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Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline …e PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 \times 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 \times 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 \times 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 \times 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 \times 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Authors: Xin Yang, Goska Leslie, Alicja Doroszuk, Sandra Schneider, Jamie Allen, Brennan Decker, Alison M. Dunning, James Redman, James Scarth, Inga Plaskocinska, Craig Luccarini, Mitul Shah, Karen Pooley, Leila Dorling, Andrew Lee, Muriel A. Adank, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Peter Ang, Julian Barwell, Jonine L. Bernstein, Kristie Bobolis, Åke Borg, Carl Blomqvist, Kathleen B. M. Claes, Patrick Concannon, Adeline Cuggia, Julie O. Culver, Francesca Damiola, Antoine de Pauw, Orland Diez, Jill S. Dolinsky, Susan M. Domchek, Christoph Engel, D. Gareth Evans, Florentia Fostira, Judy Garber, Lisa Golmard, Ellen L. Goode, Stephen B. Gruber, Eric Hahnen, Christopher Hake, Tuomas Heikkinen, Judith E. Hurley, Ramunas Janavicius, Zdenek Kleibl, Petra Kleiblova, Irene Konstantopoulou, Anders Kvist, Holly Laduca, Ann S. G. Lee, Fabienne Lesueur, Eamonn R. Maher, Arto Mannermaa, Siranoush Manoukian, Rachel McFarland, Wendy McKinnon, Alfons Meindl, Kelly Metcalfe, Nur Aishah Mohd Taib, Jukka Moilanen, Katherine L. Nathanson, Susan Neuhausen, Pei Sze Ng, Tu Nguyen-Dumont, Sarah M. Nielsen, Florian Obermair, Kenneth Offit, Olufunmilayo I. Olopade, Laura Ottini, Judith Penkert, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Vilius Rudaitis, Lucy Side, Rachel Silva-Smith, Valentina Silvestri, Anne-Bine Skytte, Thomas Slavin, Jana Soukupova, Carlo Tondini, Alison H. Trainer, Gary Unzeitig, Lydia Usha, Thomas van Overeem Hansen, James Whitworth, Marie Wood, Cheng Har Yip, Sook-Yee Yoon, Amal Yussuf, George Zogopoulos, David Goldgar, John L. Hopper, Georgia Chenevix-Trench, Paul Pharoah, Sophia H. L. George, Judith Balmaña, Claude Houdayer, Paul James, Zaki El-Haffaf, Hans Ehrencrona, Marketa Janatova, Paolo Peterlongo, Heli Nevanlinna, Rita Schmutzler, Soo-Hwang Teo, Mark Robson, Tuya Pal, Fergus Couch, Jeffrey N. Weitzel, Aaron Elliott, Melissa Southey, Robert Winqvist, Douglas F. Easton, William D. Foulkes, Antonis C. Antoniou, Marc Tischkowitz

Date Published: 1st Mar 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type …e 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. OBJECTIVES AND DESIGN Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. RESULTS In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non-insulin-treated diabetes (OR 1.37; P = 0.002). CONCLUSIONS Genetic variation in the HLA class II locus exerts risk and protective effects on non-insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.

Authors: Thomas Jacobi, Lucas Massier, Nora Klöting, Katrin Horn, Alexander Schuch, Peter Ahnert, Christoph Engel, Markus Löffler, Ralph Burkhardt, Joachim Thiery, Anke Tönjes, Michael Stumvoll, Matthias Blüher, Ilias Doxiadis, Markus Scholz, Peter Kovacs

Date Published: 1st Mar 2020

Publication Type: Journal article

Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS We … We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 \times 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 \times 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 \times 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Authors: Xin Yang, Honglin Song, Goska Leslie, Christoph Engel, Eric Hahnen, Bernd Auber, Judit Horváth, Karin Kast, Dieter Niederacher, Clare Turnbull, Richard Houlston, Helen Hanson, Chey Loveday, Jill S. Dolinsky, Holly Laduca, Susan J. Ramus, Usha Menon, Adam N. Rosenthal, Ian Jacobs, Simon A. Gayther, Ed Dicks, Heli Nevanlinna, Kristiina Aittomäki, Liisa M. Pelttari, Hans Ehrencrona, Åke Borg, Anders Kvist, Barbara Rivera, Thomas v. O. Hansen, Malene Djursby, Andrew Lee, Joe Dennis, David D. Bowtell, Nadia Traficante, Orland Diez, Judith Balmaña, Stephen B. Gruber, Georgia Chenevix-Trench, Allan Jensen, Susanne K. Kjær, Estrid Høgdall, Laurent Castéra, Judy Garber, Ramunas Janavicius, Ana Osorio, Lisa Golmard, Ana Vega, Fergus J. Couch, Mark Robson, Jacek Gronwald, Susan M. Domchek, Julie O. Culver, Miguel de La Hoya, Douglas F. Easton, William D. Foulkes, Marc Tischkowitz, Alfons Meindl, Rita K. Schmutzler, Paul D. P. Pharoah, Antonis C. Antoniou

Date Published: 28th Feb 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: results from The BRCA1 and BRCA2 Cohort Consortium
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examined …d these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential. METHODS Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HRP) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR=1.25,95%CI:1.01,1.55 and HRP=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk. CONCLUSIONS The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation. IMPACT This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

Authors: Hongyan Li, Mary Beth Terry, Antonis C. Antoniou, Kelly-Anne Phillips, Karin Kast, Thea M. Mooij, Christoph Engel, Catherine Noguès, Dominique Stoppa-Lyonnet, Christine Lasset, Pascaline Berthet, Veronique Mari, Olivier Caron, Daniel Barrowdale, Debra Frost, Carole Brewer, D. Gareth Evans, Louise Izatt, Lucy Side, Lisa Walker, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Hanne E. J. Meijers-Heijboer, Johan Jp Gille, Marinus J. Blok, Nicoline Hoogerbrugge, Mary B. Daly, Irene L. Andrulis, Saundra S. Buys, Esther M. John, Sue-Anne McLachlan, Michael Friedlander, Yen Y. Tan, Ana Osorio, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Brita Arver, Håkan Olsson, Rita K. Schmutzler, John L. Hopper, Roger L. Milne, Douglas F. Easton, Flora E. van Leeuwen, Matti A. Rookus, Nadine Andrieu, David E. Goldgar

Date Published: 5th Feb 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining … association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors: Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel R. Barnes, Jamie Allen, Siddhartha Kar, Karen A. Pooley, Joe Dennis, Kyriaki Michailidou, Constance Turman, Penny Soucy, Audrey Lemaçon, Michael Lush, Jonathan P. Tyrer, Maya Ghoussaini, Mahdi Moradi Marjaneh, Xia Jiang, Simona Agata, Kristiina Aittomäki, M. Rosario Alonso, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Bernd Auber, Paul L. Auer, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Amie M. Blanco, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ake Borg, Kristin Bosse, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Ian W. Brock, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Nicola J. Camp, Ian Campbell, Federico Canzian, Jason S. Carroll, Brian D. Carter, Jose E. Castelao, Jocelyne Chiquette, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, J. Margriet Collée, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Susan M. Domchek, Thilo Dörk, Isabel Dos-Santos-Silva, Arnaud Droit, Stéphane Dubois, Martine Dumont, Mercedes Duran, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Giuseppe Floris, Henrik Flyger, Lenka Foretova, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Gaetana Gambino, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Maria Grazia Tibiletti, Mark H. Greene, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Wei He, Catherine S. Healey, Bernadette A. M. Heemskerk-Gerritsen, Jane Heyworth, Peter Hillemanns, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, John L. Hopper, Anthony Howell, Guanmengqian Huang, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Judy Kirk, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Stella Koutros, Katerina Kubelka-Sabit, Ava Kwong, Kyriacos Kyriacou, Yael Laitman, Diether Lambrechts, Eunjung Lee, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annika Lindblom, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Jan Lubiński, Robert J. MacInnis, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Rebecca Mayes, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Austin Miller, Nicola Miller, Marco Montagna, Fernando Moreno, Kenneth Muir, Anna Marie Mulligan, Victor M. Muñoz-Garzon, Taru A. Muranen, Steven A. Narod, Rami Nassir, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Liene Nikitina-Zake, Aaron Norman, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Ana Osorio, V. Shane Pankratz, Janos Papp, Sue K. Park, Tjoung-Won Park-Simon, Michael T. Parsons, James Paul, Inge Sokilde Pedersen, Bernard Peissel, Beth Peshkin, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Miquel Angel Pujana, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Johanna Rantala, Rohini Rau-Murthy, Gad Rennert, Harvey A. Risch, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Estela Sánchez-Herrero, Dale P. Sandler, Marta Santamariña, Christobel Saunders, Elinor J. Sawyer, Maren T. Scheuner, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schöttker, Peter Schürmann, Christopher Scott, Rodney J. Scott, Leigha Senter, Caroline M. Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Christian F. Singer, Thomas P. Slavin, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Rulla M. Tamimi, Yen Yen Tan, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Nadine Tung, Maria Tzardi, Hans-Ulrich Ulmer, Celine M. Vachon, Christi J. van Asperen, Lizet E. van der Kolk, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Joseph Vijai, Maartje J. Vogel, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Hans Wildiers, Robert Winqvist, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, David Hunter, Paul D. P. Pharoah, Jenny Chang-Claude, Montserrat García-Closas, Marjanka K. Schmidt, Roger L. Milne, Vessela N. Kristensen, Juliet D. French, Stacey L. Edwards, Antonis C. Antoniou, Georgia Chenevix-Trench, Jacques Simard, Douglas F. Easton, Peter Kraft, Alison M. Dunning

Date Published: 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

The budgetary impact of genetic testing for hereditary breast cancer for the statutory health insurance
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Objectives: Potential opportunities and challenges of predictive genetic risk classification of healthy persons are currently discussed. However, the budgetary impact of rising demand is uncertain. … This project aims to evaluate budgetary consequences of predictive genetic risk classification for statutory health insurance in Germany. Methods: A Markov model was developed in the form of a cohort simulation. It analyzes a population of female relatives of hereditary breast cancer patients. Mutation carriers are offered intensified screening, women with a BRCA1 or BRCA2 mutation can decide on prophylactic mastectomy and/or ovarectomy. The model considers the following scenarios: (a) steady demand for predictive genetic testing, and (b) rising demand. Most input parameters are based on data of the German Consortium for Hereditary Breast and Ovarian Cancer. The model contains 49 health states, starts in 2015, and runs for 10 years. Prices were evaluated from the perspective of statutory health insurance. Results: Steady demand leads to an expenditure of \text€49.8 million during the 10-year period. Rising demands lead to additional expenses of \text€125.5 million. The model reveals the genetic analysis to be the main cost driver while cost savings in treatment costs of breast and ovarian cancer are indicated. Conclusions: The results contribute to close the knowledge gap concerning the budgetary consequences due to genetic risk classification. A rising demand leads to additional costs especially due to costs for genetic analysis. The model indicates budget shifts with cost savings due to breast and ovarian cancer treatment in the scenario of rising demands.

Authors: Silke Neusser, Beate Lux, Cordula Barth, Kathrin Pahmeier, Kerstin Rhiem, Rita Schmutzler, Christoph Engel, Jürgen Wasem, Stefan Huster, Peter Dabrock, Anja Neumann

Date Published: 2nd Dec 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed …d to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs). RESULTS We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P \textless 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD \textless 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P \textless 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P \textless 0.00001) was observed when stratified for an AAD \textless 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC. CONCLUSIONS Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.

Authors: Nana Weber-Lassalle, Julika Borde, Konstantin Weber-Lassalle, Judit Horváth, Dieter Niederacher, Norbert Arnold, Silke Kaulfuß, Corinna Ernst, Victoria G. Paul, Ellen Honisch, Kristina Klaschik, Alexander E. Volk, Christian Kubisch, Steffen Rapp, Nadine Lichey, Janine Altmüller, Louisa Lepkes, Esther Pohl-Rescigno, Holger Thiele, Peter Nürnberg, Mirjam Larsen, Lisa Richters, Kerstin Rhiem, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen, Jan Hauke

Date Published: 1st Dec 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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