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102. Using polyacrylamide to control erosion on agricultural and disturbed soils in rainfed areas

Author

Flanagan, Dennis C., Norton, L. Darren, Peterson, Joel R., and Chaudhari, Kiran

Subjects
Soils -- Research, Polyacrylamide -- Research, Environmental issues, Research
Abstract

********** Polyacrylamide (PAM) is a water-soluble, high molecular weight (5 to 30 Mg*[mol.sup.-1], or 6 to 33 tons*[mol.sup.-1]), long-chain, synthetic, organic polymer that is produced from natural gas. When applied [...]

Published
2003

107. Análise da situação de saúde dos idosos usuários de uma política municipal de atividades físicas

Author

Fernando Matos Dourado, Nórton Luis Oliveira, Luiza Isnardi Cardoso Ricardo, Leandro dos Santos, Angélica Trevisan de Nardi, Cíntia Ehlers Botton, Lucinéia Orsolin Pfeifer, Laura Milán Vasques, Lucas Porto Santos, Larissa Neves da Silva, Bruna Góes Moraes, Lucas Helal, and Daniel Umpierre

Subjects
Idoso, Atividade física, Análise de situação de saúde, Saúde coletiva., Medicine (General), R5-920, Public aspects of medicine, RA1-1270
Abstract

Introdução: Políticas públicas intersetoriais em saúde são intervenções populacionais (e de cunho ecológico) muito utilizadas para a redução da carga global de doença e otimização de recursos tanto financeiros quanto humanos. Objetivo: O objetivo deste estudo foi analisar a situação de saúde de usuários idosos de uma política municipal de atividades físicas. Métodos: Trata-se de um estudo transversal com amostragem baseada em centros comunitários (N dispositivos comunitários=11), que disponibilizam práticas de movimentos corporais e outros, subsidiados pela Secretaria Municipal de Desenvolvimento Social e Esporte (SMDSE), Prefeitura Municipal de Porto Alegre (RS). A amostragem de usuários foi ponderada para o total de usuários atendidos por centro, adotando seleção aleatória simples. A coleta de dados ocorreu entre abril de 2018 e fevereiro de 2019, em que a equipe de coleta se deslocou ao território adscrito dos usuários para a condução de inquérito de saúde autoaplicado e a avaliação funcional; de forma contrária, os usuários compareceram a um centro de coleta para a série laboratorial (sem jejum). Resultados: Foram incluídos e analisados 351 usuários (média±desvio padrão, 70±6 anos). Para fatores de risco cardiovasculares, a prevalência de hipercolesterolemia foi de 54,2% e de 49,3% para hipertensão arterial sistêmica — as mais elevadas. O transtorno de sono foi prevalente em 55,3% da amostra. Entre as doenças autorrelatadas, os participantes listaram as cardiovasculares (14,3%), câncer prévio (14,6%), diabetes (13,2%), artrite reumatoide/ reumatismo (29,6%) e depressão (sem discriminador de depressão maior/ menor) (18,6%). A capacidade funcional, estimada pelo teste de caminhada em 6 minutos e a força de preensão manual, preditores de mortalidade cardiovascular e agravos, tiveram valores médios encontrados de 498,05±78,96 m e 27,08±8,14 kg, respectivamente. Conclusão: Os achados do presente estudo permitem contrastar prevalências estimadas em idosos participantes de um programa público de atividades físicas com outras estimativas em grupos de comparação, possibilitando a análise de situação de saúde com base em diferentes comportamentos e fatores de risco. Por fim, o trabalho viabilizou a monitorização de intervenções públicas para idosos em nível comunitário, sendo um ponto de base para acompanhamento futuro.

Published
2024
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108. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report

Author

Vilmer, E, Suciu, S, Ferster, A, Bertrand, Y, Cavé, H, Thyss, A, Benoit, Y, Dastugue, N, Fournier, M, Souillet, G, Manel, A-M, Robert, A, Nelken, B, Millot, F, Lutz, P, Rialland, X, Mechinaud, F, Boutard, P, Behar, C, Chantraine, J-M, Plouvier, E, Laureys, G, Brock, P, Uyttebroeck, A, Margueritte, G, Plantaz, D, Norton, L, Francotte, N, Gyselinck, J, Waterkeyn, C, Solbu, G, Philippe, N, and Otten, J

Published
2000
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110. Uterine carcinosarcomas and metaplastic breast carcinomas: Genetically related cancers?

Author

Moukarzel, L.A., primary, Ferrando, L., additional, Paula, A.D.C., additional, Brown, D., additional, Geyer, F.C., additional, Pareja, F., additional, Piscuoglio, S., additional, Papanastasiou, A.D., additional, Fusco, N., additional, Marchio, C., additional, Abu-Rustum, N.R., additional, Murali, R., additional, Brogi, E., additional, Wen, H., additional, Norton, L., additional, Soslow, R.A., additional, Vincent-Salomon, A., additional, Reis-Filho, J., additional, and Weigelt, B., additional

Published
2020
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111. DIGITAL TECHNOLOGIES, DATA, AND ANALYTICS

Author

Mehta, S., primary, Hume, E., additional, Troxel, A., additional, Reitz, C., additional, Norton, L., additional, Lacko, H., additional, McDonald, C., additional, Freeman, J., additional, Marcus, N., additional, Volpp, K., additional, and Asch, D., additional

Published
2020
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120. Site-directed engineering of defined chromosomal sites for recombinant protein and virus expression

Author

Wirth, D., Gama-Norton, L., Schucht, R., Nehlsen, K., and Hauser, H.

Subjects
Gene therapy -- Health aspects, Gene therapy -- Analysis, Genetic research -- Health aspects, Genetic research -- Analysis, Virus diseases -- Health aspects, Virus diseases -- Analysis, Animal genetics -- Health aspects, Animal genetics -- Analysis, Genetic engineering -- Health aspects, Genetic engineering -- Analysis, Recombinant proteins -- Health aspects, Recombinant proteins -- Analysis, Cell research -- Health aspects, Cell research -- Analysis, Cancer -- Genetic aspects, Cancer -- Health aspects, Cancer -- Analysis, Biotechnology industry, Business, Pharmaceuticals and cosmetics industries
Abstract

ABSTRACT In cell line development, the integration of transgenes into the chromosomal DNA of the host cell is a crucial step. Targeted introduction has many advantages over classical random integration [...]

Published
2009

122. Homologous recombination DNA repair defects in PALB2-associated breast cancers

Author

Li, A. (Anqi), Geyer, F. C. (Felipe C.), Blecua, P. (Pedro), Lee, J. Y. (Ju Youn), Selenica, P. (Pier), Brown, D. N. (David N.), Pareja, F. (Fresia), Lee, S. S. (Simon S. K.), Kumar, R. (Rahul), Rivera, B. (Barbara), Bi, R. (Rui), Piscuoglio, S. (Salvatore), Wen, H. Y. (Hannah Y.), Lozada, J. R. (John R.), Gularte-Merida, R. (Rodrigo), Cavallone, L. (Luca), Rezoug, Z. (Zoulikha), Nguyen-Dumont, T. (Tu), Peterlongo, P. (Paolo), Tondini, C. (Carlo), Terkelsen, T. (Thorkild), Ronlund, K. (Karina), Boonen, S. E. (Susanne E.), Mannerma, A. (Arto), Winqvist, R. (Robert), Janatova, M. (Marketa), Rajadurai, P. (Pathmanathan), Xia, B. (Bing), Norton, L. (Larry), Robson, M. E. (Mark E.), Ng, P.-S. (Pei-Sze), Looi, L.-M. (Lai-Meng), Southey, M. C. (Melissa C.), Weigelt, B. (Britta), Soo-Hwang, T. (Teo), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Reis-Filho, J. S. (Jorge S.), Aghmesheh, M. (Morteza), Amor, D. (David), Andrews, L. (Leslie), Antill, Y. (Yoland), Balleine, R. (Rosemary), Beesley, J. (Jonathan), Blackburn, A. (Anneke), Bogwitz, M. (Michael), Brown, M. (Melissa), Burgess, M. (Matthew), Burke, J. (Jo), Butow, P. (Phyllis), Caldon, L. (Liz), Campbell, I. (Ian), Christian, A. (Alice), Clarke, C. (Christine), Cohen, P. (Paul), Crook, A. (Ashley), Cui, J. (James), Cummings, M. (Margaret), Dawson, S.-J. (Sarah-Jane), De Fazio, A. (Anna), Delatycki, M. (Martin), Dobrovic, A. (Alex), Dudding, T. (Tracy), Duijf, P. (Pascal), Edkins, E. (Edward), Edwards, S. (Stacey), Farshid, G. (Gelareh), Fellows, A. (Andrew), Field, M. (Michael), Flanagan, J. (James), Fong, P. (Peter), Forbes, J. (John), Forrest, L. (Laura), Fox, S. (Stephen), French, J. (Juliet), Friedlander, M. (Michael), Ortega, D. G. (David Gallego), Gattas, M. (Michael), Giles, G. (Graham), Gill, G. (Grantley), Gleeson, M. (Margaret), Greening, S. (Sian), Haan, E. (Eric), Harris, M. (Marion), Hayward, N. (Nick), Hickie, I. (Ian), Hopper, J. (John), Hunt, C. (Clare), James, P. (Paul), Jenkins, M. (Mark), Kefford, R. (Rick), Kentwell, M. (Maira), Kirk, J. (Judy), Kollias, J. (James), Lakhani, S. (Sunil), Lindeman, G. (Geoff), Lipton, L. (Lara), Lobb, L. (Lizz), Lok, S. (Sheau), Macrea, F. (Finlay), Mane, G. (Graham), Marsh, D. (Deb), Mclachlan, S.-A. (Sue-Anne), Meiser, B. (Bettina), Milne, R. (Roger), Nightingale, S. (Sophie), O'Connell, S. (Shona), Pachter, N. (Nick), Patterson, B. (Briony), Phillips, K. (Kelly), Saleh, M. (Mona), Salisbury, E. (Elizabeth), Saunders, C. (Christobel), Saunus, J. (Jodi), Scott, C. (Clare), Scott, R. (Rodney), Sexton, A. (Adrienne), Shelling, A. (Andrew), Simpson, P. (Peter), Spigelman, A. (Allan), Spurdle, M. (Mandy), Stone, J. (Jennifer), Taylor, J. (Jessica), Thorne, H. (Heather), Trainer, A. (Alison), Trench, G. (Georgia), Tucker, K. (Kathy), Visvader, J. (Jane), Walker, L. (Logan), Wallis, M. (Mathew), Williams, R. (Rachael), Winship, I. (Ingrid), Wu, K. (Kathy), Young, M. A. (Mary Anne), Li, Anqi, Geyer, Felipe C, Blecua, Pedro, Lee, Ju Youn, Duijf, Pascal, Reis-Filho, Jorge S, Li, Anqi [0000-0003-1409-1858], Kumar, Rahul [0000-0002-6927-5390], Rivera, Barbara [0000-0001-9434-6288], Piscuoglio, Salvatore [0000-0003-2686-2939], Lozada, John R. [0000-0001-8953-4110], Gularte-Mérida, Rodrigo [0000-0002-4383-2523], Peterlongo, Paolo [0000-0001-6951-6855], Robson, Mark E. [0000-0002-3109-1692], Looi, Lai-Meng [0000-0001-8325-0117], Foulkes, William D. [0000-0001-7427-4651], Apollo - University of Cambridge Repository, Lozada, John R [0000-0001-8953-4110], Robson, Mark E [0000-0002-3109-1692], and Foulkes, William D [0000-0001-7427-4651]

Subjects
0301 basic medicine, IMPACT, DNA repair, PALB2, gene frequency, lcsh:RC254-282, RECOMMENDATIONS, Germline, Article, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, breast cancer, Breast cancer, 631/67/68, MUTATIONAL PROCESSES, Cancer genomics, Medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Allele, AMERICAN SOCIETY, Cancer genetics, Genetics, Science & Technology, Massive parallel sequencing, LANDSCAPE, business.industry, 631/67/1347, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 692/699/67/69, BRCA2, GENE, 3. Good health, 030104 developmental biology, Oncology, gene inactivation, 030220 oncology & carcinogenesis, kConFab Investigators, Homologous recombination, business, Life Sciences & Biomedicine, CLINICAL ONCOLOGY/COLLEGE
Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Published
2019

124. Understanding and Acting in Loweswater: a Community Approach to Catchment Management

Author

Norton, L., Watson, N., and Waterton, C.

Abstract

This qualitative data collection is part of the Rural Economy and Land Use (RELU) programme. This project adopted an interdisciplinary approach to the ecological, social and economic interactions at Loweswater in the English Lake District with the aim to gain a better understanding of the environmental problem of potentially toxic algal blooms formed by cyanobacteria, (blue-green algae) in Loweswater Lake. Following findings from an earlier scoping study the project achieved to: link aquatic and terrestrial ecological knowledge; to understand how economic issues for those living and working in the catchment affect resource use and management (including waste disposal), and hence Loweswater's aquatic and terrestrial ecology; to understand how institutional arrangements pertaining to agriculture, water resources, environmental protection, economic regeneration, local government, tourism and recreation shape opportunities and constraints for catchment management; to understand the role of local culture, local knowledge and understanding in shaping land and resource use and management in the catchment and to move away from a command and control regulatory style and innovate with a new bottom-up approach to addressing the catchment's problems and opportunities. Central to the project was the creation of a participatory, local- and stakeholder-relevant framework within which problems could be framed and re-framed, methodologies debated, and results and findings critically scrutinized by all participants. This took the form of a new experimental partnership known as the Loweswater Care Project which included relevant publics and varied forms of expertise. It followed three research objectives and research clusters (methods). These were: the creation of a new institutional mechanism the Loweswater Care Project, the creation of a knowledge-base for decision making and the transferability of the approach. Further information for this study may be found through the ESRC Research Catalogue webpage: Understanding and Acting Within Loweswater: A Community Approach to Catchment Management.

Published
2019
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125. ‘Welcome to the Machine!’ Resisting isomorphic, masculinised corporatisation of Higher Education through feminist scholarship

Author

Ashencaen Crabtree, Sara, Shiel, Chris, Hemingway, Ann, Sudbury, Sue, Quinney, C.A., Esteves, Luciana, Thompson, Shelley, Bradley, Peri, Scammell, Janet, Hall, Jenny, Board, Michele, Feigenbaum, Anna, Brown, Lorraine, Diaz, Anita, Heaslip, Vanessa, Hutchings, Maggie, Norton, L., and Jacey, Helen

Abstract

This paper discusses the synthesised findings from two interdisciplinary, feminist studies conducted under the auspices of the non-corporate nexus, the Women’s Academic Network at Bournemouth University, UK, of which the main author is a co-convenor and co-founder. These qualitative studies focus on academic women’s experiences of managing careers in the work culture of corporate Institutions of Higher Education (HEI) in a modern UK university. The background to this work draws from a body of international research into the slower career progression rates of women academics in comparison to male counterparts and gendered barriers the former encounter. While there has encouragement within Higher Education bodies across the EU to balance out the current gendered inequities within academia, our findings indicate that these are woven into the institutional fabric of enacted daily academic practices serving to disadvantage women scholars.

Published
2019

131. Drafting the percentage rent clause.

Author

Steuben, Norton L.

Subjects
Leases -- Interpretation and construction, Landlord and tenant -- Laws, regulations and rules
Abstract

The use of a percentage rent clause has advantages from the standpoint of both the lessor and lessee. From the lessor's standpoint, it permits the lessor to enter into a relatively long-term lease with some confidence that the rent, over the years, will represent a fair-market rent for the leased premises. While the lessor might be better off with a series of short-term leases, it is unlikely that a lessee, especially one who has incurred ignificant fixturing and setup costs, will agree, From the lessee's standpoint, a percentage rent clause permits the execution of a lease with a term long enough to reasonably write off the lessee's investment. In addition, it fgives the lessee some assurance that the rent will be affordable, because it is measured, in whole or in part, by the business operations of the lessee.

Published
1998

133. Measurements and Models of Soil Loss Rates

Author

Nearing, M. A., Romkens, M. J. M., Norton, L. D., Stott, D. E., Rhoton, F. E., Laflen, J. M., Flanagan, D. C., Alonso, C. V., Binger, R. L., Dabney, S. M., Doering, O. C., Huang, C. H., McGregor, K. C., Simon, A., Trimble, Stanley W., and Crosson, Pierre

Published
2000

136. Surface roughness changes as affected by rainfall erosivity, tillage, and canopy cover

Author

Eltz, Flavio Luiz Foletto and Norton, L. Darrell

Subjects
Surface roughness -- Research, Tillage -- Research, Soil erosion -- Research, Plant canopies -- Research, Earth sciences
Abstract

Surface roughness and canopy cover are important factors in preventing soil erosion. There is limited information on how soil surface roughness changes as a function of natural rainfall erosivity and canopy cover by plants. We hypothesized that canopy cover, tillage systems, and cumulative rainfall erosivity (CRE) would have unique effects on roughness. We tested this hypothesis on a Miami silt loam soil (fine-silty, mixed, mesic Typic Hapludalf) using a portable laser microtopographer. Tillage treatments of conventional (moldboard plowing + disking), chisel plowing, and chisel plowing + dragging a chain produced three initial roughness levels. Surface cover was none (fallow) or soybean [Glycine max (L.) Merr.]. Random roughness (RR), standard deviation (SD), tortuosity (T), and fractal roughness functions, expressed by the fractal index (D) and the crossover length (l), were calculated from microtopography data. Chisel tillage had the greatest initial values of surface roughness, followed by chisel + chain and conventional tillage, as measured by the l index. All indices but D generally decreased with CRE. The RR and SD indices decreased quadratically with CRE, with decreases of 38 and 36%, respectively, from initial values after 200 units of CRE, while the T and l indices decreased exponentially, with decreases of 40 and 60%, respectively, from initial values after 200 units of CRE. Soybean cover lowered soil surface roughness 7% less than fallow, as measured by the 1 index. The l index was 50, 71, and 205% more sensitive to changes in CRE than RR, SD, and T indices, respectively. The fractal roughness functions, with D and l indices calculated, were the best approaches to characterize surface roughness at small scales, such as existing plant rows, mainly due to l index sensitivity to changes in CRE.

Published
1997

137. The Stark Reality About Shared Nuclear Medicine Imaging Equipment Leasing Arrangements After January 1, 2007

Author

Travis, Norton L., Chananie, Steven J., and Finnegan, Jacqueline H.

Subjects
Image processing -- Equipment and supplies, Imaging systems, Lease and rental services industry, Leases, Imaging technology, Image processor, Health
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jacr.2006.09.008 Byline: Norton L. Travis, Steven J. Chananie, Jacqueline H. Finnegan

Published
2006

138. The stark reality about shared nuclear medicine imaging equipment leasing arrangements after January 1, 2007

Author

Reisman, Gregg D., Travis, Norton L., Chananie, Steven J., and Finnegan, Jacqueline H.

Subjects
Nuclear medicine -- Equipment and supplies, Medical equipment and supplies industry -- Contracts, Medical test kit industry -- Contracts, Prospective payment systems (Medical care) -- Laws, regulations and rules, Contract agreement, Government regulation, Health, Medicare Catastrophic Coverage Repeal Act of 1989
Published
2006

143. Fluidized bed combustion bottom-ash effects on infiltration and erosion of variable-charge soils

Author

Reichert, Jose Miguel and Norton, L. Darrell

Subjects
Fluidized-bed combustion -- Observations, Erosion -- Analysis, Electrolytes -- Conductivity, Earth sciences
Abstract

Highly weathered soils generally maintain low electrolyte levels in soil solution, which, along with raindrop impact, causes aggregate dispersion and enhanced erosion. This study was conducted to deter mine if application of fluidized bed combustion bottom ash (FBCBA) could control erosion of variable-charge soils. Seven highly weathered soils (six Oxisols and one Utisol) were prewetted and then subjected to high-intensity rainfall (110 mm [h.sup.-1]) for 2 h. The FBCBA was surface applied at a rate of 5 Mg ha-1. Infiltration, runoff, and erosion were measured throughout the rains. The FBCBA increase EC and pH of the soil solution, because it contained CaO (23%), [CA(OH).sub.2] 3%), and Ca[SO.sub.4] (73%). Steady-state infiltration rates (1) ranged from 7.2 to 54.8 nun [h.sup.-1] for the control and from 9.5 to 44.4 mm [h.sup.-1] for the FBCBA. Th FBCBA had either a favorable, an unfavorable, or no effect on the parameters tested, depending on the soil. On soils with a favorable response to FBCBA, [I.sub.s] was increased by 1.7 to two times, total runoff reduced by two times, and total erosion reduced by 2.2 to 2.4 times. On soils with an unfavorable response, 12 was decreased by 1.2 to 1.6 times, total runoff increased by 1.2 to 1.6 times, and erosion increased by 1.6 times. The increased infiltration and reduced erosion and runoff occurred only for soils that had low pH ([delta]pH [greater than or equal to] 0.6) and negative charge ([greater than or equal to] 2.0 [cmol.sub.c] [kg.sup.-1]). Unfavorable responses were found when [delta]ph was >2.1, charge increase was at least 6.8 cmok [kg.sup.-1], and final pH was >9.

Published
1996

145. Homologous recombination DNA repair defects in PALB2-associated breast cancers.

Author

Duijf P., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Harris M., Tucker K., Visvader J., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Cummings M., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Duijf P., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Harris M., Tucker K., Visvader J., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Cummings M., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., and Kefford R.

Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.Copyright © 2019, The Author(s).

Published
2019

146. Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers (npj Breast Cancer, (2019), 5, 1, (23), 10.1038/s41523-019-0115-9).

Author

Cummings M., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Duijf P., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Harris M., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Tucker K., Visvader J., Cummings M., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Duijf P., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Harris M., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Tucker K., and Visvader J.

Abstract

In the original version of this paper, the link to the data record in the Data Availability Statement was incorrectly listed as https:// doi.org/10.6084/m9.figshare.8138912.44. The link has been corrected to https://doi.org/10.6084/m9.figshare.8138912. This has been corrected in the HTML and PDF versions of this article.Copyright © 2019, The Author(s).

Published
2019

147. Homologous recombination DNA repair defects in PALB2-associated breast cancers (vol 5, 23, 2019)

Author

Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Tu, N-D, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mann, G, Marsh, D, McLachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, Young, MA, Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Tu, N-D, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mann, G, Marsh, D, McLachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, and Young, MA

Abstract

[This corrects the article DOI: 10.1038/s41523-019-0115-9.].

Published
2019

148. Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37298 women with early breast cancer in 26 randomised trials

Author

Boddington, C, Bradley, R, Braybrooke, J, Burrett, J, Clarke, M, Davies, C, Davies, L, Dodwell, D, Duane, F, Evans, V, Gettins, L, Godwin, J, Gray, R, Hills, R, James, S, Liu, H, Liu, Z, MacKinnon, E, Mannu, G, McGale, P, McHugh, T, Morris, P, Pan, H, Peto, R, Read, S, Taylor, C, Wang, Y, Wang, Z, Bergh, J, Barlow, W, Bliss, J, Bruzzi, P, Cameron, D, Fountzilas, G, Loibl, S, Mackey, J, Martin, M, Del Mastro, L, Moebus, V, Nekljudova, V, De Placido, S, Swain, S, Untch, M, Pritchard, KI, Norton, L, Fasching, P, Harbeck, N, Piedbois, P, Gnant, M, Steger, G, Di Leo, A, Dolci, S, Francis, P, Larsimont, D, Nogaret, JM, Philippson, C, Piccart-Gebhart, MJ, Linn, S, Peer, P, Tjan-Heijnen, V, Vliek, S, Slamon, D, Bartlett, JMS, Bramwell, VH, Chen, BE, Chia, SKL, Gelmon, K, Goss, PE, Levine, MN, Parulekar, W, Pater, JL, Rakovitch, E, Shepherd, LE, Tu, D, Whelan, T, Berry, D, Broadwater, G, Cirrincione, C, Muss, H, Weiss, RB, Shan, Y, Shao, YF, Wang, X, Xu, B, Zhao, DB, Bartelink, H, Bijker, N, Bogaerts, J, Cardoso, F, Cufer, T, Julien, JP, Poortmans, PM, Rutgers, E, van de Velde, CJH, Carrasco, E, Segui, MA, Blohmer, JU, Costa, SD, Gerber, B, Jackisch, C, von Minckwitz, G, Giuliano, M, De laurentiis, M, Bamia, C, Koliou, G-A, Mavroudis, D, A'Hern, R, Ellis, P, Kilburn, L, Morden, J, Yarnold, JR, Sadoon, M, Tulusan, AH, Anderson, S, Bass, G, Costantino, J, Dignam, J, Fisher, B, Geyer, C, Mamounas, EP, Paik, S, Redmond, C, Wickerham, L, Wolmark, N, Venturini, M, Bighin, C, Pastorino, S, Pronzato, P, Sertoli, MR, Foukakis, T, Albain, K, Arriagada, R, Bartlett, J, Bergsten-Nordstrom, E, Boccardo, F, Brain, E, Carey, L, Coates, A, Coleman, R, Correa, C, Cuzick, J, Davidson, N, Dowsett, M, Ewertz, M, Forbes, J, Gelber, R, Goldhirsch, A, Goodwin, P, Hayes, D, Hill, C, Ingle, J, Jagsi, R, Janni, W, Mukai, H, Ohashi, Y, Piccart, M, Pierce, L, Poortmans, P, Raina, V, Ravdin, P, Rea, D, Regan, M, Robertson, J, Sparano, J, Tutt, A, Viale, G, Wilcken, N, Wood, W, Zambetti, M, Boddington, C, Bradley, R, Braybrooke, J, Burrett, J, Clarke, M, Davies, C, Davies, L, Dodwell, D, Duane, F, Evans, V, Gettins, L, Godwin, J, Gray, R, Hills, R, James, S, Liu, H, Liu, Z, MacKinnon, E, Mannu, G, McGale, P, McHugh, T, Morris, P, Pan, H, Peto, R, Read, S, Taylor, C, Wang, Y, Wang, Z, Bergh, J, Barlow, W, Bliss, J, Bruzzi, P, Cameron, D, Fountzilas, G, Loibl, S, Mackey, J, Martin, M, Del Mastro, L, Moebus, V, Nekljudova, V, De Placido, S, Swain, S, Untch, M, Pritchard, KI, Norton, L, Fasching, P, Harbeck, N, Piedbois, P, Gnant, M, Steger, G, Di Leo, A, Dolci, S, Francis, P, Larsimont, D, Nogaret, JM, Philippson, C, Piccart-Gebhart, MJ, Linn, S, Peer, P, Tjan-Heijnen, V, Vliek, S, Slamon, D, Bartlett, JMS, Bramwell, VH, Chen, BE, Chia, SKL, Gelmon, K, Goss, PE, Levine, MN, Parulekar, W, Pater, JL, Rakovitch, E, Shepherd, LE, Tu, D, Whelan, T, Berry, D, Broadwater, G, Cirrincione, C, Muss, H, Weiss, RB, Shan, Y, Shao, YF, Wang, X, Xu, B, Zhao, DB, Bartelink, H, Bijker, N, Bogaerts, J, Cardoso, F, Cufer, T, Julien, JP, Poortmans, PM, Rutgers, E, van de Velde, CJH, Carrasco, E, Segui, MA, Blohmer, JU, Costa, SD, Gerber, B, Jackisch, C, von Minckwitz, G, Giuliano, M, De laurentiis, M, Bamia, C, Koliou, G-A, Mavroudis, D, A'Hern, R, Ellis, P, Kilburn, L, Morden, J, Yarnold, JR, Sadoon, M, Tulusan, AH, Anderson, S, Bass, G, Costantino, J, Dignam, J, Fisher, B, Geyer, C, Mamounas, EP, Paik, S, Redmond, C, Wickerham, L, Wolmark, N, Venturini, M, Bighin, C, Pastorino, S, Pronzato, P, Sertoli, MR, Foukakis, T, Albain, K, Arriagada, R, Bartlett, J, Bergsten-Nordstrom, E, Boccardo, F, Brain, E, Carey, L, Coates, A, Coleman, R, Correa, C, Cuzick, J, Davidson, N, Dowsett, M, Ewertz, M, Forbes, J, Gelber, R, Goldhirsch, A, Goodwin, P, Hayes, D, Hill, C, Ingle, J, Jagsi, R, Janni, W, Mukai, H, Ohashi, Y, Piccart, M, Pierce, L, Poortmans, P, Raina, V, Ravdin, P, Rea, D, Regan, M, Robertson, J, Sparano, J, Tutt, A, Viale, G, Wilcken, N, Wood, W, and Zambetti, M

Abstract

BACKGROUND: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. METHODS: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). FINDINGS: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82-0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83-0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83-0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78-0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76-0·91; p<0·0001), in the six t

Published
2019

149. Homologous recombination DNA repair defects in PALB2-associated breast cancers

Author

Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Nguyen-Dumont, T, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mane, G, Marsh, D, Mclachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, Young, MA, Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Nguyen-Dumont, T, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mane, G, Marsh, D, Mclachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, and Young, MA

Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Published
2019

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