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1.  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
2.  Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial 
BMC Cancer  2012;12:440.
Background
To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.
The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.
Methods/Design
This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).
Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.
Discussion
Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.
Trial registration
Netherland Trial Register NTR2789
doi:10.1186/1471-2407-12-440
PMCID: PMC3488502  PMID: 23031619
Breast cancer; Familial risk; Screening; MRI; Breast density; Cost-effectiveness
3.  Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers 
Antoniou, Antonis C | Kuchenbaecker, Karoline B | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | McGuffog, Lesley | Lee, Andrew | Barrowdale, Daniel | Healey, Sue | Sinilnikova, Olga M | Caligo, Maria A | Loman, Niklas | Harbst, Katja | Lindblom, Annika | Arver, Brita | Rosenquist, Richard | Karlsson, Per | Nathanson, Kate | Domchek, Susan | Rebbeck, Tim | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowowcka-Perłowska, Elżbieta | Osorio, Ana | Durán, Mercedes | Andrés, Raquel | Benítez, Javier | Hamann, Ute | Hogervorst, Frans B | van Os , Theo A | Verhoef, Senno | Meijers-Heijboer, Hanne EJ | Wijnen, Juul | Gómez Garcia, Encarna B | Ligtenberg, Marjolijn J | Kriege, Mieke | Collée, J Margriet | Ausems, Margreet GEM | Oosterwijk, Jan C | Peock, Susan | Frost, Debra | Ellis, Steve D | Platte, Radka | Fineberg, Elena | Evans, D Gareth | Lalloo, Fiona | Jacobs, Chris | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Douglas, Fiona | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J | Walker, Lisa | Rogers, Mark T | Donaldson, Alan | Dorkins, Huw | Godwin, Andrew K | Bove, Betsy | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Buecher, Bruno | de Pauw, Antoine | Mazoyer, Sylvie | Calender, Alain | Léoné, Mélanie | Bressac- de Paillerets, Brigitte | Caron, Olivier | Sobol, Hagay | Frenay, Marc | Prieur, Fabienne | Ferrer, Sandra Fert | Mortemousque, Isabelle | Buys, Saundra | Daly, Mary | Miron, Alexander | Terry, Mary Beth | Hopper, John L | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Fink-Retter, Anneliese | Tea, Muy-Kheng | Kaulich, Daphne Geschwantler | Hansen, Thomas VO | Nielsen, Finn C | Barkardottir, Rosa B | Gaudet, Mia | Kirchhoff, Tomas | Joseph, Vijai | Dutra-Clarke, Ana | Offit, Kenneth | Piedmonte, Marion | Kirk, Judy | Cohn, David | Hurteau, Jean | Byron, John | Fiorica, James | Toland, Amanda E | Montagna, Marco | Oliani, Cristina | Imyanitov, Evgeny | Isaacs, Claudine | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Teulé, Alex | Valle, J Del | Gayther, Simon A | Odunsi, Kunle | Gross, Jenny | Karlan, Beth Y | Olah, Edith | Teo, Soo-Hwang | Ganz, Patricia A | Beattie, Mary S | Dorfling, Cecelia M | van Rensburg, Elizabeth Jansen | Diez, Orland | Kwong, Ava | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Schäfer, Dieter | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Muranen, Taru A | Lespérance, Bernard | Spurdle, Amanda B | Neuhausen, Susan L | Ding, Yuan C | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Lindor, Noralane M | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Bonanni, Bernardo | Bernard, Loris | Dolcetti, Riccardo | Papi, Laura | Ottini, Laura | Radice, Paolo | Greene, Mark H | Loud, Jennifer T | Andrulis, Irene L | Ozcelik, Hilmi | Mulligan, Anna Marie | Glendon, Gord | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe B | Skytte, Anne-Bine | Kruse, Torben A | Chenevix-Trench, Georgia | Couch, Fergus J | Simard, Jacques | Easton, Douglas F
Introduction
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
doi:10.1186/bcr3121
PMCID: PMC3496151  PMID: 22348646
4.  The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family 
Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan–Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a ‘wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients.
doi:10.1038/ejhg.2009.112
PMCID: PMC2987152  PMID: 19584903
paraganglioma; phaeochromocytoma; inheritance; SDHD; penetrance
5.  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, 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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
6.  A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example 
BMC Cancer  2009;9:211.
Background
Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting.
Methods
We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer.
Results
We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality.
Conclusion
Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.
doi:10.1186/1471-2407-9-211
PMCID: PMC2714556  PMID: 19563646
7.  A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history 
Introduction
Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs.
Methods
We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families).
Results
The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain.
Conclusions
The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
doi:10.1186/bcr2223
PMCID: PMC2687711  PMID: 19200354
8.  Design of the BRISC study: a multicentre controlled clinical trial to optimize the communication of breast cancer risks in genetic counselling 
BMC Cancer  2008;8:283.
Background
Understanding risks is considered to be crucial for informed decision-making. Inaccurate risk perception is a common finding in women with a family history of breast cancer attending genetic counseling. As yet, it is unclear how risks should best be communicated in clinical practice. This study protocol describes the design and methods of the BRISC (Breast cancer RISk Communication) study evaluating the effect of different formats of risk communication on the counsellee's risk perception, psychological well-being and decision-making regarding preventive options for breast cancer.
Methods and design
The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measurements using questionnaires. The intervention-an additional risk consultation-consists of one of 5 conditions that differ in the way counsellee's breast cancer risk is communicated: 1) lifetime risk in numerical format (natural frequencies, i.e. X out of 100), 2) lifetime risk in both numerical format and graphical format (population figures), 3) lifetime risk and age-related risk in numerical format, 4) lifetime risk and age-related risk in both numerical format and graphical format, and 5) lifetime risk in percentages. Condition 6 is the control condition in which no intervention is given (usual care). Participants are unaffected women with a family history of breast cancer attending one of three participating clinical genetic centres in the Netherlands.
Discussion
The BRISC study allows for an evaluation of the effects of different formats of communicating breast cancer risks to counsellees. The results can be used to optimize risk communication in order to improve informed decision-making among women with a family history of breast cancer. They may also be useful for risk communication in other health-related services.
Trial registration
Current Controlled Trials ISRCTN14566836.
doi:10.1186/1471-2407-8-283
PMCID: PMC2576334  PMID: 18834503

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