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1. Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

Author

Yuwei Wang, Gwen M. H. E. Dackus, Efraim H. Rosenberg, Sten Cornelissen, Leonora W. de Boo, Annegien Broeks, Wim Brugman, Terry W. S. Chan, Paul J. van Diest, Michael Hauptmann, Natalie D. ter Hoeve, Olga I. Isaeva, Vincent M. T. de Jong, Katarzyna Jóźwiak, Roelof J. C. Kluin, Marleen Kok, Esther Koop, Petra M. Nederlof, Mark Opdam, Philip C. Schouten, Sabine Siesling, Charlaine van Steenis, Adri C. Voogd, Willem Vreuls, Roberto F. Salgado, Sabine C. Linn, and Marjanka K. Schmidt

Subjects
BRCA1 status, Tumor-infiltrating lymphocytes, Triple-negative breast cancer, Chemotherapy-naïve, Long-term outcomes, Risk classification, Medicine
Abstract

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

Published
2024
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2. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A. R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami Belhadj, Lieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, GEMO Study Collaborators, EMBRACE Collaborators, Marie-Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman, Megan Frone, Debra Frost, Judy Garber, Simon A. Gayther, Andrea Gehrig, Paul Gesta, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Eric Hahnen, Christopher R. Hake, Ute Hamann, Thomas V. O. Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J. Hulick, Evgeny N. Imyanitov, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, John W. M. Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C. Rodriguez, Karina Rønlund, Efraim H. Rosenberg, Maria Rossing, Rita K. Schmutzler, Payal D. Shah, Saba Sharif, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Alison H. Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N. Weitzel, Marike R. Wevers, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, and Logan C. Walker

Subjects
Biology (General), QH301-705.5
Abstract

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.

Published
2022
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3. Molecular characterization of gastric adenocarcinoma diagnosed in patients previously treated for Hodgkin lymphoma or testicular cancer

Author

Lisanne S. Rigter, Petur Snaebjornsson, Efraim H. Rosenberg, Estelle Altena, Nicole C. T. van Grieken, Berthe M. P. Aleman, Jan M. Kerst, Lindsay Morton, Michael Schaapveld, Gerrit A. Meijer, Flora E. van Leeuwen, Monique E. van Leerdam, and PALGA group

Subjects
Medicine, Science
Abstract

Introduction The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Methods Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature. Results Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). Conclusion Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive.

Published
2022

4. Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome

Author

Willemina R. Geurts‐Giele, Efraim H. Rosenberg, Anja van Rens, Monique E. van Leerdam, Winand N. Dinjens, and Fonnet E. Bleeker

Subjects
Lynch syndrome, MLH1, mosaicism, Genetics, QH426-470
Abstract

Abstract Background Lynch syndrome (LS) is caused by germline mismatch repair (MMR) gene mutations. De novo MMR gene mutations are rare, and somatic mosaicism in LS is thought to be infrequent. We describe the first case of somatic mosaicism by a de novo MLH1 mutation for a patient diagnosed with a rectosigmoid adenocarcinoma at age 31. Methods Twelve years after initial colorectal cancer diagnosis, tumor tissue of the patient was tested with sensitive next generation sequencing (NGS) analysis for the presence of somatic MMR mutations. Results In tumor tissue, an inactivating MLH1 mutation (c.518_519del; p.(Tyr173Trpfs*18)) was detected, which was also present at low level in the blood of the patient. In both parents, as well as the patient's sisters, the mutation was not present. Conclusion We show that low‐level mosaicism can be detected by using high‐coverage targeted NGS panels on constitutional and/or tumor DNA. This report illustrates that by using sensitive sequencing techniques, more cases of genetic diseases driven by mosaic mutations may be identified, with important clinical consequences for patients and family members.

Published
2019
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5. Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

Author

Wang, Yuwei, Dackus, Gwen M. H. E., Rosenberg, Efraim H., Cornelissen, Sten, de Boo, Leonora W., Broeks, Annegien, Brugman, Wim, Chan, Terry W. S., van Diest, Paul J., Hauptmann, Michael, ter Hoeve, Natalie D., Isaeva, Olga I., de Jong, Vincent M. T., Jóźwiak, Katarzyna, Kluin, Roelof J. C., Kok, Marleen, Koop, Esther, Nederlof, Petra M., Opdam, Mark, Schouten, Philip C., Siesling, Sabine, van Steenis, Charlaine, Voogd, Adri C., Vreuls, Willem, Salgado, Roberto F., Linn, Sabine C., and Schmidt, Marjanka K.

Published
2024
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6. A Likelihood Ratio Approach for Utilizing Case‐Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author

Zanti, Maria, O′Mahony, Denise G, Parsons, Michael T, Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brown, Melissa A, Buys, Saundra S, Canzian, Federico, Caputo, Sandrine M, Castelao, Jose E, Chang-Claude, Jenny, Collaborators, GC-HBOC study, Czene, Kamila, Daly, Mary B, De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Gentry-Maharaj, Aleksandra, Giele, Willemina RR Geurts-, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Garcia, Encarna B Gómez, Güendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Houdayer, Claude, Houlston, Richard S, Howell, Anthony, Investigators, ABCTB, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M, Kaaks, Rudolf, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Lacey, James V, Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L, Monteiro, Alvaro N, Murphy, Rachel A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Park, Sue K, James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U, Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H, Saloustros, Emmanouil, Sandler, Dale P, Schmidt, Marjanka K, Schmutzler, Rita K, and Shu, Xiao-Ou

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Genetic Testing, Prevention, Cancer, Human Genome, Women's Health, Breast Cancer, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Case-Control Studies, BRCA2 Protein, Genetic Predisposition to Disease, Female, BRCA1 Protein, Breast Neoplasms, Likelihood Functions, Genetic Variation, Penetrance, GC-HBOC study Collaborators, ABCTB Investigators, ACMG/AMP, BRCA, PS4, VUS, case-control, likelihood ratio, variant classification, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

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

Published
2023

7. RAD51B in Familial Breast Cancer.

Author

Liisa M Pelttari, Sofia Khan, Mikko Vuorela, Johanna I Kiiski, Sara Vilske, Viivi Nevanlinna, Salla Ranta, Johanna Schleutker, Robert Winqvist, Anne Kallioniemi, Thilo Dörk, Natalia V Bogdanova, Jonine Figueroa, Paul D P Pharoah, Marjanka K Schmidt, Alison M Dunning, Montserrat García-Closas, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, John L Hopper, Melissa C Southey, Efraim H Rosenberg, Peter A Fasching, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Harald Surowy, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Javier Benitez, Anna González-Neira, Susan L Neuhausen, Hoda Anton-Culver, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Thomas Brüning, Annika Lindblom, Sara Margolin, Arto Mannermaa, Jaana M Hartikainen, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Laurien Van Dyck, Hilde Janssen, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Emily Hallberg, Janet E Olson, Graham G Giles, Roger L Milne, Christopher A Haiman, Fredrick Schumacher, Jacques Simard, Martine Dumont, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Alicia Beeghly-Fadiel, Mervi Grip, Irene L Andrulis, Gord Glendon, Peter Devilee, Caroline Seynaeve, Maartje J Hooning, Margriet Collée, Angela Cox, Simon S Cross, Mitul Shah, Robert N Luben, Ute Hamann, Diana Torres, Anna Jakubowska, Jan Lubinski, Fergus J Couch, Drakoulis Yannoukakos, Nick Orr, Anthony Swerdlow, Hatef Darabi, Jingmei Li, Kamila Czene, Per Hall, Douglas F Easton, Johanna Mattson, Carl Blomqvist, Kristiina Aittomäki, and Heli Nevanlinna

Subjects
Medicine, Science
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2016
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8. Optimized whole-genome sequencing workflow for tumor diagnostics in routine pathology practice

Author

Samsom, Kris G., Bosch, Linda J. W., Schipper, Luuk J., Schout, Daoin, Roepman, Paul, Boelens, Mirjam C., Lalezari, Ferry, Klompenhouwer, Elisabeth G., de Langen, Adrianus J., Buffart, Tineke E., van Linder, Berit M. H., van Deventer, Kelly, van den Burg, Kay, Unmehopa, Unga, Rosenberg, Efraim H., Koster, Roelof, Hogervorst, Frans B. L., van den Berg, José G., Riethorst, Immy, Schoenmaker, Lieke, van Beek, Daphne, de Bruijn, Ewart, van der Hoeven, Jacobus J. M., van Snellenberg, Hans, van der Kolk, Lizet E., Cuppen, Edwin, Voest, Emile E., Meijer, Gerrit A., and Monkhorst, Kim

Published
2024
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9. Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics

Author

Koster, Roelof, Schipper, Luuk J., Giesbertz, Noor A.A., van Beek, Daphne, Mendeville, Matías, Samsom, Kris G., Rosenberg, Efraim H., Hogervorst, Frans B.L., Roepman, Paul, Boelens, Mirjam C., Bosch, Linda J.W., van den Berg, Jose G., Meijer, Gerrit A., Voest, Emile E., Cuppen, Edwin, Ruijs, Marielle W.G., van Wezel, Tom, van der Kolk, Lizet, and Monkhorst, Kim

Published
2024
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11. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Hakkaart, Christopher, Pearson, John F., Marquart, Louise, Dennis, Joe, Wiggins, George A. R., Barnes, Daniel R., Robinson, Bridget A., Mace, Peter D., Aittomäki, Kristiina, Andrulis, Irene L., Arun, Banu K., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Belhadj, Sami, Berger, Lieke, Blok, Marinus J., Boonen, Susanne E., Borde, Julika, Bradbury, Angela R., Brunet, Joan, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Chung, Wendy K., Claes, Kathleen B. M., Collonge-Rame, Marie-Agnès, Cook, Jackie, Cosgrove, Casey, Couch, Fergus J., Daly, Mary B., Dandiker, Sita, Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Dhawan, Mallika, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Donaldson, Alan, Eason, Jacqueline, Easton, Douglas F., Ehrencrona, Hans, Engel, Christoph, Evans, D. Gareth, Faust, Ulrike, Feliubadaló, Lidia, Fostira, Florentia, Friedman, Eitan, Frone, Megan, Frost, Debra, Garber, Judy, Gayther, Simon A., Gehrig, Andrea, Gesta, Paul, Godwin, Andrew K., Goldgar, David E., Greene, Mark H., Hahnen, Eric, Hake, Christopher R., Hamann, Ute, Hansen, Thomas V. O., Hauke, Jan, Hentschel, Julia, Herold, Natalie, Honisch, Ellen, Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, John, Esther M., Joseph, Vijai, Karlan, Beth Y., Kemp, Zoe, Kirk, Judy, Konstantopoulou, Irene, Koudijs, Marco, Kwong, Ava, Laitman, Yael, Lalloo, Fiona, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Mai, Phuong L., Manoukian, Siranoush, Mari, Véronique, Martens, John W. M., McGuffog, Lesley, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Montagna, Marco, Moserle, Lidia, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Nambot, Sophie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nguyen-Dumont, Tu, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Osorio, Ana, Ott, Claus-Eric, Park, Sue K., Parsons, Michael T., Pedersen, Inge Sokilde, Peixoto, Ana, Perez-Segura, Pedro, Peterlongo, Paolo, Pocza, Timea, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Rodriguez, Gustavo C., Rønlund, Karina, Rosenberg, Efraim H., Rossing, Maria, Schmutzler, Rita K., Shah, Payal D., Sharif, Saba, Sharma, Priyanka, Side, Lucy E., Simard, Jacques, Singer, Christian F., Snape, Katie, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Trainer, Alison H., Tripathi, Vishakha, Tung, Nadine, van Engelen, Klaartje, van Rensburg, Elizabeth J., Vega, Ana, Viel, Alessandra, Walker, Lisa, Weitzel, Jeffrey N., Wevers, Marike R., Chenevix-Trench, Georgia, Spurdle, Amanda B., Antoniou, Antonis C., and Walker, Logan C.

Published
2022
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12. Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

Author

Pathologie, Cancer, Pathologie Pathologen staf, Wang, Yuwei, Dackus, Gwen M H E, Rosenberg, Efraim H, Cornelissen, Sten, de Boo, Leonora W, Broeks, Annegien, Brugman, Wim, Chan, Terry W S, van Diest, Paul J, Hauptmann, Michael, Ter Hoeve, Natalie D, Isaeva, Olga I, de Jong, Vincent M T, Jóźwiak, Katarzyna, Kluin, Roelof J C, Kok, Marleen, Koop, Esther, Nederlof, Petra M, Opdam, Mark, Schouten, Philip C, Siesling, Sabine, van Steenis, Charlaine, Voogd, Adri C, Vreuls, Willem, Salgado, Roberto F, Linn, Sabine C, Schmidt, Marjanka K, Pathologie, Cancer, Pathologie Pathologen staf, Wang, Yuwei, Dackus, Gwen M H E, Rosenberg, Efraim H, Cornelissen, Sten, de Boo, Leonora W, Broeks, Annegien, Brugman, Wim, Chan, Terry W S, van Diest, Paul J, Hauptmann, Michael, Ter Hoeve, Natalie D, Isaeva, Olga I, de Jong, Vincent M T, Jóźwiak, Katarzyna, Kluin, Roelof J C, Kok, Marleen, Koop, Esther, Nederlof, Petra M, Opdam, Mark, Schouten, Philip C, Siesling, Sabine, van Steenis, Charlaine, Voogd, Adri C, Vreuls, Willem, Salgado, Roberto F, Linn, Sabine C, and Schmidt, Marjanka K

Published
2024

13. Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction

Author

Yiangou, Kristia, primary, Mavaddat, Nasim, additional, Dennis, Joe, additional, Zanti, Maria, additional, Wang, Qin, additional, Bolla, Manjeet K., additional, Abubakar, Mustapha, additional, Ahearn, Thomas U., additional, Andrulis, Irene L., additional, Anton-Culver, Hoda, additional, Antonenkova, Natalia N., additional, Arndt, Volker, additional, Aronson, Kristan J., additional, Augustinsson, Annelie, additional, Baten, Adinda, additional, Behrens, Sabine, additional, Bermisheva, Marina, additional, Berrington de Gonzalez, Amy, additional, Bialkowska, Katarzyna, additional, Boddicker, Nicholas, additional, Bodelon, Clara, additional, Bogdanova, Natalia V., additional, Bojesen, Stig E., additional, Brantley, Kristen D., additional, Brauch, Hiltrud, additional, Brenner, Hermann, additional, Camp, Nicola J., additional, Canzian, Federico, additional, Castelao, Jose E., additional, Cessna, Melissa H., additional, Chang-Claude, Jenny, additional, Chenevix-Trench, Georgia, additional, Chung, Wendy K., additional, Collaborators, NBCS, additional, Colonna, Sarah V., additional, Couch, Fergus J., additional, Cox, Angela, additional, Cross, Simon S., additional, Czene, Kamila, additional, Daly, Mary B., additional, Devilee, Peter, additional, Dork, Thilo, additional, Dunning, Alison M., additional, Eccles, Diana M., additional, Eliassen, A. Heather, additional, Engel, Christoph, additional, Eriksson, Mikael, additional, Evans, D. Gareth, additional, Fasching, Peter A., additional, Fletcher, Olivia, additional, Flyger, Henrik, additional, Fritschi, Lin, additional, Gago-Dominguez, Manuela, additional, Gentry-Maharaj, Aleksandra, additional, Gonzalez-Neira, Anna, additional, Guenel, Pascal, additional, Hahnen, Eric, additional, Haiman, Christopher A., additional, Hamann, Ute, additional, Hartikainen, Jaana M., additional, Ho, Vikki, additional, Hodge, James, additional, Hollestelle, Antoinette, additional, Honisch, Ellen, additional, Hooning, Maartje J., additional, Hoppe, Reiner, additional, Hopper, John L., additional, Howell, Sacha, additional, Howell, Anthony, additional, Investigators, ABCTB, additional, Investigators, kConFab, additional, Jakovchevska, Simona, additional, Jakubowska, Anna, additional, Jernstrom, Helena, additional, Johnson, Nichola, additional, Kaaks, Rudolf, additional, Khusnutdinova, Elza K., additional, Kitahara, Cari M., additional, Koutros, Stella, additional, Kristensen, Vessela N., additional, Lacey, James V., additional, Lambrechts, Diether, additional, Lejbkowicz, Flavio, additional, Lindblom, Annika, additional, Lush, Michael, additional, Mannermaa, Arto, additional, Mavroudis, Dimitrios, additional, Menon, Usha, additional, Murphy, Rachel A., additional, Nevanlinna, Heli, additional, Obi, Nadia, additional, Offit, Kenneth, additional, Park-Simon, Tjoung-Won, additional, Patel, Alpa V., additional, Peng, Cheng, additional, Peterlongo, Paolo, additional, Pita, Guillermo, additional, Plaseska-Karanfilska, Dijana, additional, Pylkas, Katri, additional, Radice, Paolo, additional, Rashid, Muhammad U., additional, Rennert, Gad, additional, Roberts, Eleanor, additional, Rodriguez, Juan, additional, Romero, Atocha, additional, Rosenberg, Efraim H., additional, Saloustros, Emmanouil, additional, Sandler, Dale P., additional, Sawyer, Elinor J., additional, Schmutzler, Rita K., additional, Scott, Christopher G., additional, Shu, Xiao-Ou, additional, Southey, Melissa C., additional, Stone, Jennifer, additional, Taylor, Jack A., additional, Teras, Lauren R., additional, van de Beek, Irma, additional, Willett, Walter, additional, Winqvist, Robert, additional, Zheng, Wei, additional, Vachon, Celine M., additional, Schmidt, Marjanka K., additional, Hall, Per, additional, MacInnis, Robert J., additional, Milne, Roger L., additional, Pharoah, Paul D.P., additional, Simard, Jacques, additional, Antoniou, Antonis C., additional, Easton, Douglas F., additional, and Michailidou, Kyriaki, additional

Published
2024
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14. RAD51B in Familial Breast Cancer.

Author

Pelttari, Liisa M, Khan, Sofia, Vuorela, Mikko, Kiiski, Johanna I, Vilske, Sara, Nevanlinna, Viivi, Ranta, Salla, Schleutker, Johanna, Winqvist, Robert, Kallioniemi, Anne, Dörk, Thilo, Bogdanova, Natalia V, Figueroa, Jonine, Pharoah, Paul DP, Schmidt, Marjanka K, Dunning, Alison M, García-Closas, Montserrat, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Hopper, John L, Southey, Melissa C, Rosenberg, Efraim H, Fasching, Peter A, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Nordestgaard, Børge G, Benitez, Javier, González-Neira, Anna, Neuhausen, Susan L, Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Brüning, Thomas, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Hartikainen, Jaana M, Chenevix-Trench, Georgia, kConFab/AOCS Investigators, Van Dyck, Laurien, Janssen, Hilde, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Peterlongo, Paolo, Hallberg, Emily, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Schumacher, Fredrick, Simard, Jacques, Dumont, Martine, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Zheng, Wei, Beeghly-Fadiel, Alicia, Grip, Mervi, Andrulis, Irene L, Glendon, Gord, Devilee, Peter, Seynaeve, Caroline, Hooning, Maartje J, Collée, Margriet, Cox, Angela, Cross, Simon S, Shah, Mitul, Luben, Robert N, Hamann, Ute, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Couch, Fergus J, Yannoukakos, Drakoulis, Orr, Nick, Swerdlow, Anthony, Darabi, Hatef, Li, Jingmei, Czene, Kamila, Hall, Per, Easton, Douglas F, Mattson, Johanna, Blomqvist, Carl, Aittomäki, Kristiina, and Nevanlinna, Heli

Subjects
kConFab/AOCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, DNA-Binding Proteins, Haplotypes, Heterozygote, Mutation, Missense, Polymorphism, Single Nucleotide, Middle Aged, Finland, Female, Male, Genotyping Techniques, General Science & Technology
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2016

15. Optimized whole-genome sequencing workflow for tumor diagnostics in routine pathology practice

Author

Samsom, Kris G., primary, Bosch, Linda J. W., additional, Schipper, Luuk J., additional, Schout, Daoin, additional, Roepman, Paul, additional, Boelens, Mirjam C., additional, Lalezari, Ferry, additional, Klompenhouwer, Elisabeth G., additional, de Langen, Adrianus J., additional, Buffart, Tineke E., additional, van Linder, Berit M. H., additional, van Deventer, Kelly, additional, van den Burg, Kay, additional, Unmehopa, Unga, additional, Rosenberg, Efraim H., additional, Koster, Roelof, additional, Hogervorst, Frans B. L., additional, van den Berg, José G., additional, Riethorst, Immy, additional, Schoenmaker, Lieke, additional, van Beek, Daphne, additional, de Bruijn, Ewart, additional, van der Hoeven, Jacobus J. M., additional, van Snellenberg, Hans, additional, van der Kolk, Lizet E., additional, Cuppen, Edwin, additional, Voest, Emile E., additional, Meijer, Gerrit A., additional, and Monkhorst, Kim, additional

Published
2023
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16. Impact of genetic counselling strategy on diagnostic yield and workload for genome sequencing-based tumour diagnostics

Author

Koster, Roelof, primary, Schipper, Luuk J., additional, Giesbertz, Noor A.A., additional, van Beek, Daphne, additional, Mendeville, Matías, additional, Samsom, Kris G., additional, Rosenberg, Efraim H., additional, Hogervorst, Frans B.L., additional, Roepman, Paul, additional, Boelens, Mirjam C., additional, Bosch, Linda J.W., additional, van den Berg, Jose G., additional, Meijer, Gerrit A., additional, Voest, Emile E., additional, Cuppen, Edwin, additional, Ruijs, Marielle W.G., additional, van Wezel, Tom, additional, van der Kolk, Lizet, additional, and Monkhorst, Kim, additional

Published
2023
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18. Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Author

Vincent M.T. de Jong, Yuwei Wang, Natalie D. ter Hoeve, Mark Opdam, Nikolas Stathonikos, Katarzyna Jóźwiak, Michael Hauptmann, Sten Cornelissen, Willem Vreuls, Efraim H. Rosenberg, Esther A. Koop, Zsuzsanna Varga, Carolien H.M. van Deurzen, Antien L. Mooyaart, Alicia Córdoba, Emma J. Groen, Joost Bart, Stefan M. Willems, Vasiliki Zolota, Jelle Wesseling, Anna Sapino, Ewa Chmielik, Ales Ryska, Annegien Broeks, Adri C. Voogd, Sherene Loi, Stefan Michiels, Gabe S. Sonke, Elsken van der Wall, Sabine Siesling, Paul J. van Diest, Marjanka K. Schmidt, Marleen Kok, Gwen M.H.E. Dackus, Roberto Salgado, Sabine C. Linn, RS: GROW - R1 - Prevention, RS: CAPHRI - R5 - Optimising Patient Care, Epidemiologie, TechMed Centre, Health Technology & Services Research, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Pathology

Subjects
Adult, Cancer Research, IMPACT, Triple Negative Breast Neoplasms, GERMLINE MUTATIONS, HISTOPATHOLOGY, CHEMOTHERAPY, Prognosis, Neoadjuvant Therapy, Lymphocytes, Tumor-Infiltrating, Oncology, SDG 3 - Good Health and Well-being, Chemotherapy, Adjuvant, SURVIVAL OUTCOMES, Biomarkers, Tumor, Humans, TRIAL, Prospective Studies
Abstract

PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population–based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

Published
2022

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

Author

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

Abstract

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

Published
2023

20. Data from 19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus

Author

Stevens, Kristen N., primary, Fredericksen, Zachary, primary, Vachon, Celine M., primary, Wang, Xianshu, primary, Margolin, Sara, primary, Lindblom, Annika, primary, Nevanlinna, Heli, primary, Greco, Dario, primary, Aittomäki, Kristiina, primary, Blomqvist, Carl, primary, Chang-Claude, Jenny, primary, Vrieling, Alina, primary, Flesch-Janys, Dieter, primary, Sinn, Hans-Peter, primary, Wang-Gohrke, Shan, primary, Nickels, Stefan, primary, Brauch, Hiltrud, primary, Ko, Yon-Dschun, primary, Fischer, Hans-Peter, primary, Schmutzler, Rita K., primary, Meindl, Alfons, primary, Bartram, Claus R., primary, Schott, Sarah, primary, Engel, Christoph, primary, Godwin, Andrew K., primary, Weaver, JoEllen, primary, Pathak, Harsh B., primary, Sharma, Priyanka, primary, Brenner, Hermann, primary, Müller, Heiko, primary, Arndt, Volker, primary, Stegmaier, Christa, primary, Miron, Penelope, primary, Yannoukakos, Drakoulis, primary, Stavropoulou, Alexandra, primary, Fountzilas, George, primary, Gogas, Helen J., primary, Swann, Ruth, primary, Dwek, Miriam, primary, Perkins, Annie, primary, Milne, Roger L., primary, Benítez, Javier, primary, Zamora, María Pilar, primary, Pérez, José Ignacio Arias, primary, Bojesen, Stig E., primary, Nielsen, Sune F., primary, Nordestgaard, Børge G., primary, Flyger, Henrik, primary, Guénel, Pascal, primary, Truong, Thérèse, primary, Menegaux, Florence, primary, Cordina-Duverger, Emilie, primary, Burwinkel, Barbara, primary, Marmé, Frederick, primary, Schneeweiss, Andreas, primary, Sohn, Christof, primary, Sawyer, Elinor, primary, Tomlinson, Ian, primary, Kerin, Michael J., primary, Peto, Julian, primary, Johnson, Nichola, primary, Fletcher, Olivia, primary, dos Santos Silva, Isabel, primary, Fasching, Peter A., primary, Beckmann, Matthias W., primary, Hartmann, Arndt, primary, Ekici, Arif B., primary, Lophatananon, Artitaya, primary, Muir, Kenneth, primary, Puttawibul, Puttisak, primary, Wiangnon, Surapon, primary, Schmidt, Marjanka K., primary, Broeks, Annegien, primary, Braaf, Linde M., primary, Rosenberg, Efraim H., primary, Hopper, John L., primary, Apicella, Carmel, primary, Park, Daniel J., primary, Southey, Melissa C., primary, Swerdlow, Anthony J., primary, Ashworth, Alan, primary, Orr, Nicholas, primary, Schoemaker, Minouk J., primary, Anton-Culver, Hoda, primary, Ziogas, Argyrios, primary, Bernstein, Leslie, primary, Dur, Christina Clarke, primary, Shen, Chen-Yang, primary, Yu, Jyh-Cherng, primary, Hsu, Huan-Ming, primary, Hsiung, Chia-Ni, primary, Hamann, Ute, primary, Dünnebier, Thomas, primary, Rüdiger, Thomas, primary, Ulmer, Hans Ulrich, primary, Pharoah, Paul P., primary, Dunning, Alison M., primary, Humphreys, Manjeet K., primary, Wang, Qin, primary, Cox, Angela, primary, Cross, Simon S., primary, Reed, Malcom W., primary, Hall, Per, primary, Czene, Kamila, primary, Ambrosone, Christine B., primary, Ademuyiwa, Foluso, primary, Hwang, Helena, primary, Eccles, Diana M., primary, Garcia-Closas, Montserrat, primary, Figueroa, Jonine D., primary, Sherman, Mark E., primary, Lissowska, Jolanta, primary, Devilee, Peter, primary, Seynaeve, Caroline, primary, Tollenaar, Rob A.E.M., primary, Hooning, Maartje J., primary, Andrulis, Irene L., primary, Knight, Julia A., primary, Glendon, Gord, primary, Mulligan, Anna Marie, primary, Winqvist, Robert, primary, Pylkäs, Katri, primary, Jukkola-Vuorinen, Arja, primary, Grip, Mervi, primary, John, Esther M., primary, Miron, Alexander, primary, Alnæs, Grethe Grenaker, primary, Kristensen, Vessela, primary, Børresen-Dale, Anne-Lise, primary, Giles, Graham G., primary, Baglietto, Laura, primary, McLean, Catriona A., primary, Severi, Gianluca, primary, Kosel, Matthew L., primary, Pankratz, V.S., primary, Slager, Susan, primary, Olson, Janet E., primary, Radice, Paolo, primary, Peterlongo, Paolo, primary, Manoukian, Siranoush, primary, Barile, Monica, primary, Lambrechts, Diether, primary, Hatse, Sigrid, primary, Dieudonne, Anne-Sophie, primary, Christiaens, Marie-Rose, primary, Chenevix-Trench, Georgia, primary, Beesley, Jonathan, primary, Chen, Xiaoqing, primary, Mannermaa, Arto, primary, Kosma, Veli-Matti, primary, Hartikainen, Jaana M., primary, Soini, Ylermi, primary, Easton, Douglas F., primary, and Couch, Fergus J., primary

Published
2023
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21. Supplementary Tables 1-13 from 19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus

Author

Stevens, Kristen N., primary, Fredericksen, Zachary, primary, Vachon, Celine M., primary, Wang, Xianshu, primary, Margolin, Sara, primary, Lindblom, Annika, primary, Nevanlinna, Heli, primary, Greco, Dario, primary, Aittomäki, Kristiina, primary, Blomqvist, Carl, primary, Chang-Claude, Jenny, primary, Vrieling, Alina, primary, Flesch-Janys, Dieter, primary, Sinn, Hans-Peter, primary, Wang-Gohrke, Shan, primary, Nickels, Stefan, primary, Brauch, Hiltrud, primary, Ko, Yon-Dschun, primary, Fischer, Hans-Peter, primary, Schmutzler, Rita K., primary, Meindl, Alfons, primary, Bartram, Claus R., primary, Schott, Sarah, primary, Engel, Christoph, primary, Godwin, Andrew K., primary, Weaver, JoEllen, primary, Pathak, Harsh B., primary, Sharma, Priyanka, primary, Brenner, Hermann, primary, Müller, Heiko, primary, Arndt, Volker, primary, Stegmaier, Christa, primary, Miron, Penelope, primary, Yannoukakos, Drakoulis, primary, Stavropoulou, Alexandra, primary, Fountzilas, George, primary, Gogas, Helen J., primary, Swann, Ruth, primary, Dwek, Miriam, primary, Perkins, Annie, primary, Milne, Roger L., primary, Benítez, Javier, primary, Zamora, María Pilar, primary, Pérez, José Ignacio Arias, primary, Bojesen, Stig E., primary, Nielsen, Sune F., primary, Nordestgaard, Børge G., primary, Flyger, Henrik, primary, Guénel, Pascal, primary, Truong, Thérèse, primary, Menegaux, Florence, primary, Cordina-Duverger, Emilie, primary, Burwinkel, Barbara, primary, Marmé, Frederick, primary, Schneeweiss, Andreas, primary, Sohn, Christof, primary, Sawyer, Elinor, primary, Tomlinson, Ian, primary, Kerin, Michael J., primary, Peto, Julian, primary, Johnson, Nichola, primary, Fletcher, Olivia, primary, dos Santos Silva, Isabel, primary, Fasching, Peter A., primary, Beckmann, Matthias W., primary, Hartmann, Arndt, primary, Ekici, Arif B., primary, Lophatananon, Artitaya, primary, Muir, Kenneth, primary, Puttawibul, Puttisak, primary, Wiangnon, Surapon, primary, Schmidt, Marjanka K., primary, Broeks, Annegien, primary, Braaf, Linde M., primary, Rosenberg, Efraim H., primary, Hopper, John L., primary, Apicella, Carmel, primary, Park, Daniel J., primary, Southey, Melissa C., primary, Swerdlow, Anthony J., primary, Ashworth, Alan, primary, Orr, Nicholas, primary, Schoemaker, Minouk J., primary, Anton-Culver, Hoda, primary, Ziogas, Argyrios, primary, Bernstein, Leslie, primary, Dur, Christina Clarke, primary, Shen, Chen-Yang, primary, Yu, Jyh-Cherng, primary, Hsu, Huan-Ming, primary, Hsiung, Chia-Ni, primary, Hamann, Ute, primary, Dünnebier, Thomas, primary, Rüdiger, Thomas, primary, Ulmer, Hans Ulrich, primary, Pharoah, Paul P., primary, Dunning, Alison M., primary, Humphreys, Manjeet K., primary, Wang, Qin, primary, Cox, Angela, primary, Cross, Simon S., primary, Reed, Malcom W., primary, Hall, Per, primary, Czene, Kamila, primary, Ambrosone, Christine B., primary, Ademuyiwa, Foluso, primary, Hwang, Helena, primary, Eccles, Diana M., primary, Garcia-Closas, Montserrat, primary, Figueroa, Jonine D., primary, Sherman, Mark E., primary, Lissowska, Jolanta, primary, Devilee, Peter, primary, Seynaeve, Caroline, primary, Tollenaar, Rob A.E.M., primary, Hooning, Maartje J., primary, Andrulis, Irene L., primary, Knight, Julia A., primary, Glendon, Gord, primary, Mulligan, Anna Marie, primary, Winqvist, Robert, primary, Pylkäs, Katri, primary, Jukkola-Vuorinen, Arja, primary, Grip, Mervi, primary, John, Esther M., primary, Miron, Alexander, primary, Alnæs, Grethe Grenaker, primary, Kristensen, Vessela, primary, Børresen-Dale, Anne-Lise, primary, Giles, Graham G., primary, Baglietto, Laura, primary, McLean, Catriona A., primary, Severi, Gianluca, primary, Kosel, Matthew L., primary, Pankratz, V.S., primary, Slager, Susan, primary, Olson, Janet E., primary, Radice, Paolo, primary, Peterlongo, Paolo, primary, Manoukian, Siranoush, primary, Barile, Monica, primary, Lambrechts, Diether, primary, Hatse, Sigrid, primary, Dieudonne, Anne-Sophie, primary, Christiaens, Marie-Rose, primary, Chenevix-Trench, Georgia, primary, Beesley, Jonathan, primary, Chen, Xiaoqing, primary, Mannermaa, Arto, primary, Kosma, Veli-Matti, primary, Hartikainen, Jaana M., primary, Soini, Ylermi, primary, Easton, Douglas F., primary, and Couch, Fergus J., primary

Published
2023
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22. Supplementary Tables 1-13 from 19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus

Author

Fergus J. Couch, Douglas F. Easton, Ylermi Soini, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Marie-Rose Christiaens, Anne-Sophie Dieudonne, Sigrid Hatse, Diether Lambrechts, Monica Barile, Siranoush Manoukian, Paolo Peterlongo, Paolo Radice, Janet E. Olson, Susan Slager, V.S. Pankratz, Matthew L. Kosel, Gianluca Severi, Catriona A. McLean, Laura Baglietto, Graham G. Giles, Anne-Lise Børresen-Dale, Vessela Kristensen, Grethe Grenaker Alnæs, Alexander Miron, Esther M. John, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Anna Marie Mulligan, Gord Glendon, Julia A. Knight, Irene L. Andrulis, Maartje J. Hooning, Rob A.E.M. Tollenaar, Caroline Seynaeve, Peter Devilee, Jolanta Lissowska, Mark E. Sherman, Jonine D. Figueroa, Montserrat Garcia-Closas, Diana M. Eccles, Helena Hwang, Foluso Ademuyiwa, Christine B. Ambrosone, Kamila Czene, Per Hall, Malcom W. Reed, Simon S. Cross, Angela Cox, Qin Wang, Manjeet K. Humphreys, Alison M. Dunning, Paul P. Pharoah, Hans Ulrich Ulmer, Thomas Rüdiger, Thomas Dünnebier, Ute Hamann, Chia-Ni Hsiung, Huan-Ming Hsu, Jyh-Cherng Yu, Chen-Yang Shen, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, Minouk J. Schoemaker, Nicholas Orr, Alan Ashworth, Anthony J. Swerdlow, Melissa C. Southey, Daniel J. Park, Carmel Apicella, John L. Hopper, Efraim H. Rosenberg, Linde M. Braaf, Annegien Broeks, Marjanka K. Schmidt, Surapon Wiangnon, Puttisak Puttawibul, Kenneth Muir, Artitaya Lophatananon, Arif B. Ekici, Arndt Hartmann, Matthias W. Beckmann, Peter A. Fasching, Isabel dos Santos Silva, Olivia Fletcher, Nichola Johnson, Julian Peto, Michael J. Kerin, Ian Tomlinson, Elinor Sawyer, Christof Sohn, Andreas Schneeweiss, Frederick Marmé, Barbara Burwinkel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Pascal Guénel, Henrik Flyger, Børge G. Nordestgaard, Sune F. Nielsen, Stig E. Bojesen, José Ignacio Arias Pérez, María Pilar Zamora, Javier Benítez, Roger L. Milne, Annie Perkins, Miriam Dwek, Ruth Swann, Helen J. Gogas, George Fountzilas, Alexandra Stavropoulou, Drakoulis Yannoukakos, Penelope Miron, Christa Stegmaier, Volker Arndt, Heiko Müller, Hermann Brenner, Priyanka Sharma, Harsh B. Pathak, JoEllen Weaver, Andrew K. Godwin, Christoph Engel, Sarah Schott, Claus R. Bartram, Alfons Meindl, Rita K. Schmutzler, Hans-Peter Fischer, Yon-Dschun Ko, Hiltrud Brauch, Stefan Nickels, Shan Wang-Gohrke, Hans-Peter Sinn, Dieter Flesch-Janys, Alina Vrieling, Jenny Chang-Claude, Carl Blomqvist, Kristiina Aittomäki, Dario Greco, Heli Nevanlinna, Annika Lindblom, Sara Margolin, Xianshu Wang, Celine M. Vachon, Zachary Fredericksen, and Kristen N. Stevens

Abstract

PDF file - 272K

Published
2023
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23. Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer

Author

Lilian van Wagensveld, Juliette O. A. M. van Baal, Maite Timmermans, Duco Gaillard, Lauri Borghuis, Seth B. Coffelt, Efraim H. Rosenberg, Christianne A. R. Lok, Hans W. Nijman, Loes F. S. Kooreman, Joyce Sanders, Marco de Bruijn, Lodewyk F. A. Wessels, Rianne van der Wiel, Christian Rausch, Annegien Broeks, Roy F. P. M. Kruitwagen, Maaike A. van der Aa, Gabe S. Sonke, Philip C. Schouten, Koen K. Van de Vijver, Hugo M. Horlings, Translational Immunology Groningen (TRIGR), Targeted Gynaecologic Oncology (TARGON), RS: GROW - R2 - Basic and Translational Cancer Biology, Pathologie, MUMC+: DA Pat Pathologie (9), MUMC+: MA Obstetrie Gynaecologie (3), MUMC+: Vrouw Moeder en Kind Centrum (3), Obstetrie & Gynaecologie, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (6), VU University medical center, Obstetrics and Gynaecology, AII - Cancer immunology, and CCA - Cancer biology and immunology

Subjects
epithelial ovarian carcinoma, microenvironment, tumor, recombination, homologous, prognosis, ovarian neoplasms/genetics, Cancer Research, Oncology
Abstract

How the tumor’s genetic make up (i.e. molecular profiles) is associated with changes in the tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood, while these factors influence survival. To investigate this we analyzed the TME and molecular profiles (homologous recombination deficiency (HRD) and Cyclin E1 (CCNE1) amplification) of HGSOC and assessed their associations with each other and overall survival (OS). Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient, treatment, and outcome data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define five molecular profiles. Immunecell densites were assessed with immunohistochemical staining for T- (CD8 and CD103), B- cells (CD20) and macrophages (CD68). This resulted in the assessability of 348 patients who were categorized as; BRCA mutation or promotor methylation (BRCAm) (30%), non-BRCA mutated HRD (19%), CCNE1-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm tumors showed the highest immune cell densities and CCNE1-amplification the lowest. BRCAm showed the most favorable OS (52.5months), compared to non-BRCAmut HRD (41.0months), CCNE1-amplification (28.0months), double classifier (27.8months), and NSMP (35.4months). CCNE1-amplification and double classifier remained to have a significantly worse OS in multivariable analysis. Higher immune cell densities showed a favorable OS compared to lower densities, also within the molecular profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. These results depict that both molecular profiles and TME are associated with OS. Immune composition for lymphocytes and macrophages differ per molecular profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different variants based on molecular profiles and TME, which ideally is translated into tailored treatment approaches.

Published
2022
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24. Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer

Author

van Wagensveld, Lilian, primary, van Baal, Juliette O. A. M., additional, Timmermans, Maite, additional, Gaillard, Duco, additional, Borghuis, Lauri, additional, Coffelt, Seth B., additional, Rosenberg, Efraim H., additional, Lok, Christianne A. R., additional, Nijman, Hans W., additional, Kooreman, Loes F. S., additional, Sanders, Joyce, additional, de Bruijn, Marco, additional, Wessels, Lodewyk F. A., additional, van der Wiel, Rianne, additional, Rausch, Christian, additional, Broeks, Annegien, additional, Kruitwagen, Roy F. P. M., additional, van der Aa, Maaike A., additional, Sonke, Gabe S., additional, Schouten, Philip C., additional, Van de Vijver, Koen K., additional, and Horlings, Hugo M., additional

Published
2022
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25. Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Author

de Jong, Vincent M.T., primary, Wang, Yuwei, additional, ter Hoeve, Natalie D., additional, Opdam, Mark, additional, Stathonikos, Nikolas, additional, Jóźwiak, Katarzyna, additional, Hauptmann, Michael, additional, Cornelissen, Sten, additional, Vreuls, Willem, additional, Rosenberg, Efraim H., additional, Koop, Esther A., additional, Varga, Zsuzsanna, additional, van Deurzen, Carolien H.M., additional, Mooyaart, Antien L., additional, Córdoba, Alicia, additional, Groen, Emma J., additional, Bart, Joost, additional, Willems, Stefan M., additional, Zolota, Vasiliki, additional, Wesseling, Jelle, additional, Sapino, Anna, additional, Chmielik, Ewa, additional, Ryska, Ales, additional, Broeks, Annegien, additional, Voogd, Adri C., additional, Loi, Sherene, additional, Michiels, Stefan, additional, Sonke, Gabe S., additional, van der Wall, Elsken, additional, Siesling, Sabine, additional, van Diest, Paul J., additional, Schmidt, Marjanka K., additional, Kok, Marleen, additional, Dackus, Gwen M.H.E., additional, Salgado, Roberto, additional, and Linn, Sabine C., additional

Published
2022
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26. Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Author

Pathologie Support, Pathologie Pathologen staf, Cancer, Speerpunt Cancer, Pathologie, Pathologie Opleiding, de Jong, Vincent M T, Wang, Yuwei, Ter Hoeve, Natalie D, Opdam, Mark, Stathonikos, Nikolas, Jóźwiak, Katarzyna, Hauptmann, Michael, Cornelissen, Sten, Vreuls, Willem, Rosenberg, Efraim H, Koop, Esther A, Varga, Zsuzsanna, van Deurzen, Carolien H M, Mooyaart, Antien L, Córdoba, Alicia, Groen, Emma J, Bart, Joost, Willems, Stefan M, Zolota, Vasiliki, Wesseling, Jelle, Sapino, Anna, Chmielik, Ewa, Ryska, Ales, Broeks, Annegien, Voogd, Adri C, Loi, Sherene, Michiels, Stefan, Sonke, Gabe S, van der Wall, Elsken, Siesling, Sabine, van Diest, Paul J, Schmidt, Marjanka K, Kok, Marleen, Dackus, Gwen M H E, Salgado, Roberto, Linn, Sabine C, Pathologie Support, Pathologie Pathologen staf, Cancer, Speerpunt Cancer, Pathologie, Pathologie Opleiding, de Jong, Vincent M T, Wang, Yuwei, Ter Hoeve, Natalie D, Opdam, Mark, Stathonikos, Nikolas, Jóźwiak, Katarzyna, Hauptmann, Michael, Cornelissen, Sten, Vreuls, Willem, Rosenberg, Efraim H, Koop, Esther A, Varga, Zsuzsanna, van Deurzen, Carolien H M, Mooyaart, Antien L, Córdoba, Alicia, Groen, Emma J, Bart, Joost, Willems, Stefan M, Zolota, Vasiliki, Wesseling, Jelle, Sapino, Anna, Chmielik, Ewa, Ryska, Ales, Broeks, Annegien, Voogd, Adri C, Loi, Sherene, Michiels, Stefan, Sonke, Gabe S, van der Wall, Elsken, Siesling, Sabine, van Diest, Paul J, Schmidt, Marjanka K, Kok, Marleen, Dackus, Gwen M H E, Salgado, Roberto, and Linn, Sabine C

Published
2022

28. Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Author

de Jong, Vincent M T, Wang, Yuwei, Ter Hoeve, Natalie D, Opdam, Mark, Stathonikos, Nikolas, Jóźwiak, Katarzyna, Hauptmann, Michael, Cornelissen, Sten, Vreuls, Willem, Rosenberg, Efraim H, Koop, Esther A, Varga, Zsuzsanna, van Deurzen, Carolien H M, Mooyaart, Antien L, Córdoba, Alicia, Groen, Emma J, Bart, Joost, Willems, Stefan M, Zolota, Vasiliki, Wesseling, Jelle, Sapino, Anna, Chmielik, Ewa, Ryska, Ales, Broeks, Annegien, Voogd, Adri C, Loi, Sherene, Michiels, Stefan, Sonke, Gabe S, van der Wall, Elsken, Siesling, Sabine, et al, and University of Zurich

Subjects
10049 Institute of Pathology and Molecular Pathology, 610 Medicine & health
Published
2022
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29. Challenges in breast cancer genetic testing. A call for novel forms of multidisciplinary care and long-term evaluation

Author

Fred H. Menko, Kim Monkhorst, Frans B.L. Hogervorst, Efraim H. Rosenberg, Muriel A. Adank, Mariëlle W.G. Ruijs, Eveline M.A. Bleiker, Gabe S. Sonke, Nicola S. Russell, Hester S.A. Oldenburg, and Lizet E. van der Kolk

Subjects
Oncology, High-Throughput Nucleotide Sequencing, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genetic Testing, Hematology, Germ-Line Mutation
Abstract

Current methods of next generation sequencing may simultaneously detect multiple germline breast cancer susceptibility variants. However, it is a challenge to maximize the clinical benefit of genetic analysis for patients and family members while minimizing potentially harmful effects. Relevant issues include criteria for referral, the choice of gene panel, handling of variants of unknown significance, cancer risk counselling in clinical context including family history data, risks of tumours other than breast cancer, handling of potential germline findings revealed by tumour testing and the clinical management of gene variant carriers, including surveillance, targeted therapy, radiotherapy and risk-reducing surgery. We outline current challenges in the field of breast cancer genetics and call for novel forms of multidisciplinary care and long-term evaluation.

Published
2022
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31. Molecular characterization of gastric adenocarcinoma diagnosed in patients previously treated for Hodgkin lymphoma or testicular cancer.

Author

Rigter, Lisanne S., Snaebjornsson, Petur, Rosenberg, Efraim H., Altena, Estelle, van Grieken, Nicole C. T., Aleman, Berthe M. P., Kerst, Jan M., Morton, Lindsay, Schaapveld, Michael, Meijer, Gerrit A., van Leeuwen, Flora E., and van Leerdam, Monique E.

Subjects
TESTICULAR cancer, HODGKIN'S disease, ADENOCARCINOMA, STOMACH cancer, EPSTEIN-Barr virus
Abstract

Introduction: The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Methods: Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature. Results: Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). Conclusion: Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive. [ABSTRACT FROM AUTHOR]

Published
2022
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33. A squamous cell carcinoma in a young woman with Lynch syndrome

Author

Petur Snaebjornsson, Marianne B. Crijns, Efraim H. Rosenberg, M E van Leerdam, Barbara A. J. Bastiaansen, O. Lapid, E. Dekker, F. Adan, M. W. Bekkenk, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, Gastroenterology and Hepatology, AGEM - Re-generation and cancer of the digestive system, AGEM - Digestive immunity, Plastic, Reconstructive and Hand Surgery, ACS - Diabetes & metabolism, AMS - Restoration & Development, and Dermatology

Subjects
Adult, 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Skin Neoplasms, Colorectal cancer, 030105 genetics & heredity, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Muir–Torre syndrome, Genetics, medicine, Humans, neoplasms, Genetics (clinical), Skin, business.industry, Melanoma, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, MSH6, stomatognathic diseases, Cheek, MutS Homolog 2 Protein, Oncology, MSH2, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Immunohistochemistry, Female, business
Abstract

Lynch syndrome (LS) is an autosomal-dominant inherited disorder characterized by a predisposition to colorectal cancer and extracolonic cancers (particularly endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, urothelial tract, brain, and skin). Muir-Torre syndrome (MTS) is considered a phenotypical variant of LS, where patients develop sebaceous neoplasms and keratoacanthomas. Currently, only few studies and case reports suggest an association between LS and other skin cancers, such as Bowens' disease, melanoma and squamous cell carcinoma (SCC). In this case-report we describe the case of a 33-year-old woman with LS and a proven MSH2 germline mutation, presenting with a SCC on the right cheek. Immunohistochemistry lacked MSH2 and MSH6 protein staining. The tumor showed a discordance between immunohistochemistry and micro-satellite instability status, for which a clear explanation cannot be provided yet. To conclude whether this pattern is indicative for SCC occurring in LS patients, further analyses of other LS patients presenting with SCC should be carried out. Our patient's young age and skin type (Fitzpatrick phototype VI) suggest a possible link between LS and cutaneous SCC.

Published
2018
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34. Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

Author

Sayed M.S. Hashemi, Egbert F. Smit, Bianca van Veggel, Adrianus J. de Langen, Teodora Radonic, Efraim H. Rosenberg, Daniëlle A.M. Heideman, Kim Monkhorst, AII - Inflammatory diseases, Pulmonary medicine, CCA - Cancer Treatment and quality of life, and Pathology

Subjects
Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, 03 medical and health sciences, Egfr tki, 0302 clinical medicine, Crizotinib, Carcinoma, Non-Small-Cell Lung, Internal medicine, medicine, Humans, Anaplastic Lymphoma Kinase, In patient, Epidermal growth factor receptor, Protein Kinase Inhibitors, Aged, biology, business.industry, Gene Amplification, Egfr tki resistance, Middle Aged, Proto-Oncogene Proteins c-met, medicine.disease, Survival Analysis, respiratory tract diseases, ErbB Receptors, Treatment Outcome, 030104 developmental biology, Drug Resistance, Neoplasm, Egfr mutation, 030220 oncology & carcinogenesis, Mutation, biology.protein, Female, Non small cell, business, Progressive disease, medicine.drug
Abstract

Purpose Next to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib. Materials and methods Eight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6). Results Four out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2–5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4–5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3–6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification. Conclusion Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms.

Published
2018
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35. Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

Author

Gerrit A. Meijer, Flora E. van Leeuwen, Johan Hoeksel, Willemina R. R. Geurts-Giele, Winand N.M. Dinjens, Peggy N. Atmodimedjo, Petur Snaebjornsson, Efraim H. Rosenberg, Berthe M.P. Aleman, Jelle ten Hoeve, Hein te Riele, Thomas W. van Ravesteyn, Monique E. van Leerdam, Lisanne S. Rigter, Human genetics, CCA - Cancer biology and immunology, Epidemiology and Data Science, APH - Quality of Care, and Pathology

Subjects
0301 basic medicine, Male, Loss of Heterozygosity, Gene mutation, medicine.disease_cause, Bioinformatics, DNA Mismatch Repair, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, Promoter Regions, Genetic, Mismatch Repair Endonuclease PMS2, education.field_of_study, Gastroenterology, Neoplasms, Second Primary, Middle Aged, Hodgkin Disease, Immunohistochemistry, Lynch syndrome, DNA-Binding Proteins, MutS Homolog 2 Protein, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, KRAS, Colorectal Neoplasms, MutL Protein Homolog 1, Adult, Proto-Oncogene Proteins B-raf, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Population, Antineoplastic Agents, Biology, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, medicine, Humans, Computer Simulation, education, neoplasms, Aged, Radiotherapy, Microsatellite instability, DNA Methylation, medicine.disease, digestive system diseases, MSH6, 030104 developmental biology, DNA Repair Enzymes, MSH2, Procarbazine, Mutation, Cancer research, CpG Islands
Abstract

ObjectiveHodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.Design54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).ResultsKRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, pMLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.ConclusionsWe have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.

Published
2018
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36. 9P BRCA1 promoter methylation confers a more favorable prognosis to systemically untreated young triple-negative breast cancer patients than tumour BRCA1 mutation

Author

N.D. ter Hoeve, Gwen M. H. E. Dackus, Willem Vreuls, Efraim H. Rosenberg, P. J. Van Diest, Annegien Broeks, Esther A. Koop, Sabine Siesling, Marleen Kok, Michael Hauptmann, Katarzyna Jozwiak, Y. Wang, Marjanka K. Schmidt, V. De Jong, Sten Cornelissen, Mark Opdam, Sabine C. Linn, Petra M. Nederlof, Adri C. Voogd, and N. Stathonikos

Subjects
Oncology, business.industry, Promoter methylation, Cancer research, Medicine, Hematology, Favorable prognosis, business, Triple-negative breast cancer, Brca1 gene
Published
2021
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37. High prevalence of SLC6A8 deficiency in X-linked mental retardation

Author

Rosenberg, Efraim H., Almeida, Ligia S., Kleefstra, Tjitske, deGrauw, Rose S., Yntema, Helger G., Bahi, Nadia, Moraine, Claude, Ropers, Hans-Hilger, Fryns, Jean-Pierre, deGrauw, Ton J., Jakobs, Cornelis, and Salomons, Gajja S.

Subjects
Human genetics -- Research, Biological sciences
Published
2004

38. Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome

Author

Anja van Rens, Willemina R. R. Geurts-Giele, Efraim H. Rosenberg, Fonnet E. Bleeker, Winand N.M. Dinjens, Monique E. van Leerdam, and Pathology

Subjects
Adult, Male, 0301 basic medicine, lcsh:QH426-470, Somatic cell, Genetic Counseling, 030105 genetics & heredity, Gene mutation, medicine.disease_cause, MLH1, DNA Mismatch Repair, Clinical Reports, Germline, 03 medical and health sciences, Rectosigmoid Adenocarcinoma, Gene Frequency, Genetics, medicine, Humans, Molecular Biology, Alleles, Germ-Line Mutation, Genetics (clinical), Mutation, Clinical Report, Mosaicism, business.industry, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, lcsh:Genetics, 030104 developmental biology, Cancer research, DNA mismatch repair, Colorectal Neoplasms, MutL Protein Homolog 1, business
Abstract

textabstractBackground: Lynch syndrome (LS) is caused by germline mismatch repair (MMR) gene mutations. De novo MMR gene mutations are rare, and somatic mosaicism in LS is thought to be infrequent. We describe the first case of somatic mosaicism by a de novo MLH1 mutation for a patient diagnosed with a rectosigmoid adenocarcinoma at age 31. Methods: Twelve years after initial colorectal cancer diagnosis, tumor tissue of the patient was tested with sensitive next generation sequencing (NGS) analysis for the presence of somatic MMR mutations. Results: In tumor tissue, an inactivating MLH1 mutation (c.518_519del; p.(Tyr173Trpfs*18)) was detected, which was also present at low level in the blood of the patient. In both parents, as well as the patient's sisters, the mutation was not present. Conclusion: We show that low‐level mosaicism can be detected by using high‐coverage targeted NGS panels on constitutional and/or tumor DNA. This report illustrates that by using sensitive sequencing techniques, more cases of genetic diseases driven by mosaic mutations may be identified, with important clinical consequences for patients and family members.

Published
2019
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39. [BRCAmutations more frequent in people of Jewish ancestry]

Author

Fred H, Menko, Efraim H, Rosenberg, and Lizet E, van der Kolk

Subjects
Adult, BRCA2 Protein, Ovarian Neoplasms, BRCA1 Protein, Jews, Mutation, Humans, Breast Neoplasms, Female, Genetic Testing, Middle Aged
Abstract

Three BRCA1/BRCA2 mutations occur more frequently in the Jewish population than in the general population. In Jewish patients with breast cancer about 10% of cases are caused by one of these mutations; consequently, all patients with breast cancer and who are of Jewish ancestry, or their healthy family members, are eligible for genetic testing.

Published
2019

44. HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53

Author

Didier Meulendijks, Luc Dewit, Paul H.M. Smits, Annemieke Cats, R. Bakker, M-L F van Velthuysen, Jan H.M. Schellens, Jos H. Beijnen, Efraim H. Rosenberg, N B Tomasoa, Pharmacoepidemiology and Clinical Pharmacology, and Sub Clinical Pharmacology

Subjects
Oncology, p53, Adult, Male, medicine.medical_specialty, Cancer Research, medicine.medical_treatment, p16, Alphapapillomavirus, chemoradiotherapy, Drug Therapy, Internal medicine, medicine, Humans, Basal cell, Human papillomavirus, human papillomavirus, Molecular Diagnostics, Cyclin-Dependent Kinase Inhibitor p16, anal canal carcinoma, Aged, Aged, 80 and over, Radiotherapy, business.industry, Standard treatment, Papillomavirus Infections, virus diseases, Anal canal, Middle Aged, medicine.disease, Anus Neoplasms, Head and neck squamous-cell carcinoma, female genital diseases and pregnancy complications, Radiation therapy, medicine.anatomical_structure, Treatment Outcome, Mutation, Carcinoma, Squamous Cell, Immunohistochemistry, Female, Tumor Suppressor Protein p53, business, Chemoradiotherapy
Abstract

Background: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy. Methods: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2–11 of TP53 in tumour tissue were sequenced. Results: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV−) tumours (13%), 10 (9%) were p16-negative (HPV−/p16−) and 4 (4%) overexpressed p16 (HPV−/p16+). Patients with HPV−/p16− disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P

Published
2015

45. Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

Author

Rigter, Lisanne S., Snaebjornsson, P., Rosenberg, Efraim H., Atmodimedjo, Peggy N., Aleman, Berthe M., Hoeve, Jelle ten, Nagtegaal, I.D., Dinjens, Winand N., Leerdam, M.E. van, Rigter, Lisanne S., Snaebjornsson, P., Rosenberg, Efraim H., Atmodimedjo, Peggy N., Aleman, Berthe M., Hoeve, Jelle ten, Nagtegaal, I.D., Dinjens, Winand N., and Leerdam, M.E. van

Abstract

Contains fulltext : 198278.pdf (publisher's version ) (Closed access)

Published
2018

46. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months

Author

Leijen, Suzanne, van Geel, Robin M J M, Sonke, Gabe S, de Jong, Daphne, Rosenberg, Efraim H, Marchetti, Serena, Pluim, Dick, van Werkhoven, Erik, Rose, Shelonitda, Lee, Mark A, Freshwater, Tomoko, Beijnen, Jos H, Schellens, Jan H M, Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Pathology, CCA - Clinical Therapy Development, Laboratory Medicine, Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, RS: FHML non-thematic output, and MUMC+: DA KFT Medische Staf (9)

Subjects
0301 basic medicine, Cancer Research, Administration, Oral, Phases of clinical research, Gastroenterology, Carboplatin, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Infusions, Intravenous, Netherlands, Ovarian Neoplasms, Remission Induction, Area under the curve, Middle Aged, Prognosis, Survival Rate, Treatment Outcome, Oncology, Area Under Curve, 030220 oncology & carcinogenesis, Female, medicine.symptom, medicine.medical_specialty, Nausea, Pyrimidinones, Neutropenia, Disease-Free Survival, Drug Administration Schedule, 03 medical and health sciences, Internal medicine, medicine, Humans, Neoplasm Invasiveness, Adverse effect, Survival rate, Aged, Neoplasm Staging, Dose-Response Relationship, Drug, business.industry, medicine.disease, Surgery, Pyrimidines, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, Pyrazoles, Tumor Suppressor Protein p53, Ovarian cancer, business
Abstract

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)–mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.

Published
2016

47. RAD51B in Familial Breast Cancer

Author

kConFab, Jonine Figueroa, Elinor J. Sawyer, Manjeet K. Bolla, Carl Blomqvist, Jaana M. Hartikainen, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Fredrick Schumacher, Vessela N. Kristensen, Graham G. Giles, Isabel dos-Santos-Silva, Kamila Czene, Douglas F. Easton, Qin Wang, Javier Benitez, Janet E. Olson, Georgia Chenevix-Trench, John L. Hopper, Alicia Beeghly-Fadiel, Hoda Anton-Culver, Paolo Radice, Aocs Investigators, Nick Orr, Jacques Simard, Mervi Grip, Salla Ranta, Fergus J. Couch, Marjanka K. Schmidt, Kristiina Aittomäki, Caroline Seynaeve, Ute Hamann, Johanna Schleutker, Hilde Janssen, Robert Luben, Anna González-Neira, Peter A. Fasching, Pascal Guénel, Anja Rudolph, Arto Mannermaa, Melissa C. Southey, Ian Tomlinson, Thérèse Truong, Alison M. Dunning, Margriet Collée, Robert Winqvist, Johanna Mattson, Mikko Vuorela, Sara Vilske, Anne Lise Børresen-Dale, Johanna I. Kiiski, Paolo Peterlongo, Anna Jakubowska, Paul D.P. Pharoah, Alfons Meindl, Anthony J. Swerdlow, Roger L. Milne, Hermann Brenner, Joe Dennis, Montserrat Garcia-Closas, Thomas Brüning, Christopher A. Haiman, Martine Dumont, Wei Zheng, Per Hall, Gord Glendon, Jingmei Li, Laurien Van Dyck, Susan L. Neuhausen, Simon S. Cross, Irene L. Andrulis, Peter Devilee, Annika Lindblom, Emily Hallberg, Diana Torres, Sofia Khan, Kyriaki Michailidou, Rita K. Schmutzler, Julian Peto, Harald Surowy, Børge G. Nordestgaard, Barbara Burwinkel, Natalia Bogdanova, Drakoulis Yannoukakos, Heli Nevanlinna, Jan Lubinski, Liisa M. Pelttari, Efraim H. Rosenberg, Hiltrud Brauch, Thilo Dörk, Angela Cox, Viivi Nevanlinna, Maartje J. Hooning, Volker Arndt, Anne Kallioniemi, Stig E. Bojesen, Jenny Chang-Claude, Hatef Darabi, Obstetrics & Gynecology, Clinical Genetics, Gastroenterology & Hepatology, Medical Oncology, Brusgaard, Klaus, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Thierry, B, Zeps, N, Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Heredity, XRCC2, Genotyping Techniques, lcsh:Medicine, Genome-wide association study, 14Q24.1 RAD51L1, VARIANTS, Geographical Locations, 3123 Gynaecology and paediatrics, Cancer screening, Breast Tumors, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, Ethnicities, lcsh:Science, Finland, Genetics, RISK, education.field_of_study, Multidisciplinary, GERMLINE MUTATIONS, Genomics, Middle Aged, 3. Good health, Ovarian Cancer, Europe, DNA-Binding Proteins, Genetic Mapping, Male breast cancer, Female, Cancer Screening, Research Article, medicine.medical_specialty, Heterozygote, General Science & Technology, Population, 3122 Cancers, Mutation, Missense, Single-nucleotide polymorphism, Variant Genotypes, Breast Neoplasms, Genome Complexity, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Breast Cancer, medicine, Cancer Detection and Diagnosis, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Evolutionary Biology, Population Biology, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Odds ratio, medicine.disease, ta3122, GENE, Introns, 030104 developmental biology, Haplotypes, FANCONI-ANEMIA, People and Places, lcsh:Q, Population Groupings, business, Ovarian cancer, Gynecological Tumors, Population Genetics, Finns
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. ispartof: PLoS One vol:11 issue:5 ispartof: location:United States status: published

Published
2016
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48. RAD51B in Familial Breast Cancer

Author

Pelttari, Liisa M., Khan, Sofia, Vuorela, Mikko, Kiiski, Johanna I., Vilske, Sara, Nevanlinna, Viivi, Ranta, Salla, Schleutker, Johanna, Winqvist, Robert, Kallioniemi, Anne, Dörk, Thilo, Bogdanova, Natalia V., Figueroa, Jonine, Pharoah, Paul D. P., Schmidt, Marjanka K., Dunning, Alison M., García-Closas, Montserrat, Bolla, Manjeet K., Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Hopper, John L., Southey, Melissa C., Rosenberg, Efraim H., Fasching, Peter A., Beckmann, Matthias W., Peto, Julian, dos-Santos-Silva, Isabel, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E., Nordestgaard, Børge G., Benitez, Javier, González-Neira, Anna, Neuhausen, Susan L., Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Brüning, Thomas, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Hartikainen, Jaana M., Van Dyck, Laurien, Janssen, Hilde, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Peterlongo, Paolo, Hallberg, Emily, Olson, Janet E., Giles, Graham G., Milne, Roger L., Haiman, Christopher A., Schumacher, Fredrick, Simard, Jacques, Dumont, Martine, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Zheng, Wei, Beeghly-Fadiel, Alicia, Grip, Mervi, Andrulis, Irene L., Glendon, Gord, Devilee, Peter, Seynaeve, Caroline, Hooning, Maartje J., Collée, Margriet, Cox, Angela, Cross, Simon S., Shah, Mitul, Luben, Robert N., Hamann, Ute, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Couch, Fergus J., Yannoukakos, Drakoulis, Orr, Nick, Swerdlow, Anthony, Darabi, Hatef, Li, Jingmei, Czene, Kamila, Hall, Per, Easton, Douglas F., Mattson, Johanna, Blomqvist, Carl, Aittomäki, Kristiina, and Nevanlinna, Heli

Subjects
Medizinische Fakultät, ddc:610
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2016

49. 19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus

Author

Linde M. Braaf, Andreas Schneeweiss, Alexandra V. Stavropoulou, Elinor J. Sawyer, Christoph Engel, Pascal Guénel, Hans Ulrich Ulmer, Efraim H. Rosenberg, Mervi Grip, Hans-Peter Sinn, Chen-Yang Shen, Daniel J. Park, Monica Barile, Annie Perkins, Xianshu Wang, Susan L. Slager, Leslie Bernstein, José Ignacio Arias Peŕez, Puttisak Puttawibul, Gianluca Severi, Helen Gogas, Diana Eccles, Sara Margolin, Michael J. Kerin, Carl Blomqvist, Irene L. Andrulis, Minouk J. Schoemaker, Dario Greco, Javier Benitez, Matthias W. Beckmann, Maria Pilar Zamora, Qin Wang, Diether Lambrechts, Hoda Anton-Culver, Foluso O. Ademuyiwa, Veli-Matti Kosma, Mark E. Sherman, Anne Sophie Dieudonne, F Marmé, Helena Hwang, Peter Devilee, Shan Wang-Gohrke, Alina Vrieling, Melissa C. Southey, Annika Lindblom, Paolo Radice, Penelope Miron, Theŕeśe Truong, Per Hall, Douglas F. Easton, Siranoush Manoukian, Drakoulis Yannoukakos, Rita K. Schmutzler, Vessela N. Kristensen, Julian Peto, Jonathan Beesley, Arndt Hartmann, Priyanka Sharma, Alison M. Dunning, Paolo Peterlongo, Christine B. Ambrosone, Henrik Flyger, Nichola Johnson, Jonine D. Figueroa, Barbara Burwinkel, Kenneth Muir, Roger L. Milne, Sigrid Hatse, Julia A. Knight, Ylermi Soini, Alan Ashworth, Artitaya Lophatananon, Robert Winqvist, Alfons Meindl, Thomas Rüdiger, George Fountzilas, Annegien Broeks, Simon S. Cross, Rob A. E. M. Tollenaar, Paul D.P. Pharoah, Alexander Miron, Montserrat Garcia-Closas, Laura Baglietto, Matthew L. Kosel, Arif B. Ekici, Heiko Müller, Jyh Cherng Yu, Grethe Grenaker Alnsæ, Argyrios Ziogas, Thomas Dünnebier, Ian Tomlinson, Anna Marie Mulligan, Ruth Swann, Chia-Ni Hsiung, Sarah Schott, Christina Clarke Dur, Catriona McLean, Georgia Chenevix-Trench, Caroline Seynaeve, Hiltrud Brauch, Orr Nicholas, Carmel Apicella, Vernon S. Pankratz, Olivia Fletcher, Surapon Wiangnon, Arja Jukkola-Vuorinen, Anne Lise Brøresen-Dale, Dieter Flesch-Janys, Fergus J. Couch, Peter A. Fasching, Brøge G. Nordestgaard, Kristiina Aittomäki, Marie Rose Christiaens, Jaana M. Hartikainen, Manjeet K. Humphreys, Ute Hamann, Marjanka K. Schmidt, Isabel dos Santos Silva, Harsh B. Pathak, Janet E. Olson, Jenny Chang-Claude, Graham G. Giles, Miriam Dwek, Stig E. Bojesen, Florence Menegaux, Christa Stegmaier, Katri Pylkäs, Huan Ming Hsu, Sune F. Nielsen, Christof Sohn, Kamila Czene, Claus R. Bartram, Jo Ellen Weaver, John L. Hopper, Xiaoqing Chen, Emilie Cordina-Duverger, Stefan Nickels, Esther M. John, Heli Nevanlinna, Jolanta Lissowska, Zachary S. Fredericksen, Angela Cox, Maartje J. Hooning, Volker Arndt, MW Reed, Celine M. Vachon, Yon Ko, Anthony J. Swerdlow, Gord Glendon, Hans Fischer, Arto Mannermaa, Kristen N. Stevens, Hermann Brenner, Andrew K. Godwin, Clinical Genetics, and Medical Oncology

Subjects
Oncology, Cancer Research, Receptor, ErbB-2, population, Estrogen receptor, consortium, Genome-wide association study, brca1, ErbB-2, 0302 clinical medicine, common variants, Receptors, risk-factors, skin and connective tissue diseases, Progesterone, Triple-negative breast cancer, 0303 health sciences, education.field_of_study, Chromosome Mapping, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Receptors, Progesterone, complex, Receptor, Human, Risk, medicine.medical_specialty, Population, Breast Neoplasms, Genetic Loci, Humans, Chromosomes, Human, Pair 19, Genetic Predisposition to Disease, Biology, Article, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Genetic predisposition, education, 030304 developmental biology, Gynecology, Pair 19, tumor subtypes, confer susceptibility, medicine.disease, Estrogen, 14q24.1 rad51l1, genome-wide association, Ovarian cancer
Abstract

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Published
2012
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50. Folinic Acid-Responsive Seizures Are Identical to Pyridoxine-Dependent Epilepsy

Author

Saadet Mercimek-Mahmutoglu, Sylvia Stockler-Ipsiroglu, Cornelis Jakobs, Renata C. Gallagher, Gajja S. Salomons, Keith Hyland, Eduard A. Struys, Barbara Plecko, Johan L.K. Van Hove, Efraim H. Rosenberg, Gunter Scharer, Paula J. Waters, Laboratory Medicine, and NCA - Childhood White Matter Diseases

Subjects
Male, medicine.medical_specialty, DNA Mutational Analysis, Leucovorin, Neurological disorder, Gastroenterology, Folinic acid, chemistry.chemical_compound, Epilepsy, Seizures, Tandem Mass Spectrometry, Internal medicine, Convulsion, medicine, Humans, Biogenic Monoamines, Pyridoxine-dependent epilepsy, Pipecolic acid, business.industry, Lysine, Infant, Pyridoxine, Aldehyde Dehydrogenase, medicine.disease, B vitamins, Neurology, chemistry, Biochemistry, Pipecolic Acids, Mutation, Vitamin B Complex, Linear Models, Neurology (clinical), medicine.symptom, business, medicine.drug
Abstract

Objective Folinic acid-responsive seizures and pyridoxine-dependent epilepsy are two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. We report two patients whose CSF showed the marker of folinic acid-responsive seizures, but who responded clinically to pyridoxine. We performed genetic and biochemical testing of samples from these patients, and seven others, to determine the relation between these two disorders. Methods CSF samples were analyzed for the presence of alpha-AASA and pipecolic acid. DNA sequencing of the ALDH7A1 gene was performed. Results Both patients reported here had increased CSF alpha-AASA, CSF pipecolic acid, and known or likely pathogenic mutations in the ALDH7A1 gene, consistent with alpha-AASA dehydrogenase deficiency. Analysis of CSF samples from seven other anonymous individuals diagnosed with folinic acid-responsive seizures showed similar results. Interpretation These results demonstrate that folinic acid-responsive seizures are due to alpha-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene. Thus, folinic acid-responsive seizures are identical to the major form of pyridoxine-dependent epilepsy. We recommend consideration of treatment with both pyridoxine and folinic acid for patients with alpha-AASA dehydrogenase deficiency, and consideration of a lysine restricted diet. The evaluation of patients with neonatal epileptic encephalopathy, as well as those with later-onset seizures, should include a measurement of alpha-AASA in urine to identify this likely underdiagnosed and treatable disorder.

Published
2009
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