Peter | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Pensotti, Valeria | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Sigurdson, Alice J. | Doody, Michele M. | Hamann, Ute | Torres, Diana | Ulmer, Hans-Ulrich | Försti, Asta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Marie Mulligan, Anna | Chenevix-Trench, Georgia | Balleine, Rosemary | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Lindblom, Annika | Margolin, Sara | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Eilber, Ursula | Wang-Gohrke, Shan | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Koppert, Linetta B. | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Karina Dieffenbach, Aida | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Offit, Kenneth | Vijai, Joseph | Robson, Mark | Rau-Murthy, Rohini | Dwek, Miriam | Swann, Ruth | Annie Perkins, Katherine | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Eccles, Diana M. | Tapper, William J. | Rafiq, Sajjad | John, Esther M. | Whittemore, Alice S. | Slager, Susan | Yannoukakos, Drakoulis | Toland, Amanda E. | Yao, Song | Zheng, Wei | Halverson, Sandra L. | González-Neira, Anna | Pita, Guillermo | Rosario Alonso, M. | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Simard, Jacques | Hall, Per | Easton, Douglas F. | Garcia-Closas, Montserrat
Background:
Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
Methods:
We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
Results:
There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
Conclusions:
The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
doi:10.1093/jnci/djv036
PMCID: PMC4754625  PMID: 25855707
12.  Variants at IRX4 as prostate cancer expression quantitative trait loci 
Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer risk-associated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript–genotype associations, of which 27 were significant (false discovery rate ≤10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P=4.91 × 10−5). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.
doi:10.1038/ejhg.2013.195
PMCID: PMC3953920  PMID: 24022300
expression quantitative trait loci; eQTL; prostate cancer; GWAS; risk SNPs; IRX4
13.  Genetic Variants in Germline TP53 and MDM2 SNP309 Are Not Associated With Early Onset Colorectal Cancer 
Journal of surgical oncology  2008;97(7):621-625.
Background and Objectives
Colorectal cancer (CRC) arising in patients under age 30 is a rare disease, and few cases have been reported within Li-Fraumeni kindreds. To determine how often alterations in the p53 pathway genes contribute to disease susceptibility, we have evaluated patients with early onset CRC for the presence of germline variants in the p53 gene and MDM2 SNP309.
Methods
Thirty-five patients with CRC diagnosed before age 30 were included in this study-based on tissue availability. DNA samples from peripheral blood leukocytes were analyzed for constitutional mutations and polymorphisms in p53 as well as polymorphisms in MDM2 SNP309.
Results
No mutations were found in exons 4–10 of the p53 gene. The frequencies of polymorphisms in p53 and in MDM2 SNP309 did not differ from rates previously reported for normal control populations, and no polymorphism in either gene could be associated with early onset CRC.
Conclusions
Neither germline variants in p53 nor MDM2 SNP309 play an underlying role in the development of very early onset CRC. For the large majority of cases, the genetic basis of this disease remains unknown.
doi:10.1002/jso.20996
PMCID: PMC4381874  PMID: 18381604
early onset colorectal cancer; p53; SNP309; genetic syndromes
14.  Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers 
Blanco, Ignacio | Kuchenbaecker, Karoline | Cuadras, Daniel | Wang, Xianshu | Barrowdale, Daniel | de Garibay, Gorka Ruiz | Librado, Pablo | Sánchez-Gracia, Alejandro | Rozas, Julio | Bonifaci, Núria | McGuffog, Lesley | Pankratz, Vernon S. | Islam, Abul | Mateo, Francesca | Berenguer, Antoni | Petit, Anna | Català, Isabel | Brunet, Joan | Feliubadaló, Lidia | Tornero, Eva | Benítez, Javier | Osorio, Ana | Cajal, Teresa Ramón y | Nevanlinna, Heli | Aittomäki, Kristiina | Arun, Banu K. | Toland, Amanda E. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Greene, Mark H. | Mai, Phuong L. | Nussbaum, Robert L. | Andrulis, Irene L. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Barkardottir, Rosa B. | Jakubowska, Anna | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Claes, Kathleen | Van Maerken, Tom | Díez, Orland | Hansen, Thomas V. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | de la Hoya, Miguel | Caldés, Trinidad | Dunning, Alison M. | Oliver, Clare | Fineberg, Elena | Cook, Margaret | Peock, Susan | McCann, Emma | Murray, Alex | Jacobs, Chris | Pichert, Gabriella | Lalloo, Fiona | Chu, Carol | Dorkins, Huw | Paterson, Joan | Ong, Kai-Ren | Teixeira, Manuel R. | Hogervorst, Frans B. L. | van der Hout, Annemarie H. | Seynaeve, Caroline | van der Luijt, Rob B. | Ligtenberg, Marjolijn J. L. | Devilee, Peter | Wijnen, Juul T. | Rookus, Matti A. | Meijers-Heijboer, Hanne E. J. | Blok, Marinus J. | van den Ouweland, Ans M. W. | Aalfs, Cora M. | Rodriguez, Gustavo C. | Phillips, Kelly-Anne A. | Piedmonte, Marion | Nerenstone, Stacy R. | Bae-Jump, Victoria L. | O'Malley, David M. | Ratner, Elena S. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg J. | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Jensen, Uffe Birk | Thomassen, Mads | Kruse, Torben A. | Foretova, Lenka | Peterlongo, Paolo | Bernard, Loris | Peissel, Bernard | Scuvera, Giulietta | Manoukian, Siranoush | Radice, Paolo | Ottini, Laura | Montagna, Marco | Agata, Simona | Maugard, Christine | Simard, Jacques | Soucy, Penny | Berger, Andreas | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler-Kaulich, Daphne | Tea, Muy-Kheng | Pfeiler, Georg | John, Esther M. | Miron, Alex | Neuhausen, Susan L. | Terry, Mary Beth | Chung, Wendy K. | Daly, Mary B. | Goldgar, David E. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elisabeth J. | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Godwin, Andrew K. | Olah, Edith | Narod, Steven A. | Rennert, Gad | Paluch, Shani Shimon | Laitman, Yael | Friedman, Eitan | Liljegren, Annelie | Rantala, Johanna | Stenmark-Askmalm, Marie | Loman, Niklas | Imyanitov, Evgeny N. | Hamann, Ute | Spurdle, Amanda B. | Healey, Sue | Weitzel, Jeffrey N. | Herzog, Josef | Margileth, David | Gorrini, Chiara | Esteller, Manel | Gómez, Antonio | Sayols, Sergi | Vidal, Enrique | Heyn, Holger | Stoppa-Lyonnet, Dominique | Léoné, Melanie | Barjhoux, Laure | Fassy-Colcombet, Marion | de Pauw, Antoine | Lasset, Christine | Ferrer, Sandra Fert | Castera, Laurent | Berthet, Pascaline | Cornelis, François | Bignon, Yves-Jean | Damiola, Francesca | Mazoyer, Sylvie | Sinilnikova, Olga M. | Maxwell, Christopher A. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Corines, Marina J. | Villano, Danylko | Cunningham, Julie | Lee, Adam | Lindor, Noralane | Lázaro, Conxi | Easton, Douglas F. | Offit, Kenneth | Chenevix-Trench, Georgia | Couch, Fergus J. | Antoniou, Antonis C. | Pujana, Miguel Angel
PLoS ONE  2015;10(4):e0120020.
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
doi:10.1371/journal.pone.0120020
PMCID: PMC4382299  PMID: 25830658
15.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I | Skibola, Christine F | Slager, Susan L | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M | Conde, Lucia | Birmann, Brenda M | Wang, Sophia S | Brooks-Wilson, Angela R | Lan, Qing | de Bakker, Paul I W | Vermeulen, Roel C H | Portlock, Carol | Ansell, Stephen M | Link, Brian K | Riby, Jacques | North, Kari E | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R | Spinelli, John J | Turner, Jenny | Zhang, Yawei | Purdue, Mark P | Giles, Graham G | Kelly, Rachel S | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A | Witzig, Thomas E | Habermann, Thomas M | Weiner, George J | Smith, Martyn T | Holly, Elizabeth A | Jackson, Rebecca D | Tinker, Lesley F | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E | De Roos, Anneclaire J | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W Ryan | Vajdic, Claire M | Armstrong, Bruce K | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C H | Fraumeni, Joseph F | Wu, Xifeng | Cerhan, James R | Offit, Kenneth | Chanock, Stephen J | Rothman, Nathaniel | Nieters, Alexandra
Nature communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95×10−15) and HLA-B (rs2922994, P=2.43×10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
16.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
17.  The 6q22.33 Locus and Breast Cancer Susceptibility 
Recently, we identified a novel breast cancer (BC) susceptibility locus at 6q22.33 following a genome-wide association study (GWAS) in the Ashkenazi Jewish (AJ) genetic isolate. To replicate these findings, we performed case-control association analysis on 6q22.33 (rs2180341) in additional 487 AJ BC cases and in an independent non-Jewish (non-AJ), predominantly European-American (EU-Am), populations of 1,466 BC cases and 1,467 controls. We have confirmed the 6q22.33 association with BC risk in the replication cohorts (per-allele OR=1.18, 95%CI 1.04–1.33, p=0.0083) with the strongest effect in the aggregate meta-analysis of 3,039 BC cases and 2,616 AJ and non-AJ controls (per-allele OR=1.24, 95%CI 1.13–1.36, P=3.85×10−7).
We have also shown that the association was slightly stronger with ER positive tumors (per-allele OR=1.35, 95%CI 1.20–1.51, p=2.2×10−5) compared to ER negative tumors (per-allele OR=1.19, 95%CI 0.97–1.47, p=0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in BC susceptibility. Due to stronger association of 6q22.33 with ER-positive BC we examined the effect of candidate genes on ER response elements (ERE). Upon transfection of overexpressed RNF146 in the MCF-7 BC cell line, we observed diminished expression of an ERE reporter construct. This study confirms the association of 6q22.33 with BC, with slightly stronger effect in ER positive tumors. Further functional studies of candidate genes are in progress and a large replication analysis is being completed as part of an international consortium.
doi:10.1158/1055-9965.EPI-09-0151
PMCID: PMC4286363  PMID: 19690183
Ashkenazi Jews; Breast Cancer; Genome-wide association studies; SNPs; estrogen receptor
18.  Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers 
Kuchenbaecker, Karoline B | Neuhausen, Susan L | Robson, Mark | Barrowdale, Daniel | McGuffog, Lesley | Mulligan, Anna Marie | Andrulis, Irene L | Spurdle, Amanda B | Schmidt, Marjanka K | Schmutzler, Rita K | Engel, Christoph | Wappenschmidt, Barbara | Nevanlinna, Heli | Thomassen, Mads | Southey, Melissa | Radice, Paolo | Ramus, Susan J | Domchek, Susan M | Nathanson, Katherine L | Lee, Andrew | Healey, Sue | Nussbaum, Robert L | Rebbeck, Timothy R | Arun, Banu K | James, Paul | Karlan, Beth Y | Lester, Jenny | Cass, Ilana | Registry, Breast Cancer Family | Terry, Mary Beth | Daly, Mary B | Goldgar, David E | Buys, Saundra S | Janavicius, Ramunas | Tihomirova, Laima | Tung, Nadine | Dorfling, Cecilia M | van Rensburg, Elizabeth J | Steele, Linda | v O Hansen, Thomas | Ejlertsen, Bent | Gerdes, Anne-Marie | Nielsen, Finn C | Dennis, Joe | Cunningham, Julie | Hart, Steven | Slager, Susan | Osorio, Ana | Benitez, Javier | Duran, Mercedes | Weitzel, Jeffrey N | Tafur, Isaac | Hander, Mary | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Roversi, Gaia | Scuvera, Giulietta | Bonanni, Bernardo | Mariani, Paolo | Volorio, Sara | Dolcetti, Riccardo | Varesco, Liliana | Papi, Laura | Tibiletti, Maria Grazia | Giannini, Giuseppe | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Hamann, Ute | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D Gareth | Frost, Debra | Eccles, Diana | Douglas, Fiona | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Ong, Kai-ren | Walker, Lisa | Izatt, Louise | Side, Lucy E | Kennedy, M John | Rogers, Mark T | Porteous, Mary E | Morrison, Patrick J | Platte, Radka | Eeles, Ros | Davidson, Rosemarie | Hodgson, Shirley | Ellis, Steve | Godwin, Andrew K | Rhiem, Kerstin | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Steinemann, Doris | Bogdanova-Markov, Nadja | Kast, Karin | Varon-Mateeva, Raymonda | Wang-Gohrke, Shan | Gehrig, Andrea | Markiefka, Birgid | Buecher, Bruno | Lefol, Cédrick | Stoppa-Lyonnet, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Barjhoux, Laure | Faivre, Laurence | Longy, Michel | Sevenet, Nicolas | Sinilnikova, Olga M | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Isaacs, Claudine | Van Maerken, Tom | Claes, Kathleen | Piedmonte, Marion | Andrews, Lesley | Hays, John | Rodriguez, Gustavo C | Caldes, Trinidad | de la Hoya, Miguel | Khan, Sofia | Hogervorst, Frans BL | Aalfs, Cora M | de Lange, JL | Meijers-Heijboer, Hanne EJ | van der Hout, Annemarie H | Wijnen, Juul T | van Roozendaal, KEP | Mensenkamp, Arjen R | van den Ouweland, Ans MW | van Deurzen, Carolien HM | van der Luijt, Rob B | Olah, Edith | Diez, Orland | Lazaro, Conxi | Blanco, Ignacio | Teulé, Alex | Menendez, Mireia | Jakubowska, Anna | Lubinski, Jan | Cybulski, Cezary | Gronwald, Jacek | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Arason, Adalgeir | Maugard, Christine | Soucy, Penny | Montagna, Marco | Agata, Simona | Teixeira, Manuel R | Olswold, Curtis | Lindor, Noralane | Pankratz, Vernon S | Hallberg, Emily | Wang, Xianshu | Szabo, Csilla I | Vijai, Joseph | Jacobs, Lauren | Corines, Marina | Lincoln, Anne | Berger, Andreas | Fink-Retter, Anneliese | Singer, Christian F | Rappaport, Christine | Kaulich, Daphne Gschwantler | Pfeiler, Georg | Tea, Muy-Kheng | Phelan, Catherine M | Mai, Phuong L | Greene, Mark H | Rennert, Gad | Imyanitov, Evgeny N | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Jensen, Uffe Birk | Caligo, Maria A | Friedman, Eitan | Berger, Raanan | Laitman, Yael | Rantala, Johanna | Arver, Brita | Loman, Niklas | Borg, Ake | Ehrencrona, Hans | Olopade, Olufunmilayo I | Simard, Jacques | Easton, Douglas F | Chenevix-Trench, Georgia | Offit, Kenneth | Couch, Fergus J | Antoniou, Antonis C
Breast Cancer Research : BCR  2014;16(6):3416.
Introduction
More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.
Methods
We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.
Results
The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.
Conclusions
Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0492-9
PMCID: PMC4406179  PMID: 25919761
19.  Two Decades After BRCA: Setting Paradigms in Personalized Cancer Care and Prevention 
Science (New York, N.Y.)  2014;343(6178):1466-1470.
The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.
doi:10.1126/science.1251827
PMCID: PMC4074902  PMID: 24675953
20.  Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins 
Nature Communications  2014;5:4835.
The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.
Ashkenazi Jews are a genetically isolated population with distinct patterns of genetic diversity. Here, the authors sequence the genomes of 128 Ashkenazi Jewish individuals and use the sequence information to provide insight into the population's European and Middle Eastern origins.
doi:10.1038/ncomms5835
PMCID: PMC4164776  PMID: 25203624
21.  Description and Pilot Results from a Novel Method for Evaluating Return of Incidental Findings from Next Generation Sequencing Technologies 
Purpose
To develop, operationalize, and pilot test a transparent, reproducible, and evidence informed method to qualify when to report incidental findings from next generation sequencing technologies.
Methods
Using evidence-based principles, we propose a three stage process. Stage I ‘rules out’ incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (Stage III). We used expert opinion to determine the face validity of Stages II and III using three case studies. We evaluated the time and effort for Stages I and II.
Results
For Stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-Antitrypsin Deficiency were all recommended for routine reporting as incidental findings. The method requires less than three days per topic.
Conclusion
We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.
doi:10.1038/gim.2013.37
PMCID: PMC3927794  PMID: 23558254
whole genome sequencing; clinical actionability; population screening; secondary findings; whole exome sequencing
22.  Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma 
PLoS ONE  2014;9(7):e101685.
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
doi:10.1371/journal.pone.0101685
PMCID: PMC4092067  PMID: 25010664
24.  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
25.  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

Results 1-25 (89)