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1. Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort studyResearch in context

Author: Isaac Allen, Hend Hassan, Walburga Yvonne Joko-Fru, Catherine Huntley, Lucy Loong, Tameera Rahman, Bethany Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Katrina Lavelle, Fiona McRonald, Diana Eccles, Eva J.A Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, and Antonis C. Antoniou
Subjects: Breast cancer, Second primary cancer, Risk, Incidence, Treatment, Pathology, Public aspects of medicine, RA1-1270
Abstract: Summary: Background: Second primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets. Methods: The cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan–Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression. Findings: Both genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99–2.06) females; 55.4 (35.5–82.4) males) and non-breast (1.10 (1.09–1.11) females, 1.10 (1.00–1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31–1.38)
Published: 2024
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2. The comprehensive English National Lynch Syndrome Registry: development and description of a new genomics data resourceResearch in context

Author: Catherine Huntley, Lucy Loong, Corinne Mallinson, Rachel Bethell, Tameera Rahman, Neelam Alhaddad, Oliver Tulloch, Xue Zhou, Jason Lee, Paul Eves, Fiona McRonald, Bethany Torr, John Burn, Adam Shaw, Eva J.A. Morris, Kevin Monahan, Steven Hardy, Clare Turnbull, Jacqueline Cook, Ruth Armstrong, Munaza Ahmed, Terri McVeigh, Bianca DeSouza, Anjana Kulkarni, Heirdre Bezuidenhout, Richard Martin, Debbie Holliday, Rachel Hart, Fiona Lalloo, Alan Donaldson, Ruth Cleaver, Catherine Willis, Victoria Kiesel, Marie-Anne O'Reilly, Dorothy Halliday, Joyce Solomons, and Kai Ren Ong
Subjects: Lynch syndrome, Registry, Genomics, Data, Medicine (General), R5-920
Abstract: Summary: Background: Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established. Methods: For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD). Findings: A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40–62), compared to 73 years (IQR 64–80) in the general population (p
Published: 2024
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3. Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing, and definition of groups who may not require testing

Author: D. Gareth Evans, Emma R. Woodward, George J. Burghel, Sophie Allen, Beth Torr, Monica Hamill, Grace Kavanaugh, Mike Hubank, Stephen Bremner, Christopher I. Jones, Helene Schlecht, Susan Astley, Sarah Bowers, Sarah Gibbons, Helen Ruane, Caroline Fosbury, Sacha J. Howell, Claire Forde, Fiona Lalloo, William G. Newman, Miriam J. Smith, Anthony Howell, Clare Turnbull, and Ashu Gandhi
Subjects: BRCA1, BRCA2, Breast cancer, Manchester score, PALB2 population testing, Genetics, QH426-470, Medicine
Abstract: Purpose: To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates. Methods: Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and Partner and Localiser of BRCA2 (PALB2). The Manchester score (MS) was used at different points thresholds. Current mainstream criteria include women diagnosed
Published: 2024
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4. Risks of second non-breast primaries following breast cancer in women: a systematic review and meta-analysis

Author: Isaac Allen, Hend Hassan, Eleni Sofianopoulou, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, and Antonis C. Antoniou
Subjects: Breast neoplasms, Second primary, Second cancer, Multiple primary, Multiple cancer, Risk, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. Methods We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian–Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle–Ottawa scale. Results One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14–1.36, I 2: 99%). This varied by age: the estimate was 1.59 (95% CI 1.36–1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95% CI 1.01–1.36, p for difference:
Published: 2023
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5. P061: ATM and PALB2 variant curation guidelines progress update: ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel

Author: Megan Holdren, Marcy Richardson, Deborah Ritter, Colin Young, Terra Brannan, Tina Pesaran, Lauren Zec, Susan Hiraki, Michael Anderson, Melissa Southey, Clare Turnbull, Marc Tischkowitz, Huma Rana, Shannon McNulty Gray, Sean Tavtigian, Logan Walker, William Foulkes, Alvaro Monteiro, Sarah Brnich, Melissa Cline, Amanda Spurdle, Miguel de la Hoya, and Fergus Couch
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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6. P076: The ClinGen ENIGMA BRCA1/2 expert panel: A dynamic framework for evidence-based recommendations to improve classification criteria for variants in BRCA1/2

Author: Michael Parsons, Michael Anderson, Windy Berkofsky-Fessler, Sandrine Caputo, Raymond Chan, Melissa Cline, Fergus Couch, Miguel de la Hoya, Bing-Jian Feng, David Goldgar, Encarna Gomez-Garcia, Susan Hiraki, Megan Holdren, Claude Houdayer, Paul James, Rachid Karam, Huei San Leong, Alexandra Martins, Arjen Mensenkamp, Alvaro Monteiro, Vaishnavi Nathan, Robert O'Connor, Tina Pesaran, Paolo Radice, Marcy Richardson, Gunnar Schmidt, Inge Sokilde Pedersen, Melissa Southey, Sean Tavtigian, Bryony Thompson, Amanda Toland, Emma Tudini, Clare Turnbull, Maaike Vreeswijk, Logan Walker, Lauren Zec, and Amanda Spurdle
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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7. Identification of 22 susceptibility loci associated with testicular germ cell tumors

Author: John Pluta, Louise C. Pyle, Kevin T. Nead, Rona Wilf, Mingyao Li, Nandita Mitra, Benita Weathers, Kurt D’Andrea, Kristian Almstrup, Lynn Anson-Cartwright, Javier Benitez, Christopher D. Brown, Stephen Chanock, Chu Chen, Victoria K. Cortessis, Alberto Ferlin, Carlo Foresta, Marija Gamulin, Jourik A. Gietema, Chiara Grasso, Mark H. Greene, Tom Grotmol, Robert J. Hamilton, Trine B. Haugen, Russ Hauser, Michelle A. T. Hildebrandt, Matthew E. Johnson, Robert Karlsson, Lambertus A. Kiemeney, Davor Lessel, Ragnhild A. Lothe, Jennifer T. Loud, Chey Loveday, Paloma Martin-Gimeno, Coby Meijer, Jérémie Nsengimana, David I. Quinn, Thorunn Rafnar, Shweta Ramdas, Lorenzo Richiardi, Rolf I. Skotheim, Kari Stefansson, Clare Turnbull, David J. Vaughn, Fredrik Wiklund, Xifeng Wu, Daphne Yang, Tongzhang Zheng, Andrew D. Wells, Struan F. A. Grant, Ewa Rajpert-De Meyts, Stephen M. Schwartz, D. Timothy Bishop, Katherine A. McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, and The Testicular Cancer Consortium
Subjects: Science
Abstract: Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.
Published: 2021
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8. Will polygenic risk scores for cancer ever be clinically useful?

Author: Amit Sud, Clare Turnbull, and Richard Houlston
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2021
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9. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
Subjects: Science
Abstract: In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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10. Genomic landscape of platinum resistant and sensitive testicular cancers

Author: Chey Loveday, Kevin Litchfield, Paula Z. Proszek, Alex J. Cornish, Flavia Santo, Max Levy, Geoff Macintyre, Amy Holryod, Peter Broderick, Darshna Dudakia, Barbara Benton, Maise Al Bakir, Crispin Hiley, Emily Grist, Charles Swanton, Robert Huddart, Tom Powles, Simon Chowdhury, Janet Shipley, Simon O’Connor, James D. Brenton, Alison Reid, David Gonzalez de Castro, Richard S. Houlston, and Clare Turnbull
Subjects: Science
Abstract: Most testicular germ-cell tumours are exquisitely sensitive to platinum-based chemotherapies, but little is known about why 10% are resistant. Here, the authors explore the potential underlying mechanisms by probing the genomic landscape of platinum-resistant disease.
Published: 2020
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11. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Maria Escala-Garcia, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Alan Ashworth, Paul L. Auer, Päivi Auvinen, Matthias W. Beckmann, Jonathan Beesley, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Suet-Feung Chin, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Miriam Dwek, Helena M. Earl, Diana M. Eccles, A. Heather Eliassen, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Graham G. Giles, David E. Goldgar, Anna González-Neira, Mervi Grip, Pascal Guénel, Qi Guo, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Patricia A. Harrington, Louise Hiller, Maartje J. Hooning, John L. Hopper, Anthony Howell, Chiun-Sheng Huang, Guanmengqian Huang, David J. Hunter, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Pooja Middha Kapoor, Renske Keeman, Cari M. Kitahara, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Flavio Lejbkowicz, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Tabea Maurer, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Nick Orr, Paolo Peterlongo, Christos Petridis, Ross L. Prentice, Nadege Presneau, Kevin Punie, Dhanya Ramachandran, Gad Rennert, Atocha Romero, Mythily Sachchithananthan, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Jacques Simard, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Heather Thorne, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Clare Turnbull, Celine M. Vachon, Lizet E. van der Kolk, Qin Wang, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Argyrios Ziogas, Paul D. P. Pharoah, Per Hall, Lodewyk F. A. Wessels, Georgia Chenevix-Trench, Gary D. Bader, Thilo Dörk, Douglas F. Easton, Sander Canisius, and Marjanka K. Schmidt
Subjects: Science
Abstract: In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
Published: 2020
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12. Estimated impact of the COVID-19 pandemic on cancer services and excess 1-year mortality in people with cancer and multimorbidity: near real-time data on cancer care, cancer deaths and a population-based cohort study

Author: Richard D Neal, Amitava Banerjee, Deenan Pillay, Vahe Nafilyan, Clare Turnbull, Harry Hemingway, Bryan Williams, Mark Lawler, Monica Jones, Spiros Denaxas, Kathy Pritchard-Jones, Mahdad Noursadeghi, Richard Sullivan, Graham R Foster, Ben Humberstone, Alvina G Lai, Laura Pasea, Geoff Hall, Wai Hoong Chang, Michail Katsoulis, David Linch, Derralynn Hughes, Martin D Forster, Natalie K Fitzpatrick, Kathryn Boyd, Tariq Enver, Matt Cooper, and Charlie Davie
Subjects: Medicine
Abstract: Objectives To estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer.Methods We employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England.Results Declines in urgent referrals (median=−70.4%) and chemotherapy attendances (median=−41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=−44.5%) and chemotherapy attendances (median=−31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity.Conclusions Dramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.
Published: 2020
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13. Weekly COVID-19 testing with household quarantine and contact tracing is feasible and would probably end the epidemic

Author: Julian Peto, James Carpenter, George Davey Smith, Stephen Duffy, Richard Houlston, David J. Hunter, Klim McPherson, Neil Pearce, Paul Romer, Peter Sasieni, and Clare Turnbull
Subjects: covid-19, quarantine, screening, Science
Abstract: The COVID-19 epidemic can probably be ended and normal life restored, perhaps quite quickly, by weekly SARS-CoV-2 RNA testing together with household quarantine and systematic contact tracing. Isolated outbreaks could then be contained by contact tracing, supplemented if necessary by temporary local reintroduction of population testing or lockdown. Leading public health experts have recommended that this should be tried in a demonstration project in which a medium-sized city introduces weekly testing and lifts lockdown completely. The idea was not considered by the groups whose predictions have guided UK policy, so we have examined the statistical case for such a study. The combination of regular testing with strict household quarantine, which was not analysed in their models, has remarkable power to reduce transmission to the community from other household members as well as providing earlier diagnosis and facilitating rapid contact tracing.
Published: 2020
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14. Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

Author: Kevin Litchfield, Max Levy, Darshna Dudakia, Paula Proszek, Claire Shipley, Sander Basten, Elizabeth Rapley, D. Timothy Bishop, Alison Reid, Robert Huddart, Peter Broderick, David Gonzalez de Castro, Simon O'Connor, Rachel H. Giles, Richard S. Houlston, and Clare Turnbull
Subjects: Science
Abstract: There is some evidence of a hereditary risk for developing testicular germ cell tumours. Here, the authors use whole-exome sequencing and identify a risk variant for the disease in DNAAF1, a gene involved in microtubule-based cilia.
Published: 2016
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15. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Fergus J. Couch, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Gustavo A. Mendoza-Fandino, Silje Nord, Janna Lilyquist, Curtis Olswold, Emily Hallberg, Simona Agata, Habibul Ahsan, Kristiina Aittomäki, Christine Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Lars Beckmann, Matthias W. Beckmann, Javier Benitez, Stephanie V. Blank, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Federico Canzian, Jane Carpenter, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Miguel de la Hoya, Peter Devilee, Orland Diez, Yuan C. Ding, Riccardo Dolcetti, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Martine Dumont, Alison M. Dunning, Diana M. Eccles, Hans Ehrencrona, Arif B. Ekici, Heather Eliassen, Steve Ellis, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Asta Försti, Florentia Fostira, William D. Foulkes, Tara Friebel, Eitan Friedman, Debra Frost, Marike Gabrielson, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Mia M. Gaudet, Simon A. Gayther, Anne-Marie Gerdes, Maya Ghoussaini, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Marc Gunter, Lothar Haeberle, Christopher A. Haiman, Ute Hamann, Thomas V. O. Hansen, Steven Hart, Sue Healey, Tuomas Heikkinen, Brian E. Henderson, Josef Herzog, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Keith Humphreys, David J. Hunter, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Michael Jones, Maria Kabisch, Siddhartha Kar, Beth Y. Karlan, Sofia Khan, Kay-Tee Khaw, Muhammad G. Kibriya, Julia A. Knight, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Ava Kwong, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Eunjung Lee, Loic Le Marchand, Jenny Lester, Annika Lindblom, Noralane Lindor, Sara Lindstrom, Jianjun Liu, Jirong Long, Jan Lubinski, Phuong L. Mai, Enes Makalic, Kathleen E. Malone, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, John W. M. Martens, Lesley McGuffog, Alfons Meindl, Austin Miller, Roger L. Milne, Penelope Miron, Marco Montagna, Sylvie Mazoyer, Anna M. Mulligan, Taru A. Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Ana Osorio, Sue K. Park, Petra H. Peeters, Bernard Peissel, Paolo Peterlongo, Julian Peto, Catherine M. Phelan, Robert Pilarski, Bruce Poppe, Katri Pylkäs, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport, Gad Rennert, Andrea Richardson, Mark Robson, Isabelle Romieu, Anja Rudolph, Emiel J. Rutgers, Maria-Jose Sanchez, Regina M. Santella, Elinor J. Sawyer, Daniel F. Schmidt, Marjanka K. Schmidt, Rita K. Schmutzler, Fredrick Schumacher, Rodney Scott, Leigha Senter, Priyanka Sharma, Jacques Simard, Christian F. Singer, Olga M. Sinilnikova, Penny Soucy, Melissa Southey, Doris Steinemann, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Csilla I. Szabo, Rulla Tamimi, William Tapper, Manuel R. Teixeira, Soo-Hwang Teo, Mary B. Terry, Mads Thomassen, Deborah Thompson, Laima Tihomirova, Amanda E. Toland, Robert A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Helen Tsimiklis, Alex Teulé, Rosario Tumino, Nadine Tung, Clare Turnbull, Giski Ursin, Carolien H. M. van Deurzen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Zhaoming Wang, Shan Wang-Gohrke, Elisabete Weiderpass, Jeffrey N. Weitzel, Alice Whittemore, Hans Wildiers, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Song Yao, M Pilar Zamora, Wei Zheng, Per Hall, Peter Kraft, Celine Vachon, Susan Slager, Georgia Chenevix-Trench, Paul D. P. Pharoah, Alvaro A. N. Monteiro, Montserrat García-Closas, Douglas F. Easton, and Antonis C. Antoniou
Subjects: Science
Abstract: Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
Published: 2016
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16. MicroRNA related polymorphisms and breast cancer risk.

Author: Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, kConFab Investigators, Australian Ovarian Cancer Study Group, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, GENICA Network, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Published: 2014
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17. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author: Rebecca Hein, Melanie Maranian, John L Hopper, Miroslaw K Kapuscinski, Melissa C Southey, Daniel J Park, Marjanka K Schmidt, Annegien Broeks, Frans B L Hogervorst, H Bas Bueno-de-Mesquita, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, M Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Iosif V Zalutsky, Natalia N Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, Kconfab Investigators, AOCS Group, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Jonine D Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E Sherman, Maartje Hooning, John W M Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Shahana Ahmed, Maya Ghoussaini, Paul D P Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A Newcomb, Linda Titus, Kathleen M Egan, Georgia Chenevix-Trench, Antonis C Antoniou, Manjeet K Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F Easton, and Alison M Dunning
Subjects: Medicine, Science
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
Published: 2012
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18. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author: Tomas Kirchhoff, Mia M Gaudet, Antonis C Antoniou, Lesley McGuffog, Manjeet K Humphreys, Alison M Dunning, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Thilo Dork, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Fergus J Couch, Janet Olson, Celine Vachon, Xianshu Wang, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Barbara Burwinkel, Alfons Meindl, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Annegien Broeks, Marjanka K Schmidt, Laura J Van 't Veer, Linde M Braaf, Nichola Johnson, Olivia Fletcher, Lorna Gibson, Julian Peto, Clare Turnbull, Sheila Seal, Anthony Renwick, Nazneen Rahman, Pei-Ei Wu, Jyh-Cherng Yu, Chia-Ni Hsiung, Chen-Yang Shen, Melissa C Southey, John L Hopper, Fleur Hammet, Thijs Van Dorpe, Anne-Sophie Dieudonne, Sigrid Hatse, Diether Lambrechts, Irene L Andrulis, Natalia Bogdanova, Natalia Antonenkova, Juri I Rogov, Daria Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Christi J van Asperen, Robert A E M Tollenaar, Maartje J Hooning, Peter Devilee, Sara Margolin, Annika Lindblom, Roger L Milne, José Ignacio Arias, M Pilar Zamora, Javier Benítez, Gianluca Severi, Laura Baglietto, Graham G Giles, kConFab, AOCS Study Group, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Sue Healey, Shan Wang-Gohrke, Jenny Chang-Claude, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Bjarni A Agnarsson, Maria A Caligo, Andrew K Godwin, Heli Nevanlinna, Tuomas Heikkinen, Zachary Fredericksen, Noralane Lindor, Katherine L Nathanson, Susan M Domchek, SWE-BRCA, Niklas Loman, Per Karlsson, Marie Stenmark Askmalm, Beatrice Melin, Anna von Wachenfeldt, HEBON, Frans B L Hogervorst, Martijn Verheus, Matti A Rookus, Caroline Seynaeve, Rogier A Oldenburg, Marjolijn J Ligtenberg, Margreet G E M Ausems, Cora M Aalfs, Hans J P Gille, Juul T Wijnen, Encarna B Gómez García, EMBRACE, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Craig Luccarini, Gabriella Pichert, Rosemarie Davidson, Carol Chu, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, D Gareth Evans, Rosalind Eeles, Bert Gold, Paul D P Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F Easton, and BCAC/CIMBA
Subjects: Medicine, Science
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =
Published: 2012
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19. Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author: Rebecca Hein, Melanie Maranian, John L. Hopper, Miroslaw K. Kapuscinski, Melissa C. Southey, Daniel J. Park, Marjanka K. Schmidt, Annegien Broeks, Frans B. L. Hogervorst, H. Bas Bueno-de-Mesquit, Kenneth R. Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, M. Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Iosif V. Zalutsky, Natalia N. Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, kConFab Investigators, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M. Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M. John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Jonine D. Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E. Sherman, Maartje Hooning, John W. M. Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W. Brock, Simon S. Cross, Malcolm W. R. Reed, Shahana Ahmed, Maya Ghoussaini, Paul DP. Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A. Newcomb, Linda Titus, Kathleen M. Egan, Georgia Chenevix-Trench, Antonis C. Antoniou, Manjeet K. Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F. Easton, and Alison M. Dunning
Subjects: Medicine, Science
Published: 2012
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20. Germline predisposition to haematological malignancies: Best practice consensus guidelines from the UK Cancer Genetics Group ( <scp>UKCGG)</scp> , <scp>CanGene‐CanVar</scp> and the <scp>NHS</scp> England Haematological Oncology Working Group

Author: Clare Turnbull
Subjects: Hematology
Published: 2023

21. Talking about Risk, UncertaintieS of Testing IN Genetics (TRUSTING): development and evaluation of an educational programme for healthcare professionals about BRCA1 & BRCA2 testing

Author: Lesley Fallowfield, Ivonne Solis-Trapala, Rachel Starkings, Shirley May, Lucy Matthews, Diana Eccles, D. Gareth Evans, Clare Turnbull, Gillian Crawford, and Valerie Jenkins
Subjects: BRCA2 Protein, Heterozygote, Cancer Research, BRCA1 Protein, Health Personnel, education, Breast Neoplasms/diagnosis, Breast Neoplasms, BRCA2 Protein/genetics, R1, Oncology, BRCA1 Protein/genetics, Humans, Family, Female, Genetic Predisposition to Disease, Genetic Testing, Delivery of Health Care
Abstract: Background Mainstreaming of germline testing demands that all healthcare professionals have good communication skills, but few have genetic testing and counselling experience. We developed and evaluated educational workshops—Talking about Risk & UncertaintieS of Testing IN Genetics (TRUSTING). Contents included: presentations and exercises, an interview with a geneticist about BRCA testing, screening and prevention implications, filmed interactions between surgeons, a genetic counsellor and geneticists with a fictitious family (proband had a BRCA2 pathogenic variant with triple-negative breast cancer, her older sister—BRCA2 heterozygous, and cousin—negative for BRCA2 variant). Methods Twenty-one surgeons, 5 oncologists, 18 nurses and 9 genetic counsellors participated. Knowledge (18 item MCQ), communication skills (responses to 6 questions from proband and relatives) and self-confidence (discussing 9 genetic testing issues) were assessed pre- and post workshop. Results Knowledge scores improved significantly post workshop (mean change = 7.06; 95% confidence interval (CI) 6.37–7.74; P P P Discussion Healthcare professionals’ knowledge and self-confidence when discussing the risks and uncertainties in genetics are often poor. TRUSTING workshops significantly enhanced attendees’ navigation of communication difficulties encountered and will be rolled out more widely.
Published: 2022

22. Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018

Author: Sam Cook, Joanna Pethick, Nour Kibbi, Loes Hollestein, Katrina Lavelle, Isabella de Vere Hunt, Clare Turnbull, Brian Rous, Akhtar Husain, John Burn, Margreet Lüchtenborg, Francesco Santaniello, Fiona McRonald, Steven Hardy, Eleni Linos, Zoe Venables, Neil Rajan, and Dermatology
Subjects: SDG 3 - Good Health and Well-being, Dermatology
Abstract: Background: Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC. Objective: To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC. Methods: A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England. Results: This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient. Limitations: Retrospective design. Conclusions: Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.
Published: 2023

23. Supplementary Data from Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response

Author: Gareth L. Bond, Hannah Carter, Clare Turnbull, Ian Tomlinson, Enric Domingo, Timothy S. Maughan, Sarah P. Blagden, Meghana Pagadala, Daniel V. Ebner, Val Millar, Andrew Protheroe, Claire Palles, Lukasz F. Grochola, Rick Jansen, Chey Loveday, Paul D. Pharoah, Siddhartha Kar, Janet Shipley, Joanna L. Selfe, Anderson J. Ryan, Yanyan Jiang, Jorge Zeron-Medina, Douglas A. Bell, Xuting Wang, David Sims, Mirvat Surakhy, Sarah De Val, Svanhild Nornes, Samantha Moore, Natasha Sahgal, Elisabeth Bond, Marsha D. Wallace, Philipp H. Richter, Katherine Brown, Giovanni Stracquadanio, Lingyun Xiong, Isaac Kitchen-Smith, and Ping Zhang
Abstract: Supplementary Methods; Supplementary Figures S1-S5
Published: 2023

24. Data from A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Author: Alice S. Whittemore, Nancy J. Cox, Douglas F. Easton, Dan Nicolae, Fernando Rivadeneira, Andre G. Uitterlinden, Hanne Meijers-Heijboer, Quinten Waisfisz, Paul Pharoah, Alison M. Dunning, Clare Turnbull, Nazneen Rahman, Jianjun Liu, Astrid Irwanto, Kamila Czene, Per Hall, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna, Norbert Dahmen, Dieter Flesch-Janys, Jennifer Stone, Quang Minh Bui, Daniel F. Schmidt, Enes Makalic, Rebecca Hein, Lars Beckmann, Magdalena Lochmann, Bertram Müller-Myhsok, Rita K. Schmutzler, Alfons Meindl, Stephen J. Chanock, David J. Hunter, Mark Lathrop, Isabel dos Santos Silva, Olivia Fletcher, Julian Peto, Daniel J. Park, Carmel Apicella, Kyriaki Michailidou, Polly Newcomb, Noralane M. Lindor, Mark Jenkins, Robert Haile, Steve Gallinger, David Duggan, David Conti, Eunjung Lee, Regina M. Santella, Graham G. Giles, Melissa C. Southey, Julia A. Knight, Graham Casey, Daniela Seminara, Duncan C. Thomas, Marilie D. Gammon, Giske Ursin, Kathi Malone, Esther M. John, John L. Hopper, Irene Andrulis, Jenny Chang-Claude, Stephanie Melkonian, Maria Argos, Rachelle Brutus, Shantanu Roy, Farzana Jasmine, Jianxin Shi, Anna Felberg, Valerie McGuire, Eric Gamazon, Lin Tong, Brandon L. Pierce, Muhammad G. Kibriya, Jerry Halpern, and Habibul Ahsan
Abstract: Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.
Published: 2023

25. Data from Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score

Author: Joaquin Mateo, Ethan S. Sokol, Jorge-Antonio Lopez, Luis Garcia Palacios, Clare Turnbull, Etienne Rouleau, Volker Heinemann, Shridar Ganesan, Fabrice André, Alexander D. Fine, and C. Benedikt Westphalen
Abstract: Purpose:To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes beyond BRCA1 and BRCA2.Experimental Design:Genomic profiling using a targeted next-generation sequencing assay examining 324–465 genes (FoundationOne, FoundationOne Heme, and FoundationOne CDx; Foundation Medicine, Inc.) was performed in a cohort of 160,790 samples across different tumor types. Zygosity predictions and gLOH status were calculated and linked with alterations in 18 HRR-associated genes (BRCA1, BRCA2, PALB2, BARD1, ATR, ATRX, ATM, BAP1, RAD51B, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC, MRE11) and other genomic features, using Fisher's exact test and Mann–Whitney U tests.Results:We identified a strong correlation between elevated gLOH and biallelic alterations in a core set of HRR-associated genes beyond BRCA1 and BRCA2, such as BARD1, PALB2, FANCC, RAD51C, and RAD51D (particularly in breast, ovarian, pancreatic, and prostate cancer). Monoallelic/heterozygous alterations in HRR-associated genes were not associated with elevated gLOH. gLOH was also independently associated with TP53 loss. Co-occurrence of TP53 loss and alterations in HRR-associated genes, and combined loss of TP53-PTEN or TP53-RB1, was associated with a higher gLOH than each of the events separately.Conclusions:Biallelic alterations in core HRR-associated genes are frequent, strongly associated with elevated gLOH, and enriched in breast, ovarian, pancreatic, and prostate cancer. This analysis could inform the design of the next generation of clinical trials examining DNA repair–targeting agents, including PARP inhibitors.
Published: 2023

26. Supplementary Table 2 and Supplemental Figures from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author: Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
Abstract: Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.
Published: 2023

27. Supplementary Table 3 from Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer

Author: Douglas F. Easton, Georgia Chenevix-Trench, Qin Wang, Manjeet K. Humphreys, Xianshu Wang, Janet E. Olson, Albina Farahtdinova, Darya Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Madeleine Tilanus-Linthorst, Rogier A. Oldenburg, Antoinette Hollestelle, Maartje Hooning, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Christina Justenhoven, Volker Harth, Ute Hamann, Jonathan Beesley, Xiaoqing Chen, Sara Lindstrom, Peter Kraft, Susan E. Hankinson, David J. Hunter, Sei-Hyun Ahn, Dong-Young Noh, Keun-Young Yoo, Daehee Kang, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Anna Jakubowska, Barbara Burwinkel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Karen A. Pooley, Alison M. Dunning, Paul D.P. Pharoah, Rob A.E.M. Tollenaar, Laura J. Van ‘t Veer, Annegien Broeks, Marjanka K. Schmidt, Nicola Miller, Michael Kerin, Ian Tomlinson, Elinor Sawyer, Argyrios Ziogas, Hoda Anton-Culver, Dieter Flesch-Janys, Stefan Nickels, Julian Peto, Isabel dos Santos Silva, Lorna J. Gibson, Olivia Fletcher, Robert N. Hoover, Gilles D. Thomas, Rita K. Schmutzler, Claus R. Bartram, Joerg Heil, Alfons Meindl, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Arto Mannermaa, Anna Marie Mulligan, Gord Glendon, Julia A. Knight, Irene L. Andrulis, Christa Stegmaier, Volker Arndt, Heiko Müller, Hermann Brenner, Matthias W. Beckmann, Arif B. Ekici, Christian M. Bayer, Peter A. Fasching, Yuri I. Rogov, Iosif V. Zalutsky, Natalia N. Antonenkova, Natalia V. Bogdanova, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Stephen J. Chanock, Alexander Miron, Esther M. John, Laura Baglietto, Graham G. Giles, Monica Barile, Siranoush Manoukian, Paolo Peterlongo, Paolo Radice, Shan Wang-Gohrke, Jenny Chang-Claude, James McKay, Paul Brennan, Valerie Gaborieau, Suleeporn Sangrajrang, Karin Leunen, Giuseppe Floris, Betül T. Yesilyurt, Diether Lambrechts, Melissa C. Southey, Carmel Apicella, Gillian S. Dite, John L. Hopper, Anne-Lise Børrensen-Dale, Vessela Kristensen, Grethe Grenaker Alnæs, Charlotte Lanng, Stig E. Bojesen, Børge G. Nordestgaard, Ming-Feng Hou, Chiun-Sheng Huang, Jyh-Cherng Yu, Chen-Yang Shen, Nazneen Rahman, Anthony Renwick, Clare Turnbull, Sheila Seal, Simon S. Cross, Graeme Elliot, Ian W. Brock, Angela Cox, Peter Hillemanns, Johann H. Karstens, Peter Schürmann, Thilo Dörk, Javier Benítez, Jose Ignacio Arias Pérez, M. Pilar Zamora, Núria Malats, Zachary Fredericksen, Rebecca Hein, Gianluca Severi, Fergus J. Couch, Montserrat García-Closas, Ellen L. Goode, and Roger L. Milne
Abstract: PDF file - 71K
Published: 2023

28. Supplementary Table 2 from Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer

Author: Douglas F. Easton, Georgia Chenevix-Trench, Qin Wang, Manjeet K. Humphreys, Xianshu Wang, Janet E. Olson, Albina Farahtdinova, Darya Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Madeleine Tilanus-Linthorst, Rogier A. Oldenburg, Antoinette Hollestelle, Maartje Hooning, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Christina Justenhoven, Volker Harth, Ute Hamann, Jonathan Beesley, Xiaoqing Chen, Sara Lindstrom, Peter Kraft, Susan E. Hankinson, David J. Hunter, Sei-Hyun Ahn, Dong-Young Noh, Keun-Young Yoo, Daehee Kang, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Anna Jakubowska, Barbara Burwinkel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Karen A. Pooley, Alison M. Dunning, Paul D.P. Pharoah, Rob A.E.M. Tollenaar, Laura J. Van ‘t Veer, Annegien Broeks, Marjanka K. Schmidt, Nicola Miller, Michael Kerin, Ian Tomlinson, Elinor Sawyer, Argyrios Ziogas, Hoda Anton-Culver, Dieter Flesch-Janys, Stefan Nickels, Julian Peto, Isabel dos Santos Silva, Lorna J. Gibson, Olivia Fletcher, Robert N. Hoover, Gilles D. Thomas, Rita K. Schmutzler, Claus R. Bartram, Joerg Heil, Alfons Meindl, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Arto Mannermaa, Anna Marie Mulligan, Gord Glendon, Julia A. Knight, Irene L. Andrulis, Christa Stegmaier, Volker Arndt, Heiko Müller, Hermann Brenner, Matthias W. Beckmann, Arif B. Ekici, Christian M. Bayer, Peter A. Fasching, Yuri I. Rogov, Iosif V. Zalutsky, Natalia N. Antonenkova, Natalia V. Bogdanova, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Stephen J. Chanock, Alexander Miron, Esther M. John, Laura Baglietto, Graham G. Giles, Monica Barile, Siranoush Manoukian, Paolo Peterlongo, Paolo Radice, Shan Wang-Gohrke, Jenny Chang-Claude, James McKay, Paul Brennan, Valerie Gaborieau, Suleeporn Sangrajrang, Karin Leunen, Giuseppe Floris, Betül T. Yesilyurt, Diether Lambrechts, Melissa C. Southey, Carmel Apicella, Gillian S. Dite, John L. Hopper, Anne-Lise Børrensen-Dale, Vessela Kristensen, Grethe Grenaker Alnæs, Charlotte Lanng, Stig E. Bojesen, Børge G. Nordestgaard, Ming-Feng Hou, Chiun-Sheng Huang, Jyh-Cherng Yu, Chen-Yang Shen, Nazneen Rahman, Anthony Renwick, Clare Turnbull, Sheila Seal, Simon S. Cross, Graeme Elliot, Ian W. Brock, Angela Cox, Peter Hillemanns, Johann H. Karstens, Peter Schürmann, Thilo Dörk, Javier Benítez, Jose Ignacio Arias Pérez, M. Pilar Zamora, Núria Malats, Zachary Fredericksen, Rebecca Hein, Gianluca Severi, Fergus J. Couch, Montserrat García-Closas, Ellen L. Goode, and Roger L. Milne
Abstract: PDF file - 94K
Published: 2023

29. Supplementary Data from Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score

Author: Joaquin Mateo, Ethan S. Sokol, Jorge-Antonio Lopez, Luis Garcia Palacios, Clare Turnbull, Etienne Rouleau, Volker Heinemann, Shridar Ganesan, Fabrice André, Alexander D. Fine, and C. Benedikt Westphalen
Abstract: Supplementary Data from Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score
Published: 2023

30. Data from Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer

Author: Douglas F. Easton, Georgia Chenevix-Trench, Qin Wang, Manjeet K. Humphreys, Xianshu Wang, Janet E. Olson, Albina Farahtdinova, Darya Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Madeleine Tilanus-Linthorst, Rogier A. Oldenburg, Antoinette Hollestelle, Maartje Hooning, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Christina Justenhoven, Volker Harth, Ute Hamann, Jonathan Beesley, Xiaoqing Chen, Sara Lindstrom, Peter Kraft, Susan E. Hankinson, David J. Hunter, Sei-Hyun Ahn, Dong-Young Noh, Keun-Young Yoo, Daehee Kang, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Anna Jakubowska, Barbara Burwinkel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Karen A. Pooley, Alison M. Dunning, Paul D.P. Pharoah, Rob A.E.M. Tollenaar, Laura J. Van ‘t Veer, Annegien Broeks, Marjanka K. Schmidt, Nicola Miller, Michael Kerin, Ian Tomlinson, Elinor Sawyer, Argyrios Ziogas, Hoda Anton-Culver, Dieter Flesch-Janys, Stefan Nickels, Julian Peto, Isabel dos Santos Silva, Lorna J. Gibson, Olivia Fletcher, Robert N. Hoover, Gilles D. Thomas, Rita K. Schmutzler, Claus R. Bartram, Joerg Heil, Alfons Meindl, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Arto Mannermaa, Anna Marie Mulligan, Gord Glendon, Julia A. Knight, Irene L. Andrulis, Christa Stegmaier, Volker Arndt, Heiko Müller, Hermann Brenner, Matthias W. Beckmann, Arif B. Ekici, Christian M. Bayer, Peter A. Fasching, Yuri I. Rogov, Iosif V. Zalutsky, Natalia N. Antonenkova, Natalia V. Bogdanova, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Stephen J. Chanock, Alexander Miron, Esther M. John, Laura Baglietto, Graham G. Giles, Monica Barile, Siranoush Manoukian, Paolo Peterlongo, Paolo Radice, Shan Wang-Gohrke, Jenny Chang-Claude, James McKay, Paul Brennan, Valerie Gaborieau, Suleeporn Sangrajrang, Karin Leunen, Giuseppe Floris, Betül T. Yesilyurt, Diether Lambrechts, Melissa C. Southey, Carmel Apicella, Gillian S. Dite, John L. Hopper, Anne-Lise Børrensen-Dale, Vessela Kristensen, Grethe Grenaker Alnæs, Charlotte Lanng, Stig E. Bojesen, Børge G. Nordestgaard, Ming-Feng Hou, Chiun-Sheng Huang, Jyh-Cherng Yu, Chen-Yang Shen, Nazneen Rahman, Anthony Renwick, Clare Turnbull, Sheila Seal, Simon S. Cross, Graeme Elliot, Ian W. Brock, Angela Cox, Peter Hillemanns, Johann H. Karstens, Peter Schürmann, Thilo Dörk, Javier Benítez, Jose Ignacio Arias Pérez, M. Pilar Zamora, Núria Malats, Zachary Fredericksen, Rebecca Hein, Gianluca Severi, Fergus J. Couch, Montserrat García-Closas, Ellen L. Goode, and Roger L. Milne
Abstract: Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7].Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.
Published: 2023

31. Data from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author: Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
Abstract: Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.
Published: 2023

32. Data from Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response

Author: Gareth L. Bond, Hannah Carter, Clare Turnbull, Ian Tomlinson, Enric Domingo, Timothy S. Maughan, Sarah P. Blagden, Meghana Pagadala, Daniel V. Ebner, Val Millar, Andrew Protheroe, Claire Palles, Lukasz F. Grochola, Rick Jansen, Chey Loveday, Paul D. Pharoah, Siddhartha Kar, Janet Shipley, Joanna L. Selfe, Anderson J. Ryan, Yanyan Jiang, Jorge Zeron-Medina, Douglas A. Bell, Xuting Wang, David Sims, Mirvat Surakhy, Sarah De Val, Svanhild Nornes, Samantha Moore, Natasha Sahgal, Elisabeth Bond, Marsha D. Wallace, Philipp H. Richter, Katherine Brown, Giovanni Stracquadanio, Lingyun Xiong, Isaac Kitchen-Smith, and Ping Zhang
Abstract: Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.Significance:These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.
Published: 2023

33. Supplementary Table 1 from Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor–Positive, Lower Grade Breast Cancer

Author: Douglas F. Easton, Georgia Chenevix-Trench, Qin Wang, Manjeet K. Humphreys, Xianshu Wang, Janet E. Olson, Albina Farahtdinova, Darya Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Madeleine Tilanus-Linthorst, Rogier A. Oldenburg, Antoinette Hollestelle, Maartje Hooning, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Christina Justenhoven, Volker Harth, Ute Hamann, Jonathan Beesley, Xiaoqing Chen, Sara Lindstrom, Peter Kraft, Susan E. Hankinson, David J. Hunter, Sei-Hyun Ahn, Dong-Young Noh, Keun-Young Yoo, Daehee Kang, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Anna Jakubowska, Barbara Burwinkel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Karen A. Pooley, Alison M. Dunning, Paul D.P. Pharoah, Rob A.E.M. Tollenaar, Laura J. Van ‘t Veer, Annegien Broeks, Marjanka K. Schmidt, Nicola Miller, Michael Kerin, Ian Tomlinson, Elinor Sawyer, Argyrios Ziogas, Hoda Anton-Culver, Dieter Flesch-Janys, Stefan Nickels, Julian Peto, Isabel dos Santos Silva, Lorna J. Gibson, Olivia Fletcher, Robert N. Hoover, Gilles D. Thomas, Rita K. Schmutzler, Claus R. Bartram, Joerg Heil, Alfons Meindl, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Arto Mannermaa, Anna Marie Mulligan, Gord Glendon, Julia A. Knight, Irene L. Andrulis, Christa Stegmaier, Volker Arndt, Heiko Müller, Hermann Brenner, Matthias W. Beckmann, Arif B. Ekici, Christian M. Bayer, Peter A. Fasching, Yuri I. Rogov, Iosif V. Zalutsky, Natalia N. Antonenkova, Natalia V. Bogdanova, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Stephen J. Chanock, Alexander Miron, Esther M. John, Laura Baglietto, Graham G. Giles, Monica Barile, Siranoush Manoukian, Paolo Peterlongo, Paolo Radice, Shan Wang-Gohrke, Jenny Chang-Claude, James McKay, Paul Brennan, Valerie Gaborieau, Suleeporn Sangrajrang, Karin Leunen, Giuseppe Floris, Betül T. Yesilyurt, Diether Lambrechts, Melissa C. Southey, Carmel Apicella, Gillian S. Dite, John L. Hopper, Anne-Lise Børrensen-Dale, Vessela Kristensen, Grethe Grenaker Alnæs, Charlotte Lanng, Stig E. Bojesen, Børge G. Nordestgaard, Ming-Feng Hou, Chiun-Sheng Huang, Jyh-Cherng Yu, Chen-Yang Shen, Nazneen Rahman, Anthony Renwick, Clare Turnbull, Sheila Seal, Simon S. Cross, Graeme Elliot, Ian W. Brock, Angela Cox, Peter Hillemanns, Johann H. Karstens, Peter Schürmann, Thilo Dörk, Javier Benítez, Jose Ignacio Arias Pérez, M. Pilar Zamora, Núria Malats, Zachary Fredericksen, Rebecca Hein, Gianluca Severi, Fergus J. Couch, Montserrat García-Closas, Ellen L. Goode, and Roger L. Milne
Abstract: PDF file - 137K
Published: 2023

34. Supplementary Methods, Tables 1 - 6 from A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Author: Alice S. Whittemore, Nancy J. Cox, Douglas F. Easton, Dan Nicolae, Fernando Rivadeneira, Andre G. Uitterlinden, Hanne Meijers-Heijboer, Quinten Waisfisz, Paul Pharoah, Alison M. Dunning, Clare Turnbull, Nazneen Rahman, Jianjun Liu, Astrid Irwanto, Kamila Czene, Per Hall, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna, Norbert Dahmen, Dieter Flesch-Janys, Jennifer Stone, Quang Minh Bui, Daniel F. Schmidt, Enes Makalic, Rebecca Hein, Lars Beckmann, Magdalena Lochmann, Bertram Müller-Myhsok, Rita K. Schmutzler, Alfons Meindl, Stephen J. Chanock, David J. Hunter, Mark Lathrop, Isabel dos Santos Silva, Olivia Fletcher, Julian Peto, Daniel J. Park, Carmel Apicella, Kyriaki Michailidou, Polly Newcomb, Noralane M. Lindor, Mark Jenkins, Robert Haile, Steve Gallinger, David Duggan, David Conti, Eunjung Lee, Regina M. Santella, Graham G. Giles, Melissa C. Southey, Julia A. Knight, Graham Casey, Daniela Seminara, Duncan C. Thomas, Marilie D. Gammon, Giske Ursin, Kathi Malone, Esther M. John, John L. Hopper, Irene Andrulis, Jenny Chang-Claude, Stephanie Melkonian, Maria Argos, Rachelle Brutus, Shantanu Roy, Farzana Jasmine, Jianxin Shi, Anna Felberg, Valerie McGuire, Eric Gamazon, Lin Tong, Brandon L. Pierce, Muhammad G. Kibriya, Jerry Halpern, and Habibul Ahsan
Abstract: PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and
Published: 2023

35. Supplementary Table 1 from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author: Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
Abstract: Variants selected for replication
Published: 2023

36. Supplementary Material: Funding, Acknowledgements, Consortia, and Bioinformatics Tools Funding sources from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author: Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
Abstract: Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used
Published: 2023

37. Supplementary Table 1 from Association Study of Prostate Cancer Susceptibility Variants with Risks of Invasive Ovarian, Breast, and Colorectal Cancer

Author: Paul D.P. Pharoah, Alison M. Dunning, Simon A. Gayther, Douglas F. Easton, Rosalind A. Eeles, Nazneen Rahman, Sarah Hines, Clare Turnbull, Bruce A.J. Ponder, Valerie McGuire, Alice S. Whittemore, Estrid Hogdall, Eva Wozniak, Richard A. DiCioccio, Susanne Krüger Kjaer, Susan J. Ramus, Shahana Ahmed, Thibaud Koessler, and Honglin Song
Abstract: Supplementary Table 1 from Association Study of Prostate Cancer Susceptibility Variants with Risks of Invasive Ovarian, Breast, and Colorectal Cancer
Published: 2023

38. Supplementary Figure 1 from Mammographic Breast Density and Breast Cancer: Evidence of a Shared Genetic Basis

Author: Douglas F. Easton, Nazneen Rahman, Rulla M. Tamimi, John L. Hopper, Per Hall, Norman F. Boyd, Kamila Czene, Louise Eriksson, Jingmei Li, Jennifer Stone, Melissa C. Southey, Carmel Apicella, Fergus J. Couch, Elizabeth J. Atkinson, Christopher G. Scott, Celine M. Vachon, Lisa J. Martin, Andrew D. Paterson, Johanna Rommens, Nicholas J. Wareham, Ruth J. Loos, Robert N. Luben, Ruth M.L. Warren, Jean Leyland, Judith Brown, Clare Turnbull, Sara Lindström, Kyriaki Michailidou, Deborah J. Thompson, and Jajini S. Varghese
Abstract: PDF file - 275K, Significance of the mammographic breast density polygenic risk score (PRS) for the prediction of breast cancer risk, according to percent cut-off of SNPs used in the PRS: sensitivity analysis using imputed case:control genotype dosages.
Published: 2023

39. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author: Claire Palles, Hannah D. West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith E. Grolleman, Erik A.M. Jansen, Helen Curley, Laura Chegwidden, Edward H. Arbe-Barnes, Nicola Lander, Rebekah Truscott, Judith Pagan, Ashish Bajel, Kitty Sherwood, Lynn Martin, Huw Thomas, Demetra Georgiou, Florentia Fostira, Yael Goldberg, David J. Adams, Simone A.M. van der Biezen, Michael Christie, Mark Clendenning, Laura E. Thomas, Constantinos Deltas, Aleksandar J. Dimovski, Dagmara Dymerska, Jan Lubinski, Khalid Mahmood, Rachel S. van der Post, Mathijs Sanders, Jürgen Weitz, Jenny C. Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo-Pac, Giulio Caravagna, William Cross, Daniel Chubb, Anna Frangou, Andreas J. Gruber, Ben Kinnersley, Boris Noyvert, David Church, Trevor Graham, Richard Houlston, Nuria Lopez-Bigas, Andrea Sottoriva, David Wedge, Mark A. Jenkins, Roland P. Kuiper, Andrew W. Roberts, Jeremy P. Cheadle, Marjolijn J.L. Ligtenberg, Nicoline Hoogerbrugge, Viktor H. Koelzer, Andres Dacal Rivas, Ingrid M. Winship, Clara Ruiz Ponte, Daniel D. Buchanan, Derek G. Power, Andrew Green, Ian P.M. Tomlinson, Julian R. Sampson, Ian J. Majewski, Richarda M. de Voer, Hematology, Palles, Claire, West, Hannah D, Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E, Jansen, Erik A M, Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H, Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J, van der Biezen, Simone A M, Christie, Michael, Clendenning, Mark, Thomas, Laura E, Deltas, Constantino, Dimovski, Aleksandar J, Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S, Sanders, Mathij, Weitz, Jürgen, Taylor, Jenny C, Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J, Kinnersley, Ben, Noyvert, Bori, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Sottoriva, Andrea, Wedge, David, Jenkins, Mark A, Kuiper, Roland P, Roberts, Andrew W, Cheadle, Jeremy P, Ligtenberg, Marjolijn J L, Hoogerbrugge, Nicoline, Koelzer, Viktor H, Rivas, Andres Dacal, Winship, Ingrid M, Ponte, Clara Ruiz, Buchanan, Daniel D, Power, Derek G, Green, Andrew, Tomlinson, Ian P M, Sampson, Julian R, Majewski, Ian J, and de Voer, Richarda M
Subjects: Uveal Neoplasms, Endodeoxyribonucleases, 5′-methylcytosine deamination, polyposis, colorectal cancer, Colorectal Neoplasm, mutational signature, Germ Cell, Endodeoxyribonuclease, Germ Cells, Adenomatous Polyposis Coli, ddc:570, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], mutator phenotype, Genetics, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Colorectal Neoplasms, polyposi, Genetics (clinical), Human
Abstract: Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access) We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Published: 2022

40. UK recommendations forSDHAgermline genetic testing and surveillance in clinical practice

Author: Helen Hanson, Miranda Durkie, Fiona Lalloo, Louise Izatt, Terri P McVeigh, Jackie A Cook, Carole Brewer, James Drummond, Samantha Butler, Treena Cranston, Ruth Casey, Tricia Tan, Daniel Morganstein, Diana M Eccles, Marc Tischkowitz, Clare Turnbull, Emma Roisin Woodward, and Eamonn R Maher
Subjects: Genetics, Genetics (clinical)
Abstract: SDHApathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. MostSDHAPGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies ofSDHAPGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance forSDHAPGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely moreSDHAPGV carriers will be identified in patients with tumours not strongly associated withSDHA,or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expertSDHAworking group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management ofSDHAPGV carriers in clinical practice.
Published: 2022

41. Realistic expectations are key to realising the benefits of polygenic scores

Author: Amit Sud, Rachel H Horton, Aroon D Hingorani, Ioanna Tzoulaki, Clare Turnbull, Richard S Houlston, and Anneke Lucassen
Subjects: Risk, Multifactorial Inheritance, General & Internal Medicine, Humans, Disease, 1103 Clinical Sciences, General Medicine, 1117 Public Health and Health Services
Abstract: We must not let enthusiasm around polygenic scores allow us to forget other factors that are bigger, more modifiable, and relevant for everyone, argue Amit Sud, Rachel Horton, and colleagues
Published: 2023

42. Safety and adverse events following non-invasive electrical brain stimulation in stroke: a systematic review

Author: Clare Turnbull, Aafke Boomsma, Rachel Milte, Tasha R Stanton, Brenton Hordacre, Turnbull, Clare, Boomsma, Aafke, Milte, Rachel, Stanton, Tasha R, and Hordacre, Brenton
Subjects: Community and Home Care, safety, Rehabilitation, Neurology (clinical), noninvasive brain stimulation, stroke
Abstract: Refereed/Peer-reviewed Background: Noninvasive electrical stimulation (ES) could have therapeutic potential in stroke recovery. However, there is no comprehensive evaluation of adverse events. This study systematically searched the literature to document frequency and prevalence of adverse events. A secondary aim was to explore associations between adverse events and ES parameters or participant characteristics. Methods: Databases were searched for studies evaluating ES in adults with stroke. All included studies were required to report on adverse events. Extracted data were: (1) study design; (2) adverse events; (3) participant characteristics; (4) ES parameters. Results: Seventy-five studies were included. Adverse events were minor in nature. The most frequently reported adverse events were tingling (37.3% of papers), burning (18.7%), headaches (14.7%) and fatigue (14.7%). Cathodal stimulation was associated with greater frequency of itching (p = .02), intensities of 1-2 mA with increased tingling (p = .04) and discomfort (p = .03), and current density = 0.37). Individual participants were more likely to report adverse events with increasing current density (r = 0.99, p = .001). Two severe adverse events were noted (a seizure and percutaneous endoscopic gastrostomy placement). Conclusion: ES appears safe in people with stroke as reported adverse events were predominantly minor in nature. An adverse events questionnaire is proposed to enable a more comprehensive and nuanced analysis of the frequency and prevalence of adverse events.
Published: 2023

43. Insights for precision healthcare from the 100,000 Genomes Cancer Programme

Author: Nirupa Murugaesu, Alona Sosinsky, John Ambrose, William Cross, Clare Turnbull, Shirley Henderson, J Jones, Angela Hamblin, Prabhu Arumugam, Georgia Chan, Daniel Chubb, Boris Noyvert, Jonathan Mitchell, Susan Walker, Katy Bowman, Dorota Pasko, Marianna Pereira, Nadezda Volkova, Antonio Rueda-Martin, Daniel Perez Gil, Javier Lopez, John Pullinger, Afshan Siddiq, Tala Zainy, Tasnim Choudhury, Augusto Rendon, Tom Fowler, Sandra Hing, Zandra Deans, Genomics England Research Consortium Genomics England Resear Consortium, Sue Hill, and Mark Caulfield
Abstract: The Cancer Programme of the 100,000 Genomes Project was a transformational UK government initiative that aimed to bring whole genome sequencing (WGS) to cancer patients and evaluate the opportunities for precision cancer care. Genomics England, in partnership with NHS England, generated whole genome analyses for 13,880 solid tumours across 33 different cancer types, and genomic data were linked with real-world health data within a secure national research environment. Here, we report the overall findings of the programme, focusing on clinical actionability and potential wider clinical significance. We found variation between cancer types in the incidence of somatic mutations of different types in genes currently recommended for standard-of-care testing. For example, 94% of glioblastoma multiforme cases had small variants and 54% had copy number aberrations (CNAs) in at least one gene recommended for clinical testing, whereas sarcoma was found to have the highest proportion of actionable structural variants (13%). We confirmed the importance of utilising pan- genomic markers, such as mutational signatures, with 51% of high grade serous ovarian cancer cases showing homologous recombination deficiency, 13% of which were associated with pathogenic germline variants, indicating the value of combined somatic and germline analyses. We also observed a significant co-occurrence of somatic small variants and CNAs in several known oncogenes including EGFR, GNAS, BRAF, and KRAS. Our findings demonstrate the value of combining genomic testing with real world clinical and treatment data to inform clinical recommendations for genomic testing in cancer, to enable survival analysis and improve understanding of the long-term effects of clinical cancer genomics on patient outcomes.
Published: 2022

44. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

Author: Gill Wilson, Anna de Burca, Marta Bleda, Lucy R. Wedderburn, Matthew Welland, Kathleen Stirrups, Valentina Cipriani, Kerrie Woods, Vijeya Ganesan, Susan Hill, Rosaline Quinlivan, Georgia Chan, Mehul T. Dattani, Robert McFarland, Graeme C.M. Black, Rutendo Mapeta, Augusto Rendon, Francesco Muntoni, James O.J. Davies, Mina Ryten, Rebecca E. Foulger, Arianna Tucci, Dina Halai, Tom Fowler, Noemi B.A. Roy, Sarah Leigh, Dragana Josifova, Philip Twiss, Ana L.T. Tavares, Zerin Hyder, Detlef Bockenhauer, Patrick Yu-Wai-Man, Lara Abulhoul, Nikolas Pontikos, Anthony T. Moore, Huw R. Morris, Patrick F. Chinnery, Nicholas W. Wood, Ellen A. Thomas, Shehla Mohammed, Sofia Douzgou, Tanya Lam, Kate Gibson, Robert Sarkany, Teofila Bueser, Wei Wei, Siddharth Banka, Alexander Broomfield, Hiva Fassihi, Nils Koelling, Carolyn Campbell, James Buchanan, Melita Irving, Sandrine Compeyrot-Lacassagne, Karola Rehmström, Austen Worth, Nikhil Thapar, Andrew R. Webster, Paul Brennan, Rita Horvath, Gavin Arno, Richard H Scott, Sam Malka, Andrew O.M. Wilkie, Sofie Ashford, Maria Bitner-Glindzicz, Jana Vandrovcova, William G. Newman, Caroline F. Wright, Andrew M. Schaefer, Roger F.L. James, Robert W. Taylor, Melanie Babcock, Arjune Sen, Emma Baple, Ellen M. McDonagh, Stephanie Grunewald, Loukas Moutsianas, Melissa A. Haendel, Olivera Spasic-Boskovic, Eleanor G. Seaby, Anna Need, Clarissa Pilkington, Sarah Wordsworth, Shamima Rahman, Christine Patch, Colin Wallis, Kristina Ibanez, Bishoy Habib, Eik Haraldsdottir, Huw B. Thomas, Razvan Sultana, Andrea H. Németh, Agata Wolejko, Claire Palles, Phil Beales, Adam C. Shaw, Letizia Vestito, Emily Li, Sarah Rose, Sarah Hunter, Angela Matchan, Genevieve Say, Dalia Kasperaviciute, Henry Houlden, Raymond T. O’Keefe, R. Andres Floto, Jill Clayton-Smith, John B. Taylor, Hywel J. Williams, Volker Straub, Val Davison, Helen Savage, John Chisholm, Eleanor Dewhurst, Charles Crichton, Andrea Haworth, Clare Turnbull, Carolyn Tregidgo, Carme Camps, Christopher Penkett, Emer O’Connor, Georgina Hall, Lyn S. Chitty, Sally Halsall, Andrew D. Mumford, Annette G. Wagner, Eleanor Williams, Mark Bale, Julius O. Jacobsen, Willem H. Ouwehand, Charu Deshpande, Gavin Burns, Smita Y. Patel, James Polke, Thiloka Ratnaike, Gavin Fuller, John Burn, Kenneth E. S. Poole, Emma Footitt, John R. Bradley, Suzanne Wood, Russell J. Grocock, Jenny C. Taylor, Louise Izatt, Kikkeri N. Naresh, Katherine R. Smith, Nigel Burrows, Katrina Newland, Peter N. Robinson, Sarju G. Mehta, Michael A. Simpson, Michael R. Barnes, Pilar Cacheiro, Olivia Niblock, Tracy Lester, Dimitris Polychronopoulos, Helen Brittain, John A. Sayer, Antonio Martin, Eshika Haque, Sean Humphray, Douglass M. Turnbull, Damian Smedley, Andrew Devereau, Stefan Gräf, Sian Ellard, Ivone U.S. Leong, Martin G. Reese, Matthias Wielscher, Louise C. Daugherty, Perry M. Elliott, F. Lucy Raymond, Cecilia Compton, David Bentley, Catherine Snow, James Welch, Frances Flinter, Dom McMullan, Mark J. Caulfield, Paul Aurora, Mark Gurnell, Mary Kasanicki, I. Karen Temple, Michel Michaelides, Deborah Ruddy, Leema Robert, Janice Yip, Grainne S. Gorman, Andrew C. Browning, Richard Quinton, Maureen Cleary, Jamie M. Ellingford, Angela Douglas, Christopher Boustred, and Investigators, The 100,000 Genomes Project Pilot
Subjects: Adult, Male, Proband, medicine.medical_specialty, Adolescent, Pilot Projects, Genomics, Polymerase Chain Reaction, Genome, State Medicine, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Health care, Human Phenotype Ontology, Humans, Medicine, Child, Exome sequencing, 030304 developmental biology, Family Characteristics, 0303 health sciences, Whole Genome Sequencing, Genome, Human, business.industry, Genetic Variation, Rare Diseases/diagnosis, General Medicine, Middle Aged, United Kingdom, 3. Good health, Child, Preschool, Family medicine, Medical genetics, Female, business, Bristol, 030217 neurology & neurosurgery, Rare disease
Abstract: BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
Published: 2021

45. Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score

Author: Etienne Rouleau, Luis Garcia Palacios, Clare Turnbull, Joaquin Mateo, Jorge Antonio Lopez, Alexander D Fine, Ethan Sokol, Fabrice Andre, Benedikt Westphalen, Volker Heinemann, Shridar Ganesan, Institut Català de la Salut, [Westphalen CB, Heinemann V] Comprehensive Cancer Center Munich and Department of Medicine III, Ludwig Maximilian University of Munich, Munich, Germany. [Fine AD] Cancer Genomics Research, Foundation Medicine, Inc., Cambridge, Massachusetts. [André F, Rouleau E] Institut Gustave Roussy, INSERM U981, Universite Paris Saclay, Villejuif, France. [Ganesan S] Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey. [Mateo J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Heterozygote, ADN - Reparació, Cancer Research, endocrine system diseases, DNA Repair, PALB2, GLOH, Breast Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Biology, Article, neoplasias [ENFERMEDADES], Loss of heterozygosity, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Genetic Predisposition to Disease, Recombinació ADN, Homologous Recombination, Càncer, CHEK2, ATRX, BAP1, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Prostatic Neoplasms, Recombinational DNA Repair, FANCA, Neoplasms [DISEASES], Oncology, Cancer research, RAD51C
Abstract: Purpose: To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes beyond BRCA1 and BRCA2. Experimental Design: Genomic profiling using a targeted next-generation sequencing assay examining 324–465 genes (FoundationOne, FoundationOne Heme, and FoundationOne CDx; Foundation Medicine, Inc.) was performed in a cohort of 160,790 samples across different tumor types. Zygosity predictions and gLOH status were calculated and linked with alterations in 18 HRR-associated genes (BRCA1, BRCA2, PALB2, BARD1, ATR, ATRX, ATM, BAP1, RAD51B, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC, MRE11) and other genomic features, using Fisher's exact test and Mann–Whitney U tests. Results: We identified a strong correlation between elevated gLOH and biallelic alterations in a core set of HRR-associated genes beyond BRCA1 and BRCA2, such as BARD1, PALB2, FANCC, RAD51C, and RAD51D (particularly in breast, ovarian, pancreatic, and prostate cancer). Monoallelic/heterozygous alterations in HRR-associated genes were not associated with elevated gLOH. gLOH was also independently associated with TP53 loss. Co-occurrence of TP53 loss and alterations in HRR-associated genes, and combined loss of TP53-PTEN or TP53-RB1, was associated with a higher gLOH than each of the events separately. Conclusions: Biallelic alterations in core HRR-associated genes are frequent, strongly associated with elevated gLOH, and enriched in breast, ovarian, pancreatic, and prostate cancer. This analysis could inform the design of the next generation of clinical trials examining DNA repair–targeting agents, including PARP inhibitors.
Published: 2021

46. Reclassification of clinically-detected sequence variants:Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK)

Author: Lucy Loong, Alice Garrett, Sophie Allen, Subin Choi, Miranda Durkie, Alison Callaway, James Drummond, George J. Burghel, Rachel Robinson, Beth Torr, Ian R. Berry, Andrew J. Wallace, Diana M. Eccles, Sian Ellard, Emma Baple, D. Gareth Evans, Emma R. Woodward, Anjana Kulkarni, Fiona Lalloo, Marc Tischkowitz, Anneke Lucassen, Helen Hanson, and Clare Turnbull
Subjects: Neoplasms, Genetic Variation, Humans, Reclassification, Recontact, Genetic Predisposition to Disease, Reinterpretation, Genetic Testing, Variant, Laboratories, Classification, Genetics (clinical)
Abstract: PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely.METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification.RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score.CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.
Published: 2022

47. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes

Author: Helen, Hanson, Anjana, Kulkarni, Lucy, Loong, Grace, Kavanaugh, Bethany, Torr, Sophie, Allen, Munaza, Ahmed, Antonis C, Antoniou, Ruth, Cleaver, Tabib, Dabir, D Gareth, Evans, Ellen, Golightly, Rosalyn, Jewell, Kelly, Kohut, Ranjit, Manchanda, Alex, Murray, Jennie, Murray, Kai-Ren, Ong, Adam N, Rosenthal, Emma Roisin, Woodward, Diana M, Eccles, Clare, Turnbull, Marc, Tischkowitz, and Karin, Williamson
Abstract: Germline pathogenic variants (GPVs) in the cancer predisposition genes
Published: 2022

48. Risk of developing a second primary cancer in male breast cancer survivors: a systematic review and meta-analysis

Author: Isaac Allen, Hend Hassan, Eleni Sofianopoulou, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou, Allen, Isaac [0000-0003-4640-3617], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Male, Cancer Research, Oncology, Risk Factors, Incidence, Humans, Neoplasms, Second Primary, Survivors, Middle Aged, Colorectal Neoplasms, Retrospective Studies, Breast Neoplasms, Male
Abstract: BACKGROUND: With increasing survival after cancer diagnoses, second primary cancers (SPCs) are becoming more prevalent. We investigated the incidence and site of non-breast SPC risks following male breast cancer (BC). METHODS: PubMed, Embase and Web of Science were systematically searched for studies reporting standardised incidence ratios (SIRs) for SPCs published by March 2022. Meta-analyses used the generic inverse-variance method, assuming a random-effects model. We evaluated SIRs for overall SPCs, site-specific risks, by age at BC onset, time since BC onset and geographic region. We assessed study quality using routine techniques. RESULTS: Eight population-based retrospective cohort studies were identified. SIRs ranged from 1.05 to 2.17. The summary SIR estimate was 1.27 (95% CI: 1.03-1.56, I2: 86%), and there were increased colorectal (SIR: 1.29, 95% CI: 1.03-1.61), pancreatic (SIR: 1.64, 95% CI: 1.05-2.55) and thyroid (SIR: 5.58, 95% CI: 1.04-30.05) SPC risks. When an outlying study was excluded, the summary SIR for men diagnosed with BC before age 50 was 1.50 (95% CI: 1.21-1.85), significantly higher than men diagnosed at older ages (SIR: 1.14, 95% CI: 0.98-1.33). CONCLUSIONS: Male BC survivors are at elevated risks of developing second primary colorectal, pancreatic and thyroid cancers. The estimates may assist their clinical management and guide decisions on genetic testing., CRUK Catalyst Award CanGene-CanVar (C61296/A27223).
Published: 2022
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49. A digital pathway for genetic testing in UK NHS patients with cancer:BRCA-DIRECT randomised study internal pilot

Author: Bethany Torr, Christopher Jones, Subin Choi, Sophie Allen, Grace Kavanaugh, Monica Hamill, Alice Garrett, Suzanne MacMahon, Lucy Loong, Alistair Reay, Lina Yuan, Mikel Valganon Petrizan, Kathryn Monson, Nicky Perry, Lesley Fallowfield, Valerie Jenkins, Rochelle Gold, Amy Taylor, Rhian Gabe, Jennifer Wiggins, Anneke Lucassen, Ranjit Manchanda, Ashu Gandhi, Angela George, Michael Hubank, Zoe Kemp, D Gareth Evans, Stephen Bremner, and Clare Turnbull
Subjects: Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Genetics, Humans, Female, Breast Neoplasms, Genetic Testing, Referral and Consultation, State Medicine, United Kingdom, Genetics (clinical), Telephone
Abstract: BackgroundGermline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing.MethodsWe designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing ofBRCA1/BRCA2/PALB2(BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway).ResultsUptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with ConclusionPilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses.Trial registration numberISRCTN87845055.
Published: 2022

50. Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records

Author: Lucy Loong, Catherine Huntley, Fiona McRonald, Francesco Santaniello, Joanna Pethick, Bethany Torr, Sophie Allen, Oliver Tulloch, Shilpi Goel, Brian Shand, Tameera Rahman, Margreet Luchtenborg, Alice Garrett, Richard Barber, Tina Bedenham, David Bourn, Kirsty Bradshaw, Claire Brooks, Jonathan Bruty, George J Burghel, Samantha Butler, Chris Buxton, Alison Callaway, Jonathan Callaway, James Drummond, Miranda Durkie, Joanne Field, Lucy Jenkins, Terri P McVeigh, Roger Mountford, Rodney Nyanhete, Evgenia Petrides, Rachel Robinson, Tracy Scott, Victoria Stinton, James Tellez, Andrew J Wallace, Laura Yarram-Smith, Kate Sahan, Nina Hallowell, Diana M Eccles, Paul Pharoah, Marc Tischkowitz, Antonis C Antoniou, D Gareth Evans, Fiona Lalloo, Gail Norbury, Eva Morris, John Burn, Steven Hardy, Clare Turnbull, Huntley, Catherine [0000-0002-3797-7398], Torr, Bethany [0000-0003-3487-9749], Garrett, Alice [0000-0001-8942-283X], Burghel, George J [0000-0001-9360-8194], Eccles, Diana M [0000-0002-9935-3169], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis C [0000-0001-9223-3116], Evans, D Gareth [0000-0002-8482-5784], and Apollo - University of Cambridge Repository
Subjects: Genetics, Population, Genetics, Medical, Neoplasms, Databases, Genetic, Genetics, Humans, Genetic Testing, Genomics, Laboratories, DNA Mismatch Repair, Genetics (clinical), State Medicine
Abstract: Peer reviewed: True, OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
Published: 2022

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