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1. Screening strategy modification based on personalized breast cancer risk stratification and its implementation in the national guidelines – pilot study

Author

Krajc Mateja, Gareth Evans D, Blatnik Ana, Lokar Katarina, Žagar Tina, Tomšič Sonja, Žgajnar Janez, and Zadnik Vesna

Subjects
tyrer-cuzick model, breast cancer risk assessment, personalized breast cancer screening, breast cancer, tyrer-cuzickov model, ocena ogroženosti za raka dojk, individualizirano presejanje za raka dojk, rak dojk, Public aspects of medicine, RA1-1270
Abstract

One of the most consistent models for estimating personalized breast cancer (BC) risk is the Tyrer-Cuzick algorithm that is incorporated into the International Breast Cancer Intervention Study (IBIS) software. Our main objective was to provide criteria for the classification of the Slovenian population, which has BC incidence below the European average, into risk groups, and to evaluate the integration of the criteria in Slovenian guidelines. Our main focus was on women age

Published
2020
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2. Quantifying the effects of risk-stratified breast cancer screening when delivered in real time as routine practice versus usual screening: the BC-Predict non-randomised controlled study (NCT04359420)

Author

Gareth Evans, D., McWilliams, Lorna, Astley, Susan, Brentnall, Adam R., Cuzick, Jack, Dobrashian, Richard, Duffy, Stephen W., Gorman, Louise S., Harkness, Elaine F., Harrison, Fiona, Harvie, Michelle, Jerrison, Andrew, Machin, Matthew, Maxwell, Anthony J., Howell, Sacha J., Wright, Stuart J., Payne, Katherine, Qureshi, Nadeem, Ruane, Helen, Southworth, Jake, Fox, Lynne, Bowers, Sarah, Hutchinson, Gillian, Thorpe, Emma, Ulph, Fiona, Woof, Victoria, Howell, Anthony, and French, David P.

Published
2023
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6. Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

Author

Shu, Xiang, Wu, Lang, Khankari, Nikhil K, Shu, Xiao-Ou, Wang, Thomas J, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Pharoah, Paul DP, Andrulis, Irene L, Hunter, David J, Simard, Jacques, Easton, Douglas F, Zheng, Wei, Alicia, Beeghly-Fadiel J, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beane Freeman, Laura E, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, David Cheng, Ting-Yuan, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Dwek, Miriam, Earp, H Shelton, Eccles, Diana M, Heather Eliassen, A, Engel, Christoph, Eriksson, Mikael, Gareth Evans, D, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, He, Wei, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hogervorst, Frans B, Hollestelle, Antoinette, and Hoover, Robert N

Subjects
Clinical Research, Diabetes, Prevention, Nutrition, Obesity, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Blood Glucose, Body Mass Index, Breast Neoplasms, Diabetes Mellitus, Type 2, Female, Humans, Insulin, Mendelian Randomization Analysis, Middle Aged, Obesity, Abdominal, Waist-Hip Ratio, Breast cancer, insulin, glucose, obesity, genetics, Mendelian randomization analysis, Breast Cancer Association Consortium, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Published
2019

8. An app promoting weight gain prevention via healthy behaviours amongst young women with a family history of breast cancer: Acceptability and usability assessment.

Author

Pegington, Mary, Hawkes, Rhiannon E., Davies, Alan, Mueller, Julia, Howell, Anthony, Gareth Evans, D., Howell, Sacha J., French, David P., and Harvie, Michelle

Subjects
BREAST tumor risk factors, MOBILE apps, RISK assessment, SOCIAL media, CURRICULUM, WOMEN, RESEARCH funding, BODY mass index, MEDICAL care, SCIENTIFIC observation, QUESTIONNAIRES, FAMILY history (Medicine), INTERNET, TREATMENT effectiveness, PSYCHOLOGICAL adaptation, BEHAVIOR, CHI-squared test, DESCRIPTIVE statistics, HEALTH behavior, HEALTH promotion, DATA analysis software, COMPARATIVE studies, WEIGHT gain, EVALUATION
Abstract

Background: Breast cancer is the most frequent female malignancy in the UK. Around 20% of cases are linked to weight gain, excess weight and health behaviours. We designed a weight gain prevention, health behaviour intervention for young women at increased risk. Methods: The study comprised a single arm observational study over 2 months testing acceptability and usability of the intervention: online group welcome event, app and private Facebook group. Females aged 18–35 years at moderate or high risk of breast cancer (>17% lifetime risk) were recruited via invite letters and social media posts. The app included behaviour change techniques and education content. Online questionnaires were completed at baseline, as well as at 1 and 2 months. We also assessed feasibility of study procedures. Results: Both recruitment methods were successful. Thirty‐five women were recruited, 26% via social media posts. Median age was 33 (interquartile range = 28.2–34.5) years, the majority (94.1%) were of White ethnicity. Thirty‐four participants were included in the analyses, of which 94% downloaded the app. Median self‐monitoring logs per participant during the study period was 10.0 (interquartile range = 4.8–28.8). App quality mean (SD) score was 3.7 (0.6) at 1 and 2 months (scale: 1–5). Eighty‐nine per cent rated the app at average or above at 1 month and 75.0% at 2 months. Nineteen women (55.9%) joined the Facebook group and there were 61 comments and 83 reactions and votes from participants during the study period. Conclusions: This first iteration of the app and intervention was well received and is suitable to progress to the next stage of refining and further testing. Highlights: The newly developed intervention that focused on weight gain prevention and health behaviour change was tested in young women at increased risk of breast cancer and was well‐received by the target population.Both recruitment methods, by mailshot and social media, were successful.The study was unable to recruit and ethnically diverse population.Future research should retest the intervention in a larger population, after making refinements. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Correction To: Quantifying the effects of risk-stratified breast cancer screening when delivered in real time as routine practice versus usual screening: the BC-Predict non-randomised controlled study (NCT04359420)

Author

Gareth Evans, D., McWilliams, Lorna, Astley, Susan, Brentnall, Adam R., Cuzick, Jack, Dobrashian, Richard, Duffy, Stephen W., Gorman, Louise S., Harkness, Elaine F., Harrison, Fiona, Harvie, Michelle, Jerrison, Andrew, Machin, Matthew, Maxwell, Anthony J., Howell, Sacha J., Wright, Stuart J., Payne, Katherine, Qureshi, Nadeem, Ruane, Helen, Southworth, Jake, Fox, Lynne, Bowers, Sarah, Hutchinson, Gillian, Thorpe, Emma, Ulph, Fiona, Woof, Victoria, Howell, Anthony, and French, David P.

Published
2023
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11. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

Author

Hamdi, Yosr, Soucy, Penny, Kuchenbaeker, Karoline B, Pastinen, Tomi, Droit, Arnaud, Lemaçon, Audrey, Adlard, Julian, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Arun, Banu K, Azzollini, Jacopo, Bane, Anita, Barjhoux, Laure, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Blok, Marinus J, Bobolis, Kristie, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra S, Caligo, Maria A, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Daly, Mary B, Damiola, Francesca, Davidson, Rosemarie, De la Hoya, Miguel, De Leeneer, Kim, Diez, Orland, Ding, Yuan Chun, Dolcetti, Riccardo, Domchek, Susan M, Dorfling, Cecilia M, Eccles, Diana, Eeles, Ros, Einbeigi, Zakaria, Ejlertsen, Bent, EMBRACE, Engel, Christoph, Gareth Evans, D, Feliubadalo, Lidia, Foretova, Lenka, Fostira, Florentia, Foulkes, William D, Fountzilas, George, Friedman, Eitan, Frost, Debra, Ganschow, Pamela, Ganz, Patricia A, Garber, Judy, Gayther, Simon A, GEMO Study Collaborators, Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hart, Steven, Hays, John L, HEBON, Hogervorst, Frans BL, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M, Joseph, Vijai, Just, Walter, Kaczmarek, Katarzyna, Karlan, Beth Y, KConFab Investigators, Kets, Carolien M, Kirk, Judy, Kriege, Mieke, Laitman, Yael, Laurent, Maïté, Lazaro, Conxi, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loman, Niklas, Loud, Jennifer T, Manoukian, Siranoush, and Mariani, Milena

Subjects
EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Chromosomes, Human, Pair 11, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Risk, Gene Expression, Heterozygote, Mutation, Alleles, Genes, BRCA1, Genes, BRCA2, Quantitative Trait Loci, Female, Genetic Variation, Biomarkers, Tumor, BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility, Chromosomes, Human, Pair 11, Genes, BRCA1, BRCA2, Biomarkers, Tumor, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Clinical Sciences
Abstract

PurposeCis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.MethodsUsing data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.ResultsWe identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.ConclusionWe identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Published
2017

17. Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent

Author

Roberts, Eleanor, primary, van Veen, Elke M., additional, Byers, Helen, additional, Barnett-Griness, Ofra, additional, Gronich, Naomi, additional, Lejbkowicz, Flavio, additional, Pinchev, Mila, additional, Smith, Miriam J., additional, Howell, Anthony, additional, Newman, William G., additional, Woodward, Emma R., additional, Harkness, Elaine F., additional, Brentnall, Adam R., additional, Cuzick, Jack, additional, Rennert, Gad, additional, Howell, Sacha J., additional, and Gareth Evans, D., additional

Published
2023
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18. A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants:Application to BRCA1 and BRCA2

Author

Zanti, Maria, O'Mahony, Denise G., Parsons, Michael T., Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Aronson, Kristan J., Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Brown, Melissa A., Buys, Saundra S., Canzian, Federico, Caputo, Sandrine M., Castelao, Jose E., Chang-Claude, Jenny, Czene, Kamila, Daly, Mary B., De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Engel, Christoph, Gareth Evans, D., Fasching, Peter A., Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Gentry-Maharaj, Aleksandra, Geurts-Giele, Willemina R.R., Giles, Graham G., Glendon, Gord, Goldberg, Mark S., Gómez Garcia, Encarna B., Göendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Hall, Per, Hamann, Ute, Harkness, Elaine F., Hogervorst, Frans B.L., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Houdayer, Claude, Houlston, Richard S., Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M., Kaaks, Rudolf, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiski, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L., Monteiro, Alvaro N., Murphy, Rachel A., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Offit, Kenneth, Park, Sue K., James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H., Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K., Schmutzler, Rita K., Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teo, Soo Hwang, Teras, Lauren R., Terry, Mary Beth, Thomassen, Mads, Troester, Melissa A., Vachon, Celine M., Vega, Ana, Vreeswijk, Maaike P.G., Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Zheng, Wei, Feng, Bingjian, Couch, Fergus J., Spurdle, Amanda B., Easton, Douglas F., Goldgar, David E., Michailidou, Kyriaki, Zanti, Maria, O'Mahony, Denise G., Parsons, Michael T., Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Aronson, Kristan J., Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Brown, Melissa A., Buys, Saundra S., Canzian, Federico, Caputo, Sandrine M., Castelao, Jose E., Chang-Claude, Jenny, Czene, Kamila, Daly, Mary B., De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Engel, Christoph, Gareth Evans, D., Fasching, Peter A., Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Gentry-Maharaj, Aleksandra, Geurts-Giele, Willemina R.R., Giles, Graham G., Glendon, Gord, Goldberg, Mark S., Gómez Garcia, Encarna B., Göendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Hall, Per, Hamann, Ute, Harkness, Elaine F., Hogervorst, Frans B.L., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Houdayer, Claude, Houlston, Richard S., Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M., Kaaks, Rudolf, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiski, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L., Monteiro, Alvaro N., Murphy, Rachel A., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Offit, Kenneth, Park, Sue K., James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H., Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K., Schmutzler, Rita K., Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teo, Soo Hwang, Teras, Lauren R., Terry, Mary Beth, Thomassen, Mads, Troester, Melissa A., Vachon, Celine M., Vega, Ana, Vreeswijk, Maaike P.G., Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Zheng, Wei, Feng, Bingjian, Couch, Fergus J., Spurdle, Amanda B., Easton, Douglas F., Goldgar, David E., and Michailidou, Kyriaki

Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Published
2023

20. Infant excitation/inhibition balance interacts with executive attention to predict autistic traits in childhood

Author

Carter leno, Virginia, Begum-Ali, Jannath, Goodwin, Amy, Mason, Luke, Pasco, Greg, Pickles, Andrew, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark H., Jones, Emily J. H., Vassallo, Grace, Burkitt-Wright, Emma, Eelloo, Judith, Gareth evans, D, West, Siobhan, Hupton, Eileen, Lewis, Lauren, Robinson, Louise, Dobbie, Angus, Drimer, Ruth, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Baralle, Diana, Redman, Carolyn, Tomkins, Helen, Bhojwani, Ankita, Connelly, Shannon, Conti, Francesca, Evans, Beth, Jackson, Meg, Powell, Emily, Agyapong, Mary, Bazelmans, Tessel, Dafner, Leila, Ersoy, Mutluhan, Gliga, Teea, Haartsen, Rianne, Halkola, Hanna, Hendry, Alexandra, Holman, Rebecca, Kalwarowsky, Sarah, Kolesnik, Anna, Narvekar, Nisha, and Taylor, Chloë

Subjects
Autism, Infant, Psychiatry and Mental health, Developmental Neuroscience, NF1, E/I balance, Child, Preschool, ADHD, Humans, Executive functioning, Infants, Molecular Biology, Aged, Developmental Biology
Abstract

Background Autism is proposed to be characterised by an atypical balance of cortical excitation and inhibition (E/I). However, most studies have examined E/I alterations in older autistic individuals, meaning that findings could in part reflect homeostatic compensation. To assess the directionality of effects, it is necessary to examine alterations in E/I balance early in the lifespan before symptom emergence. Recent explanatory frameworks have argued that it is also necessary to consider how early risk features interact with later developing modifier factors to predict autism outcomes. Method We indexed E/I balance in early infancy by extracting the aperiodic exponent of the slope of the electroencephalogram (EEG) power spectrum (‘1/f’). To validate our index of E/I balance, we tested for differences in the aperiodic exponent in 10-month-old infants with (n = 22) and without (n = 27) neurofibromatosis type 1 (NF1), a condition thought to be characterised by alterations to cortical inhibition. We then tested for E/I alterations in a larger heterogeneous longitudinal cohort of infants with and without a family history of neurodevelopmental conditions (n = 150) who had been followed to early childhood. We tested the relevance of alterations in E/I balance and our proposed modifier, executive attention, by assessing whether associations between 10-month aperiodic slope and 36-month neurodevelopmental traits were moderated by 24-month executive attention. Analyses adjusted for age at EEG assessment, sex and number of EEG trials. Results Infants with NF1 were characterised by a higher aperiodic exponent, indicative of greater inhibition, supporting our infant measure of E/I. Longitudinal analyses showed a significant interaction between aperiodic slope and executive attention, such that higher aperiodic exponents predicted greater autistic traits in childhood, but only in infants who also had weaker executive functioning abilities. Limitations The current study relied on parent report of infant executive functioning-type abilities; future work is required to replicate effects with objective measures of cognition. Conclusions Results suggest alterations in E/I balance are on the developmental pathway to autism outcomes, and that higher executive functioning abilities may buffer the impact of early cortical atypicalities, consistent with proposals that stronger executive functioning abilities may modify the impact of a wide range of risk factors.

Published
2022
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22. 2022-RA-1310-ESGO Cost-effectiveness of unselected multigene germline and somatic genetic testing for epithelial ovarian cancer

Author

Sun, Li, primary, Sobocan, Monika, additional, Rodriguez, Isabel V, additional, Wei, Xia, additional, Kalra, Ashwin, additional, Oxley, Samuel, additional, Sideris, Michail, additional, Morgan, Robert D, additional, Chandrasekaran, Dhivya, additional, Rust, Kelly, additional, Spiliopoulou, Pavlina, additional, Miller, Rowan E, additional, Crusz, Shanthini M, additional, Lockley, Michelle, additional, Singh, Naveena, additional, Faruqi, Asma, additional, Casey, Laura, additional, Brockbank, Elly, additional, Phadnis, Saurabh, additional, Mills-Baldock, Tina, additional, El-Khouly, Fatima, additional, Jenkins, Lucy A, additional, Wallace, Andrew, additional, Ahmed, Munaza, additional, Kumar, Ajith, additional, Swisher, Elizabeth M, additional, Gourley, Charlie, additional, Norquist, Barbara M, additional, Gareth Evans, D, additional, Legood, Rosa, additional, and Manchanda, Ranjit, additional

Published
2022
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23. Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)

Author

Stivaros, Stavros, Garg, Shruti, Tziraki, Maria, Cai, Ying, Thomas, Owen, Mellor, Joseph, Morris, Andrew A., Jim, Carly, Szumanska-Ryt, Karolina, Parkes, Laura M, Haroon, Hamied A., Montaldi, Daniela, Webb, Nicholas, Keane, John, Castellanos, Francisco X., Silva, Alcino J., Huson, Sue, Williams, Stephen, Gareth Evans, D., Emsley, Richard, Green, Jonathan, and SANTA Consortium

Published
2018
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25. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

Author

Hanson, Helen, Kulkarni, Anjana, Loong, Lucy, Kavanaugh, Grace, Torr, Bethany, Allen, Sophie, Ahmed, Munaza, Antoniou, Antonis C., Cleaver, Ruth, Dabir, Tabib, Gareth Evans, D., Golightly, Ellen, Jewell, Rosalyn, Kohut, Kelly, Manchanda, Ranjit, Murray, Alex, Murray, Jennie, Ong, Kai-Ren, Rosenthal, Adam N., and Woodward, Emma Roisin

Abstract

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Author

Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., Ottini L., Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., and Ottini L.

Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHOD(S): 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. RESULT(S): PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI=1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR=1.73, 95% CI=1.28-2.33) and BRCA2 (OR=1.60, 95% CI=1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSION(S): Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.Copyright © The Author(s) 2021. Published by Oxford University Press.

Published
2021

30. Neurofibromatosis 2011: a report of the Children’s Tumor Foundation Annual Meeting

Author

Kalamarides, Michel, Acosta, Maria T., Babovic-Vuksanovic, Dusica, Carpen, Olli, Cichowski, Karen, Gareth Evans, D., Giancotti, Filippo, Oliver Hanemann, C., Ingram, David, Lloyd, Alison C., Mayes, Debra A., Messiaen, Ludwine, Morrison, Helen, North, Kathryn, Packer, Roger, Pan, Duojia, Stemmer-Rachamimov, Anat, Upadhyaya, Meena, Viskochil, David, Wallace, Margret R., Hunter-Schaedle, Kim, and Ratner, Nancy

Published
2012
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32. No evidence that GATA3 rs570613 SNP modifies breast cancer risk

Author

Johnatty, Sharon E., Couch, Fergus J., Fredericksen, Zachary, Tarrell, Robert, Spurdle, Amanda B., Beesley, Jonathan, Chen, Xiaoqing, Gschwantler-Kaulich, Daphne, Singer, Christian F., Fuerhauser, Christine, Fink-Retter, Anneliese, Domchek, Susan M., Nathanson, Katherine L., Pankratz, Vernon S., Lindor, Noralane M., Godwin, Andrew K., Caligo, Maria A., Hopper, John, Southey, Melissa C., Giles, Graham G., Justenhoven, Christina, Brauch, Hiltrud, Hamann, Ute, Ko, Yon-Dschun, Heikkinen, Tuomas, Aaltonen, Kirsimari, Aittomäki, Kristiina, Blomqvist, Carl, Nevanlinna, Heli, Hall, Per, Czene, Kamila, Liu, Jianjun, Peock, Susan, Cook, Margaret, Platte, Radka, Gareth Evans, D., Lalloo, Fiona, Eeles, Rosalind, Pichert, Gabriella, Eccles, Diana, Davidson, Rosemarie, Cole, Trevor, Cook, Jackie, Douglas, Fiona, Chu, Carol, Hodgson, Shirley, Paterson, Joan, Hogervorst, Frans B. L., Rookus, Matti A., Seynaeve, Caroline, Wijnen, Juul, Vreeswijk, Maaike, Ligtenberg, Marjolijn, van der Luijt, Rob B., van Os, Theo A. M., Gille, Hans J. P., Blok, Marinus J., Issacs, Claudine, Humphreys, Manjeet K., McGuffog, Lesley, Healey, Sue, Sinilnikova, Olga, Antoniou, Antonis C., Easton, Douglas F., Chenevix-Trench, Georgia, kConFab Investigators, AOCS Group, The Swedish BRCA1 and BRCA2 Study Collaborators, HEBON, and on behalf of the Breast Cancer Association Consortium and the Consortium of Investigators of Modifiers of BRCA1/2

Published
2009
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33. Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF

Author

Popp, Isabell, Punekar, Maqsood, Telford, Nick, Stivaros, Stavros, Chandler, Kate, Minnis, Meenakshi, Castleton, Anna, Higham, Claire, Hopewell, Louise, Gareth Evans, D., Raams, Anja, Theil, Arjan F., Meyer, Stefan, Schindler, Detlev, and Molecular Genetics

Subjects
XPF, lcsh:Internal medicine, ResearchInstitutes_Networks_Beacons/MICRA, lcsh:QH426-470, Mutation, Missense, DNA repair, Case Report, Cell Line, Cell Line, Tumor, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Photosensitivity Disorders, lcsh:RC31-1245, Fanconi Anaemia, Genetic Association Studies, FANCQ, Fibroblasts, Middle Aged, DNA-Binding Proteins, lcsh:Genetics, Manchester Institute for Collaborative Research on Ageing, Fanconi anemia, Female, Solar System, UV sensitivity, ERCC4, DNA Damage
Abstract

Background Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. Case presentation A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient’s cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus. Conclusions Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable. Electronic supplementary material The online version of this article (10.1186/s12881-018-0520-1) contains supplementary material, which is available to authorized users.

Published
2018
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36. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, Antonis C, Kartsonaki, Christiana, Sinilnikova, Olga M., Soucy, Penny, McGuffog, Lesley, Healey, Sue, Lee, Andrew, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Cattaneo, Elisa, Barile, Monica, Pensotti, Valeria, Pasini, Barbara, Dolcetti, Riccardo, Giannini, Giuseppe, Laura Putignano, Anna, Varesco, Liliana, Radice, Paolo, Mai, Phuong L., Greene, Mark H., Andrulis, Irene L., Glendon, Gord, Ozcelik, Hilmi, Thomassen, Mads, Gerdes, Anne-Marie, Kruse, Torben A., Birk Jensen, Uffe, Crüger, Dorthe G., Caligo, Maria A., Laitman, Yael, Milgrom, Roni, Kaufman, Bella, Paluch-Shimon, Shani, Friedman, Eitan, Loman, Niklas, Harbst, Katja, Lindblom, Annika, Arver, Brita, Ehrencrona, Hans, Melin, Beatrice, Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy, Jakubowska, Ania, Lubinski, Jan, Gronwald, Jacek, Huzarski, Tomasz, Byrski, Tomasz, Cybulski, Cezary, Gorski, Bohdan, Osorio, Ana, Ramón y Cajal, Teresa, Fostira, Florentia, Andrés, Raquel, Benitez, Javier, Hamann, Ute, Hogervorst, Frans B., Rookus, Matti A., Hooning, Maartje J., Nelen, Marcel R., van der Luijt, Rob B., van Os, Theo A.M., van Asperen, Christi J., Devilee, Peter, Meijers-Heijboer, Hanne E.J., Gómez Garcia, Encarna B., Peock, Susan, Cook, Margaret, Frost, Debra, Platte, Radka, Leyland, Jean, Gareth Evans, D., Lalloo, Fiona, Eeles, Ros, Izatt, Louise, Adlard, Julian, Davidson, Rosemarie, Eccles, Diana, Ong, Kai-ren, Cook, Jackie, Douglas, Fiona, Paterson, Joan, John Kennedy, M., Miedzybrodzka, Zosia, Godwin, Andrew, Stoppa-Lyonnet, Dominique, Buecher, Bruno, Belotti, Muriel, Tirapo, Carole, Mazoyer, Sylvie, Barjhoux, Laure, Lasset, Christine, Leroux, Dominique, Faivre, Laurence, Bronner, Myriam, Prieur, Fabienne, Nogues, Catherine, Rouleau, Etienne, Pujol, Pascal, Coupier, Isabelle, Frénay, Marc, Hopper, John L., Daly, Mary B., Terry, Mary B., John, Esther M., Buys, Saundra S., Yassin, Yosuf, Miron, Alexander, Goldgar, David, Singer, Christian F., Tea, Muy-Kheng, Pfeiler, Georg, Catharina Dressler, Anne, Hansen, Thomas v.O., Jønson, Lars, Ejlertsen, Bent, Bjork Barkardottir, Rosa, Kirchhoff, Tomas, Offit, Kenneth, Piedmonte, Marion, Rodriguez, Gustavo, Small, Laurie, Boggess, John, Blank, Stephanie, Basil, Jack, Azodi, Masoud, Ewart Toland, Amanda, Montagna, Marco, Tognazzo, Silvia, Agata, Simona, Imyanitov, Evgeny, Janavicius, Ramunas, Lazaro, Conxi, Blanco, Ignacio, Pharoah, Paul D.P., Sucheston, Lara, Karlan, Beth Y., Walsh, Christine S., Olah, Edith, Bozsik, Aniko, Teo, Soo-Hwang, Seldon, Joyce L., Beattie, Mary S., van Rensburg, Elizabeth J., Sluiter, Michelle D., Diez, Orland, Schmutzler, Rita K., Wappenschmidt, Barbara, Engel, Christoph, Meindl, Alfons, Ruehl, Ina, Varon-Mateeva, Raymonda, Kast, Karin, Deissler, Helmut, Niederacher, Dieter, Arnold, Norbert, Gadzicki, Dorothea, Schönbuchner, Ines, Caldes, Trinidad, de la Hoya, Miguel, Nevanlinna, Heli, Aittomäki, Kristiina, Dumont, Martine, Chiquette, Jocelyne, Tischkowitz, Marc, Chen, Xiaoqing, Beesley, Jonathan, Spurdle, Amanda B., Neuhausen, Susan L., Chun Ding, Yuan, Fredericksen, Zachary, Wang, Xianshu, Pankratz, Vernon S., Couch, Fergus, Simard, Jacques, Easton, Douglas F., and Chenevix-Trench, Georgia

Published
2011
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38. Development of Breast Cancer Choices: a decision support tool for young women with breast cancer deciding whether to have genetic testing for BRCA1/2 mutations

Author

Grimmett, C, Brooks, C, Recio-Saucedo, A, Armstrong, A, Cutress, RI, Gareth Evans, D, Copson, E, Turner, L, Meiser, B, Wakefield, CE, Eccles, D, Foster, C, Grimmett, C, Brooks, C, Recio-Saucedo, A, Armstrong, A, Cutress, RI, Gareth Evans, D, Copson, E, Turner, L, Meiser, B, Wakefield, CE, Eccles, D, and Foster, C

Abstract

Purpose: To develop a decision support tool for young women with breast cancer considering genetic testing for BRCA1/2 mutations soon after cancer diagnosis. Methods: A four-stage iterative development process was employed; stage 1, literature review exploring the availability and efficacy of empirically tested decision support tools; stage 2, in-depth interviews with 29 young women (< 50 years) recently diagnosed with breast cancer, exploring information requirements and experiences of genetic testing decision making; stage 3, three focus groups (N = 21) exploring preferences for information presentation and prioritisation of content; stage 4, think-aloud interviews to refine the prototype (N = 16). Results: Participants wanted information regarding the pros and cons of testing, the testing process and implications for their family, presented in a way that allowed them to choose the level of detail they required. They preferred the term ‘altered gene’, valued a medical word definition function and warnings before accessing sensitive information. Conclusion: Participants valued the decision support tool, the accessibility of the information and its clinical endorsement. The decision support tool has considerable clinical utility as an adjunct to genetic counselling or for use in busy oncology clinics where formal genetic counselling may be unavailable.

Published
2019

39. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Author

Møller, P, Seppälä, Tt, Bernstein, I, Holinski-Feder, E, Sala, P, Gareth Evans, D, Lindblom, A, Macrae, F, Blanco, I, Sijmons, Rh, Jeffries, J, Vasen, Hfa, Burn, J, Nakken, S, Hovig, E, Rødland, Ea, Tharmaratnam, K, de Vos Tot Nederveen Cappel, Wh, Hill, J, Wijnen, Jt, Jenkins, Ma, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Valentin, Md, Frayling, Im, Plazzer, Jp, Pylvanainen, K, Genuardi, Maurizio, Mecklin, Jp, Moeslein, G, Sampson, Jr, Capella, G, Mallorca, Group, Genuardi M (ORCID:0000-0002-7410-8351), Møller, P, Seppälä, Tt, Bernstein, I, Holinski-Feder, E, Sala, P, Gareth Evans, D, Lindblom, A, Macrae, F, Blanco, I, Sijmons, Rh, Jeffries, J, Vasen, Hfa, Burn, J, Nakken, S, Hovig, E, Rødland, Ea, Tharmaratnam, K, de Vos Tot Nederveen Cappel, Wh, Hill, J, Wijnen, Jt, Jenkins, Ma, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Valentin, Md, Frayling, Im, Plazzer, Jp, Pylvanainen, K, Genuardi, Maurizio, Mecklin, Jp, Moeslein, G, Sampson, Jr, Capella, G, Mallorca, Group, and Genuardi M (ORCID:0000-0002-7410-8351)

Abstract

BACKGROUND: Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. OBJECTIVE AND DESIGN: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. RESULTS: 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. CONCLUSION: Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this

Published
2018

40. Clinical utility of testing for PALB2and CHEK2c.1100delC in breast and ovarian cancer

Author

Woodward, Emma R., van Veen, Elke M., Forde, Claire, Harkness, Elaine F., Byers, Helen J., Ellingford, Jamie M., Burghel, George J., Schlech, Helene, Bowers, Naomi L., Wallace, Andrew J., Howell, Sacha J., Howell, Anthony, Lalloo, Fiona, Newman, William G., Smith, Miriam J., and Gareth Evans, D.

Abstract

To investigate the contribution of PALB2pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology.

Published
2021
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42. Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.

Author

Fortuno, Cristina, Mester, Jessica, Pesaran, Tina, Weitzel, Jeffrey N., Dolinsky, Jill, Yussuf, Amal, McGoldrick, Kelly, Garber, Judy E., Savage, Sharon A., Khincha, Payal P., Gareth Evans, D., Achatz, Maria Isabel, Nichols, Kim E., Maxwell, Kara N., Schiffman, Joshua D., Sandoval, Renata, James, Paul A., and Spurdle, Amanda B.

Abstract

Early onset breast cancer is the most common malignancy in women with Li‐Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53‐specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age. [ABSTRACT FROM AUTHOR]

Published
2020
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43. Development of Breast Cancer Choices: a decision support tool for young women with breast cancer deciding whether to have genetic testing for BRCA1/2 mutations

Author

Grimmett, Chloe, primary, Brooks, Charlotte, additional, Recio-Saucedo, Alejandra, additional, Armstrong, Anne, additional, Cutress, Ramsey I, additional, Gareth Evans, D, additional, Copson, Ellen, additional, Turner, Lesley, additional, Meiser, Bettina, additional, Wakefield, Claire E., additional, Eccles, Diana, additional, and Foster, Claire, additional

Published
2018
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44. NFM-04. INITIAL MANAGEMENT STRATEGY AS A DISCRIMINATOR OF VISUAL OUTCOME IN CHILDREN PRESENTING WITH NEUROFIBROMATOSIS TYPE 1 AND OPTIC PATHWAY GLIOMA - RESULTS FROM A SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE EUROPE (SIOPE) CLINICAL TRIALS WORKSHOP

Author

Azizi, Amedeo A, primary, Walker, David A, additional, Liu, Jo-Fen, additional, Sehested, Astrid, additional, Jaspan, Timothy, additional, Simmons, Ian, additional, Ferner, Rosalie, additional, Grill, Jacques, additional, Hargrave, Darren, additional, Hernaiz-Driever, Pablo, additional, Gareth Evans, D, additional, and Opocher, Enrico, additional

Published
2018
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45. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression:identification of a modifier of breast cancer risk at locus 11q22.3

Author

Hamdi, Yosr, Soucy, Penny, Kuchenbaeker, Karoline B, Pastinen, Tomi, Droit, Arnaud, Lemaçon, Audrey, Adlard, Julian, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Azzollini, Jacopo, Arun, Banu K, Bane, Anita, Barjhoux, Laure, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Blok, Marinus J, Bobolis, Kristie A, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra, Caligo, Maria A, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen B M, Daly, Mary B, Damiola, Francesca, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, Diez, Orland, Ding, Yuan Chun, Dolcetti, Riccardo, Domchek, Susan M, Dorfling, Cecilia M, Eccles, Diana, Eeles, Ros, Einbeigi, Zakaria, Ejlertsen, Bent, Engel, Christoph, Gareth Evans, D, Feliubadaló, Lidia, Foretova, Lenka, Fostira, Florentia, Gerdes, Anne-Marie, Easton, Douglas F., Antoniou, Antonis C, Simard, Jacques, Hamdi, Yosr, Soucy, Penny, Kuchenbaeker, Karoline B, Pastinen, Tomi, Droit, Arnaud, Lemaçon, Audrey, Adlard, Julian, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Azzollini, Jacopo, Arun, Banu K, Bane, Anita, Barjhoux, Laure, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Blok, Marinus J, Bobolis, Kristie A, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra, Caligo, Maria A, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen B M, Daly, Mary B, Damiola, Francesca, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, Diez, Orland, Ding, Yuan Chun, Dolcetti, Riccardo, Domchek, Susan M, Dorfling, Cecilia M, Eccles, Diana, Eeles, Ros, Einbeigi, Zakaria, Ejlertsen, Bent, Engel, Christoph, Gareth Evans, D, Feliubadaló, Lidia, Foretova, Lenka, Fostira, Florentia, Gerdes, Anne-Marie, Easton, Douglas F., Antoniou, Antonis C, and Simard, Jacques

Abstract

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Published
2017

46. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Author

Møller, Pål, primary, Seppälä, Toni T, additional, Bernstein, Inge, additional, Holinski-Feder, Elke, additional, Sala, Paulo, additional, Gareth Evans, D, additional, Lindblom, Annika, additional, Macrae, Finlay, additional, Blanco, Ignacio, additional, Sijmons, Rolf H, additional, Jeffries, Jacqueline, additional, Vasen, Hans F A, additional, Burn, John, additional, Nakken, Sigve, additional, Hovig, Eivind, additional, Rødland, Einar Andreas, additional, Tharmaratnam, Kukatharmini, additional, de Vos tot Nederveen Cappel, Wouter H, additional, Hill, James, additional, Wijnen, Juul T, additional, Jenkins, Mark A, additional, Green, Kate, additional, Lalloo, Fiona, additional, Sunde, Lone, additional, Mints, Miriam, additional, Bertario, Lucio, additional, Pineda, Marta, additional, Navarro, Matilde, additional, Morak, Monika, additional, Renkonen-Sinisalo, Laura, additional, Valentin, Mev Dominguez, additional, Frayling, Ian M, additional, Plazzer, John-Paul, additional, Pylvanainen, Kirsi, additional, Genuardi, Maurizio, additional, Mecklin, Jukka-Pekka, additional, Moeslein, Gabriela, additional, Sampson, Julian R, additional, and Capella, Gabriel, additional

Published
2017
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47. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, AB, Couch, FJ, Parsons, MT, McGuffog, L, Barrowdale, D, Bolla, MK, Wang, Q, Healey, S, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Ellis, S, Frost, D, Platte, R, Perkins, J, Gareth Evans, D, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Scuvera, G, Manoukian, S, Bonanni, B, Mariette, F, Fortuzzi, S, Viel, A, Pasini, B, Papi, L, Varesco, L, Balleine, R, Nathanson, KL, Domchek, SM, Offitt, K, Jakubowska, A, Lindor, N, Thomassen, M, Jensen, UB, Rantala, J, Borg, Å, Andrulis, IL, Miron, A, Hansen, TVO, Caldes, T, Neuhausen, SL, Toland, AE, Nevanlinna, H, Montagna, M, Garber, J, Godwin, AK, Osorio, A, Factor, RE, Terry, MB, Rebbeck, TR, Karlan, BY, Southey, M, Rashid, MU, Tung, N, Pharoah, PDP, Blows, FM, Dunning, AM, Provenzano, E, Hall, P, Czene, K, Schmidt, MK, Broeks, A, Cornelissen, S, Verhoef, S, Fasching, PA, Beckmann, MW, Ekici, AB, Slamon, DJ, Bojesen, SE, and Nordestgaard, BG

Subjects
endocrine system diseases, skin and connective tissue diseases
Abstract

© 2014 Spurdle et al. Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014
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48. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author

Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline, Michailidou, Kyriaki, Tyrer, Jonathan, Beesley, Jonathan, Ramus, Susan J., Li, Qiyuan, Delgado, Melissa K., Lee, Janet M., Aittomaki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K., Arver, Brita, Bandera, Elisa V., Barile, Monica, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Benitez, Javier, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Blot, William, Bogdanova, Natalia, Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Bruinsma, Fiona, Brunet, Joan, Ahmad Buhari, Shaik, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji-Yeob, Claes, Kathleen B. M., Cook, Linda S., Cox, Angela, Cramer, Daniel W., Cross, Simon S., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Doerk, Thilo, Dumont, Martine, Ehrencrona, Hans, Ejlertsen, Bent, Ellis, Steve, Engel, Christoph, Lee, Eunjung, Gareth Evans, D., Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D., Fridley, Brooke L., Friedman, Eitan, Frost, Debra, Gambino, Gaetana, Ganz, Patricia A., Garber, Judy, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Ghoussaini, Maya, Giles, Graham G., Glasspool, Rosalind, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Gonzalez-Neira, Anna, Goode, Ellen L., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Guenel, Pascal, Haiman, Christopher A., Hall, Per, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Harrington, Patricia A., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Heitz, Florian, Herzog, Josef, Hogdall, Estrid, Hogdall, Claus K., Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Hulick, Peter J., Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jensen, Allan, John, Esther M., Johnson, Nichola, Kabisch, Maria, Kang, Daehee, Kapuscinski, Miroslav, Karlan, Beth Y., Khan, Sofia, Kiemeney, Lambertus A., Kruger Kjaer, Susanne, Knight, Julia A., Konstantopoulou, Irene, Kosma, Veli-Matti, Kristensen, Vessela, Kupryjanczyk, Jolanta, Kwong, Ava, de la Hoya, Miguel, Laitman, Yael, Lambrechts, Diether, Le, Nhu, De Leeneer, Kim, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T., Lu, Karen, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Massuger, Leon F. A. G., Matsuo, Keitaro, Mazoyer, Sylvie, McGuffog, Lesley, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R., Milne, Roger L., Montagna, Marco, Moysich, Kirsten B., Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Nord, Silje, Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olswold, Curtis, OMalley, David, Orlow, Irene, Orr, Nick, Osorio, Ana, Kyung Park, Sue, Pearce, Celeste L., Pejovic, Tanja, Peterlongo, Paolo, Pfeiler, Georg, Phelan, Catherine M., Poole, Elizabeth M., Pylkas, Katri, Radice, Paolo, Rantala, Johanna, Usman Rashid, Muhammad, Rennert, Gad, Rhenius, Valerie, Rhiem, Kerstin, Risch, Harvey A., Rodriguez, Gus, Anne Rossing, Mary, Rudolph, Anja, Salvesen, Helga B., Sangrajrang, Suleeporn, Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Sellers, Thomas A., Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Sieh, Weiva, Singer, Christian F., Sinilnikova, Olga M., Slager, Susan, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stenmark Askmalm, Marie, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony, Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Kathryn L., Beth Terry, Mary, Thomassen, Mads, Grazia Tibiletti, Maria, Tihomirova, Laima, Tognazzo, Silvia, Ewart Toland, Amanda, Tomlinson, Ian, Torres, Diana, Truong, Therese, Tseng, Chiu-chen, Tung, Nadine, Tworoger, Shelley S., Vachon, Celine, van den Ouweland, Ans M. W., van Doorn, Helena C., van Rensburg, Elizabeth J., Vant Veer, Laura J., Vanderstichele, Adriaan, Vergote, Ignace, Vijai, Joseph, Wang, Qin, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Wentzensen, Nicolas, Whittemore, Alice S., Wildiers, Hans, Winqvist, Robert, Wu, Anna H., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Yu, Jyh-Cherng, Zheng, Wei, Zheng, Ying, Kum Khanna, Kum, Simard, Jacques, Monteiro, Alvaro N., French, Juliet D., Couch, Fergus J., Freedman, Matthew L., Easton, Douglas F., Dunning, Alison M., Pharoah, Paul D., Edwards, Stacey L., Chenevix-Trench, Georgia, Antoniou, Antonis C., Gayther, Simon A., Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline, Michailidou, Kyriaki, Tyrer, Jonathan, Beesley, Jonathan, Ramus, Susan J., Li, Qiyuan, Delgado, Melissa K., Lee, Janet M., Aittomaki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K., Arver, Brita, Bandera, Elisa V., Barile, Monica, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Benitez, Javier, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Blot, William, Bogdanova, Natalia, Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Bruinsma, Fiona, Brunet, Joan, Ahmad Buhari, Shaik, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji-Yeob, Claes, Kathleen B. M., Cook, Linda S., Cox, Angela, Cramer, Daniel W., Cross, Simon S., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Doerk, Thilo, Dumont, Martine, Ehrencrona, Hans, Ejlertsen, Bent, Ellis, Steve, Engel, Christoph, Lee, Eunjung, Gareth Evans, D., Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D., Fridley, Brooke L., Friedman, Eitan, Frost, Debra, Gambino, Gaetana, Ganz, Patricia A., Garber, Judy, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Ghoussaini, Maya, Giles, Graham G., Glasspool, Rosalind, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Gonzalez-Neira, Anna, Goode, Ellen L., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Guenel, Pascal, Haiman, Christopher A., Hall, Per, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Harrington, Patricia A., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Heitz, Florian, Herzog, Josef, Hogdall, Estrid, Hogdall, Claus K., Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Hulick, Peter J., Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jensen, Allan, John, Esther M., Johnson, Nichola, Kabisch, Maria, Kang, Daehee, Kapuscinski, Miroslav, Karlan, Beth Y., Khan, Sofia, Kiemeney, Lambertus A., Kruger Kjaer, Susanne, Knight, Julia A., Konstantopoulou, Irene, Kosma, Veli-Matti, Kristensen, Vessela, Kupryjanczyk, Jolanta, Kwong, Ava, de la Hoya, Miguel, Laitman, Yael, Lambrechts, Diether, Le, Nhu, De Leeneer, Kim, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T., Lu, Karen, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Massuger, Leon F. A. G., Matsuo, Keitaro, Mazoyer, Sylvie, McGuffog, Lesley, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R., Milne, Roger L., Montagna, Marco, Moysich, Kirsten B., Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Nord, Silje, Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olswold, Curtis, OMalley, David, Orlow, Irene, Orr, Nick, Osorio, Ana, Kyung Park, Sue, Pearce, Celeste L., Pejovic, Tanja, Peterlongo, Paolo, Pfeiler, Georg, Phelan, Catherine M., Poole, Elizabeth M., Pylkas, Katri, Radice, Paolo, Rantala, Johanna, Usman Rashid, Muhammad, Rennert, Gad, Rhenius, Valerie, Rhiem, Kerstin, Risch, Harvey A., Rodriguez, Gus, Anne Rossing, Mary, Rudolph, Anja, Salvesen, Helga B., Sangrajrang, Suleeporn, Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Sellers, Thomas A., Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Sieh, Weiva, Singer, Christian F., Sinilnikova, Olga M., Slager, Susan, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stenmark Askmalm, Marie, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony, Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Kathryn L., Beth Terry, Mary, Thomassen, Mads, Grazia Tibiletti, Maria, Tihomirova, Laima, Tognazzo, Silvia, Ewart Toland, Amanda, Tomlinson, Ian, Torres, Diana, Truong, Therese, Tseng, Chiu-chen, Tung, Nadine, Tworoger, Shelley S., Vachon, Celine, van den Ouweland, Ans M. W., van Doorn, Helena C., van Rensburg, Elizabeth J., Vant Veer, Laura J., Vanderstichele, Adriaan, Vergote, Ignace, Vijai, Joseph, Wang, Qin, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Wentzensen, Nicolas, Whittemore, Alice S., Wildiers, Hans, Winqvist, Robert, Wu, Anna H., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Yu, Jyh-Cherng, Zheng, Wei, Zheng, Ying, Kum Khanna, Kum, Simard, Jacques, Monteiro, Alvaro N., French, Juliet D., Couch, Fergus J., Freedman, Matthew L., Easton, Douglas F., Dunning, Alison M., Pharoah, Paul D., Edwards, Stacey L., Chenevix-Trench, Georgia, Antoniou, Antonis C., and Gayther, Simon A.

Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk., Funding Agencies|National Cancer Institute (USA) [UM1 CA164920, CA 27469]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318, NKI1998-1854, NKI2004-3088, NKI2007-3756]; Breast Cancer Research Trust, UK; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guys and St. Thomas NHS Foundation Trust; Kings College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]; California Breast Cancer Act of 1993; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [R01 CA77398, CA128978]; California Department of Public Health; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine; Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf

Published
2016
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49. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author

Hamdi, Y. (Yosr), Soucy, P. (Penny), Kuchenbaeker, K.B. (Karoline B.), Pastinen, T. (Tomi), Droit, A. (Arnaud), Lemaçon, A. (Audrey), Adlard, J.W. (Julian), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Arason, A. (Adalgeir), Arnold, N. (Norbert), Arun, B.K. (Banu), Azzollini, J., Bane, A.L. (Anita L.), Barjhoux, L. (Laure), Barrowdale, D. (Daniel), Benítez, J. (Javier), Berthet, P. (Pascaline), Blok, M.J. (Marinus), Bobolis, K.A. (Kristie A.), Bonadona, V. (Valérie), Bonnani, B. (Bernardo), Bradbury, A.R. (Angela R.), Brewer, C. (Carole), Buecher, B. (Bruno), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B.M.), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Davidson, R. (Rosemarie), Hoya, M. (Miguel) de La, De Leeneer, K. (Kim), Díez, O. (Orland), Ding, Y.C. (Yuan), Dolcetti, R. (Riccardo), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Eccles, D. (Diana), Eeles, R. (Ros), Einbeigi, Z. (Zakaria), Ejlertsen, B. (Bent), EMBRACE, Engel, C. (Christoph), Gareth Evans, D., Feliubadaló, L. (L.), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Friedman, E. (Eitan), Frost, D. (Debra), Ganschow, P. (Pamela), Ganz, P.A. (Patricia A.), Garber, J. (Judy), Gayther, S.A. (Simon), GEMO Study Collaborators, Gerdes, A-M. (Anne-Marie), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goldgar, D. (David), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Hahnen, E. (Eric), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Hart, S. (Stewart), Hays, J. (John), HEBON, Hogervorst, F.B.L. (Frans), Hulick, P.J. (Peter), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Izatt, L. (Louise), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jensen, U.B., John, E.M. (Esther), Joseph, V. (Vijai), Just, W. (Walter), Kaczmarek, K. (Katarzyna), Karlan, B.Y. (Beth Y.), KConFab Investigators, Kets, C.M. (Marleen), Kirk, J. (Judy), Kriege, M. (Mieke), Laitman, Y. (Yael), Laurent, M. (Maïté), Lázaro, C. (Conxi), Leslie, G. (Goska), Lester, K.J. (Kathryn), Lesueur, F. (Fabienne), Liljegren, A. (Annelie), Loman, N. (Niklas), Loud, J.T. (Jennifer), Manoukian, S. (Siranoush), Mariani, M. (Milena), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Miller, A. (Austin), Montagna, M. (Marco), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nussbaum, R.L. (Robert L.), Olah, E. (Edith), Olopade, O.I. (Olufunmilayo I.), Ong, K.-R. (Kai-Ren), Oosterwijk, J.C. (Jan), Osorio, A. (Ana), Papi, L. (Laura), Park, S.K. (Sue K.), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Segura, P.P. (Pedro Perez), Peterlongo, P. (Paolo), Phelan, C. (Catherine), Radice, P. (Paolo), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rookus, M.A. (Matti), Schmutzler, R.K. (Rita), Sevenet, N. (Nicolas), Shah, P.D. (Payal D.), Singer, C.F. (Christian), Slavin, T.P. (Thomas P.), Snape, K. (Katie), Sokolowska, J. (Johanna), Sønderstrup, I.M.H. (Ida Marie Heeholm), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Stoppa-Lyonnet, D. (Dominique), Sukiennicki, G. (Grzegorz), Sutter, C. (Christian), Tan, Y. (Yen), Tea, M.-K., Teixeira, P.J., Teulé, A. (A.), Teo, S.-H. (Soo-Hwang), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tung, N. (Nadine), Ouweland, A.M.W. (Ans) van den, Luijt, R.B. (Rob) van der, Engelen, K. (Klaartje) van, Rensburg, E.J. (Elizabeth) van, Varon-Mateeva, R. (Raymonda), Wapenschmidt, B. (Barbara), Wijnen, J.T. (Juul), Rebbeck, R. (Timothy), Chenevix-Trench, G. (Georgia), Offit, K. (Kenneth), Couch, F.J. (Fergus J.), Nord, S. (Silje), Easton, D.F. (Douglas F.), Antoniou, A.C. (Antonis), Simard, J. (Jacques), Hamdi, Y. (Yosr), Soucy, P. (Penny), Kuchenbaeker, K.B. (Karoline B.), Pastinen, T. (Tomi), Droit, A. (Arnaud), Lemaçon, A. (Audrey), Adlard, J.W. (Julian), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Arason, A. (Adalgeir), Arnold, N. (Norbert), Arun, B.K. (Banu), Azzollini, J., Bane, A.L. (Anita L.), Barjhoux, L. (Laure), Barrowdale, D. (Daniel), Benítez, J. (Javier), Berthet, P. (Pascaline), Blok, M.J. (Marinus), Bobolis, K.A. (Kristie A.), Bonadona, V. (Valérie), Bonnani, B. (Bernardo), Bradbury, A.R. (Angela R.), Brewer, C. (Carole), Buecher, B. (Bruno), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B.M.), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Davidson, R. (Rosemarie), Hoya, M. (Miguel) de La, De Leeneer, K. (Kim), Díez, O. (Orland), Ding, Y.C. (Yuan), Dolcetti, R. (Riccardo), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Eccles, D. (Diana), Eeles, R. (Ros), Einbeigi, Z. (Zakaria), Ejlertsen, B. (Bent), EMBRACE, Engel, C. (Christoph), Gareth Evans, D., Feliubadaló, L. (L.), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Friedman, E. (Eitan), Frost, D. (Debra), Ganschow, P. (Pamela), Ganz, P.A. (Patricia A.), Garber, J. (Judy), Gayther, S.A. (Simon), GEMO Study Collaborators, Gerdes, A-M. (Anne-Marie), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goldgar, D. (David), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Hahnen, E. (Eric), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Hart, S. (Stewart), Hays, J. (John), HEBON, Hogervorst, F.B.L. (Frans), Hulick, P.J. (Peter), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Izatt, L. (Louise), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jensen, U.B., John, E.M. (Esther), Joseph, V. (Vijai), Just, W. (Walter), Kaczmarek, K. (Katarzyna), Karlan, B.Y. (Beth Y.), KConFab Investigators, Kets, C.M. (Marleen), Kirk, J. (Judy), Kriege, M. (Mieke), Laitman, Y. (Yael), Laurent, M. (Maïté), Lázaro, C. (Conxi), Leslie, G. (Goska), Lester, K.J. (Kathryn), Lesueur, F. (Fabienne), Liljegren, A. (Annelie), Loman, N. (Niklas), Loud, J.T. (Jennifer), Manoukian, S. (Siranoush), Mariani, M. (Milena), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Miller, A. (Austin), Montagna, M. (Marco), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nussbaum, R.L. (Robert L.), Olah, E. (Edith), Olopade, O.I. (Olufunmilayo I.), Ong, K.-R. (Kai-Ren), Oosterwijk, J.C. (Jan), Osorio, A. (Ana), Papi, L. (Laura), Park, S.K. (Sue K.), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Segura, P.P. (Pedro Perez), Peterlongo, P. (Paolo), Phelan, C. (Catherine), Radice, P. (Paolo), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rookus, M.A. (Matti), Schmutzler, R.K. (Rita), Sevenet, N. (Nicolas), Shah, P.D. (Payal D.), Singer, C.F. (Christian), Slavin, T.P. (Thomas P.), Snape, K. (Katie), Sokolowska, J. (Johanna), Sønderstrup, I.M.H. (Ida Marie Heeholm), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Stoppa-Lyonnet, D. (Dominique), Sukiennicki, G. (Grzegorz), Sutter, C. (Christian), Tan, Y. (Yen), Tea, M.-K., Teixeira, P.J., Teulé, A. (A.), Teo, S.-H. (Soo-Hwang), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tung, N. (Nadine), Ouweland, A.M.W. (Ans) van den, Luijt, R.B. (Rob) van der, Engelen, K. (Klaartje) van, Rensburg, E.J. (Elizabeth) van, Varon-Mateeva, R. (Raymonda), Wapenschmidt, B. (Barbara), Wijnen, J.T. (Juul), Rebbeck, R. (Timothy), Chenevix-Trench, G. (Georgia), Offit, K. (Kenneth), Couch, F.J. (Fergus J.), Nord, S. (Silje), Easton, D.F. (Douglas F.), Antoniou, A.C. (Antonis), and Simard, J. (Jacques)

Abstract

Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of

Published
2016
Full Text
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50. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author

Ramus, Susan J., Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Sinilnikova, Olga M., Sue, Healey, Daniel, Barrowdale, Andrew, Lee, Mads, Thomassen, Anne Marie Gerdes, Kruse, Torben A., Uffe Birk Jensen, Anne Bine Skytte, Caligo, Maria A., Annelie, Liljegren, Annika, Lindblom, Hakan, Olsson, Ulf, Kristoffersson, Marie Stenmark Askmalm, Swe Brca Melin, B., Swe, Brca, Domchek, Susan M., Domchek, Sm, Nathanson, Katherine L., Rebbeck, Timothy R., Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Elzbieta, Złowocka, Jacek, Gronwald, Tomasz, Huzarski, Tomasz, Byrski, Cezary, Cybulski, Aleksandra Toloczko Grabarek, Ana, Osorio, Javier, Benitez, Mercedes, Duran, Maria Isabel Tejada, Ute, Hamann, Matti, Rookus, Van Leeuwen, Flora E., Aalfs, Cora M., Meijers Heijboer, Hanne E. J., Van Asperen, Christi J., Van Roozendaal, K. E. P., Nicoline, Hoogerbrugge, Collee, Margriet J., Margriet Collee, J., Mieke, Kriege, Hebon Van Der Luijt, R. B., Embrace, Embrace, Hebon, Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Diana, Eccles, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Porteous, Mary E., John Kennedy, M., Harsh, Pathak, Godwin, Andrew K., Dominique Stoppa Lyonnet, Virginie Caux Moncoutier, Antoine Pauw, D. E., De Pauw, A., Marion Gauthier Villars, Sylvie, Mazoyer, Melanie, Leone, Alain, Calender, Christine, Lasset, Valerie, Bonadona, Agnes, Hardouin, Pascaline, Berthet, Yves Jean Bignon, Nancy, Uhrhammer, Laurence, Faivre, Catherine, Loustalot, Gemo, Saundra, Buys, Mary, Daly, Buys, Daly, S., Alex, Miron, Beth, Terry M., Mary Beth Terry, Terry, M. B., Chung, Wendy K., Esther, John M., John, Em, Melissa, Southey, David, Goldgar, Singer, Christian F., Muy Kheng Tea, Georg, Pfeiler, Anneliese Fink Retter, Hansen, Thomas V. O., Hansen, Tv, Bent, Ejlertsen, Oskar Th Johannsson, Kenneth, Offit, Tomas, Kirchhoff, Gaudet, Mia M., Joseph, Vijai, Mark, Robson, Marion, Piedmonte, Kelly Anne Phillips, Linda Van Le, Hoffman, James S., Amanda Ewart Toland, Ewart Toland, A., Marco, Montagna, Silvia, Tognazzo, Evgeny, Imyanitov, Claudine, Isaacs, Issacs, C., Ramunas, Janavicius, Conxi, Lazaro, Ignacio, Blanco, Eva, Tornero, Matilde, Navarro, Moysich, Kirsten B., Karlan, Beth Y., Jenny, Gross, Edith, Olah, Tibor, Vaszko, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Van Rensburg, Elizabeth J., Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorotehea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Kristiina, Aittomaki, Marie, Plante, Kconfab Spurdle, A. B., Kconfab, Neuhausen, Susan L., Neuhausen, Sl, Yuan Chun Ding, Xianshu, Wang, Noralane, Lindor, Zachary, Fredericksen, Shane Pankratz, V., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Mai, Phuong L., Andrulis, Irene L., Gord, Glendon, Ocgn Ozcelik, H., Ocgn, Pharoah, Paul D. P., Pharoah, Pd, Gayther, Simon A., Jacques, Simard, Easton, Douglas F., Couch, Fergus J., Georgia Chenevix Trench, Behalf Of The Consortium Of Investigators Of Modifiers Of Brca1/2, O. N., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Universitat de Barcelona, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, and Clinical Genetics

Subjects
Oncology, endocrine system diseases, [SDV]Life Sciences [q-bio], Càncer d'ovari, DCN PAC - Perception action and control, Cohort Studies, Breast cancer, 0302 clinical medicine, brca1, brca2, Odds Ratio, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Hazard ratio, Middle Aged, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Female, Adult, Heterozygote, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, Single-nucleotide polymorphism, Biology, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], education, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], association, Retrospective cohort study, snp, Odds ratio, BRCA1 Protein - genetics, medicine.disease, BRCA2 Protein - genetics, Mutation
Abstract

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext

Published
2012
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