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1. The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor

Author

Manuela Gago-Dominguez, Karina Dalsgaard Sørensen, Radka Kaneva, Canary Pass Investigators, Rosalind A. Eeles, Stella Koutros, Kim De Ruyck, Sonja I. Berndt, Manolis Kogevinas, Sofia Maia, Eli Marie Grindedal, Christopher J. Logothetis, Davor Lessel, Nora Pashayan, Ana Peixoto, Catarina Santos, Nawaid Usmani, Zsofia Kote-Jarai, Olivier Cussenot, Esther M. John, Christopher A. Haiman, Catherine M. Tangen, Jong Y. Park, Lorelei A. Mucci, Johanna Schleutker, Ruth C. Travis, Andreia Brandão, Sune F. Nielsen, Manuel R. Teixeira, Melissa C. Southey, Ana Vega, Adam S. Kibel, Ying Wang, Børge G. Nordestgaard, Cezary Cybulski, Jyotsna Batra, Kenneth Muir, Henrik Grönberg, Janet L. Stanford, Lisa F. Newcomb, Hermann Brenner, Manuela Pinheiro, Apcb BioResource, David E. Neal, Marta Cardoso, Paula Paulo, Barry S. Rosenstein, Monique J. Roobol, Robert J. Hamilton, Catharine M L West, Frank Claessens, Paul A. Townsend, Kathryn L. Penney, Susan L. Neuhausen, Alicja Wolk, Christiane Maier, Demetrius Albanes, Fredrik Wiklund, Maria P. Silva, Azad Hassan Abdul Razack, Sue A. Ingles, Urology, Brandão, Andreia [0000-0003-0938-1543], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Wang, Ying [0000-0002-1241-6252], Pashayan, Nora [0000-0003-0843-2468], Nordestgaard, Børge G [0000-0002-1954-7220], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Cybulski, Cezary [0000-0002-2819-3057], Park, Jong Y [0000-0002-6384-6447], Wiklund, Fredrik [0000-0002-4623-0544], Brenner, Hermann [0000-0002-6129-1572], Lessel, Davor [0000-0003-4496-244X], Gago-Dominguez, Manuela [0000-0001-6713-4351], Roobol, Monique J [0000-0001-6967-1708], Teixeira, Manuel R [0000-0002-4896-5982], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, SUSCEPTIBILITY LOCI, Cancer-Predisposing Gene, ancer predisposition, cancer predisposition, Biology, WHOLE-GENOME ASSOCIATION, CHEK2-ASTERISK-1100DELC, lcsh:RC254-282, G84E GERMLINE MUTATION, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, SDG 3 - Good Health and Well-being, medicine, BREAST-CANCER, Missense mutation, CHEK2, METAANALYSIS, Prostate cancer risk, Genetics, Cancer och onkologi, Science & Technology, founder variant, Manchester Cancer Research Centre, MISMATCH REPAIR GENES, ResearchInstitutes_Networks_Beacons/mcrc, Haplotype, 1100DELC, HOXB13, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, prostate cancer, BRCA2, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Relative risk, Cancer and Oncology, Life Sciences & Biomedicine, SNP array
Abstract

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. We thank the funding support from IPO-Porto Research Center (CI-IPOP-16-2012) and from Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/ UI0776/2014 and PTDC/DTP-PIC/1308/2014). The following authors were awarded with grants from FCT: PPa (UID/DTP/00776/2013/POCI-01-0145-FEDER-006868), SM (SFRH/BD/71397/2010) and PPi (SFRH/BD/73719/2010). The PRACTICAL consortium (http://practical.icr.ac.uk/) was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, NIHR funding to the Manchester Biomedical Research Centre and the Manchester Academic Health Sciences Centre.

Published
2020
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2. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Sara Benlloch, Roger L. Milne, Azad Hassan Abdul Razack, José Manuel Ruiz-Dominguez, Steven Joniau, Maria P. Silva, Martin Andreas Røder, Constance Turman, Anne-Maree Haynes, Jin Ling, Robert N. Hoover, Jong Y. Park, Johanna Schleutker, Brian E. Henderson, Amy Hutchinson, Stephanie J. Weinstein, Manolis Kogevinas, Melissa Papargiris, Monique J. Roobol, Gill Barnett, Wayne D. Tilley, Elio Riboli, Samantha E.T. Larkin, Melissa C. Southey, Michelle Guy, Jeanette T. Bensen, Henrik Grönberg, Fredrick R. Schumacher, Karina Dalsgaard Sørensen, Davor Lessel, Carin Cavalli-Bjoerkman, Tomislav Kuliš, Barry S. Rosenstein, Paula Kujala, Michael Davis, Andrzej M. Kierzek, Antonio Finelli, Gerald L. Andriole, Leire Moya, Antonio Gómez-Caamaño, Demetrius Albanes, Jianming Guo, Lisa F. Newcomb, Koveela Govindasami, Ji Lin, Gert De Meerleer, Manuel Luedeke, Richard M. Martin, Zeljko Kastelan, Kay-Tee Khaw, Ruth C. Travis, Rebecca Elliott, Alexandre R. Zlotta, Xin Guo, Kirsi Talala, Yangling Zhang, Lorelei A. Mucci, Marie Sanchez, Paul D.P. Pharoah, Mariona Bustamante, Peter Klarskov, Aleksandrina Vlahova, Srilakshmi Srinivasan, Aik T. Ong, David E. Neal, Sylvie Cénée, Esther M. John, Sonja I. Berndt, Kan Wang, Peter Iversen, Harry Ostrer, Michael Borre, Freddie C. Hamdy, Christopher A. Haiman, Ji Wu, Florence Menegaux, Jacek Marzec, Sara S. Strom, David P. Dearnaley, Jyotsna Batra, Piet Ost, Mariana C. Stern, Kim De Ruyck, Hyun Soo Park, Trina Yeadon, Elenko Popov, Yudong Wu, Svetlana Christova, Thomas Van den Broeck, Loic Le Marchand, Daniel J. Schaid, Babu Zachariah, Sune F. Nielsen, Mary-Anne Kedda, Judith A. Clements, Olivier Cussenot, Robert Szulkin, Shiro Saito, Andrew Evans, Douglas F. Easton, Gemma Castaño-Vinyals, Steve Hazel, Thérèse Truong, Guomin Wang, Katarina Cuk, Ants Toi, Rosalind A. Eeles, Darina Kachakova, Lourdes Mengual, Lisa G. Horvath, Yuan Chun Ding, Catharine M L West, Ana Carballo, Suzanne K. Chambers, Aurelie Vogt, Angela Cox, Daniel W. Lin, Dominika Wokołorczyk, Manuela Gago-Dominguez, Stephen J. Chanock, Federico Canzian, Aleksandra Klim, Tokhir Dadaev, Kathleen Herkommer, Tihomir Dikov, Lovise Maehle, Jasmine Lim, Janet L. Stanford, Martin Eklund, Guido Jenster, Soo-Hwang Teo, Teemu J. Murtola, Torben F. Ørntoft, Stella Koutros, Christa Stegmaier, Sofia Maia, Mitchell J. Machiela, Lisa A. Cannon-Albright, Clare Berry, Pamela Saunders, Lluís Cecchini, Jeri Kim, Radka Kaneva, Brigitte Trétarre, Anne George, Meir J. Stampfer, Marija Gamulin, Meng H. Tan, Angela Morgan, Jenny L Donovan, Graham G. Giles, Geraldine Cancel-Tassin, Neil Fleshner, Shannon K. McDonnell, Hardeep Ranu, Naomi Livni, Kimmo Taari, Sarah L. Kerns, Csilla Sipeky, Alicja Wolk, Edward Giovannucci, Ninghan Feng, Marta Cardoso, Jan-Erik Johansson, Catherine M. Tangen, Guangwen Cao, Adam S. Kibel, Robert J. MacInnis, Bernd Holleczek, Sarah J Lewis, Bo Zhou, Michael Broms, Maria Elena Martinez, Renea A. Taylor, Børge G. Nordestgaard, Fritz H. Schröder, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jie Li, Lori S. Tillmans, Ana Vega, Patricia Calvo, Christopher J. Logothetis, David V. Conti, Miguel Aguado, Inés Gómez-Acebo, Tobias Nordström, Meiling Li, Elaine A. Ostrander, C.H. Bangma, Cyril Fisher, Joanne F. Aitken, Matthew Parliament, Gail P. Risbridger, John L. Hopper, Takashi Imai, Belynda Hicks, Victoria L. Stevens, Cezary Cybulski, G Marsden, Brian D. Carter, Vanessa M. Hayes, Nawaid Usmani, Vanio Mitev, Shan-Chao Zhao, Margaret Cook, Milan S. Geybels, Phyllis J. Goodman, Mark N. Brook, Nora Pashayan, Timothy J. Key, Yongwei Yu, Xavier Rebillard, David J. Hunter, Laura Fachal, Javier Llorca, Afshan Siddiq, Claire Aukim-Hastie, Trinidad Dierssen-Sotos, Walther Vogel, Angel Carracedo, Laura E. Beane Freeman, Julio M. Pow-Sang, Hardev Pandha, Robert A. Gardiner, Shaun M. Riska, Yong-Jie Lu, Zan Sun, Ramón Lobato-Busto, Ami Karlsson, Hongwei Zhang, Guoping Ren, Jing Ma, Huihai Wu, Søren M. Bentzen, John Pedersen, Claire Mulot, Girish S. Kulkarni, Jan Lubinski, Antonio Alcaraz, Jose E. Castelao, Athene Lane, Rasmus Bisbjerg, Thomas A. Sellers, Robert J. Hamilton, Jianfeng Xu, Sofie De Langhe, Artitaya Lophatananon, Maren Weisher, Agnieszka Michael, Yves Akoli Koudou, Niclas Håkansson, Alison M. Dunning, Hubert Thierens, Matthew L. Freedman, Kenneth Muir, Ian M. Thompson, Ian Whitmore, Susan L. Neuhausen, Chavdar Slavov, Wojciech Kluzniak, Laurence N. Kolonel, Lisa M. Butler, Teuvo L.J. Tammela, Alison Thwaites, Theodorus van der Kwast, Liesel M. FitzGerald, Thomas J. Schnoeller, Hermann Brenner, Christiane Maier, Amanda B. Spurdle, Jan Adolfsson, Atanaska Mitkova, Peter Kraft, Paula Peleteiro, Pär Stattin, Xin Sheng, Paul D. Brown, Ron H.N. van Schaik, Zsofia Kote-Jarai, Susan M. Gapstur, Paul A. Townsend, Edward J. Saunders, Bettina F. Drake, Stephen N. Thibodeau, Fredrik Wiklund, Paula Paulo, Esther Gracia-Lavedan, Xueying Mao, Marco Matejcic, Neil G. Burnet, A. L. Eckert, Manuel R. Teixeira, Sara Lindström, Weiyang He, Hui-Yi Lin, Suzanne Kolb, Linda Steele, Philipp Bohnert, Anssi Auvinen, Eli Marie Grindedal, Frank Claessens, and Kathryn L. Penney

Subjects
Urologic Diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Internal medicine, medicine, PRACTICAL Consortium, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, business.industry, Prostate Cancer, Published Erratum, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Spelling, 3. Good health, 030104 developmental biology, Variation (linguistics), lcsh:Q, 0210 nano-technology, business
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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3. Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis

Author

Paula Paulo, Marta Cardoso, Sofia Maia, and Manuel R. Teixeira

Subjects
0301 basic medicine, Cancer Research, Mutation, Cell, Mutagenesis (molecular biology technique), Biology, medicine.disease_cause, medicine.disease, Phenotype, 3. Good health, 03 medical and health sciences, Prostate cancer, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Germline mutation, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, Missense mutation, Gene
Abstract

The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.

Published
2016
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4. Truncating and missensePPM1Dmutations in early-onset and/or familial/hereditary prostate cancer patients

Author

Marta Cardoso, Paula Paulo, Manuel R. Teixeira, and Sofia Maia

Subjects
0301 basic medicine, Oncology, Cancer Research, Chemotherapy, Mutation, medicine.medical_specialty, medicine.medical_treatment, Case-control study, Biology, medicine.disease_cause, medicine.disease, 03 medical and health sciences, Exon, 030104 developmental biology, 0302 clinical medicine, Germline mutation, 030220 oncology & carcinogenesis, Internal medicine, Genetics, medicine, Missense mutation, Adenocarcinoma, Age of onset
Abstract

Truncating activating mutations in the last exon of PPM1D have been described in patients with breast, ovarian, colorectal and non-small cell lung cancer, but recent data indicate that they may be associated with previous chemotherapy. In this study we evaluated the prevalence of PPM1D mutations in white blood cells (WBC) of 462 patients with early-onset and/or familial/hereditary prostate cancer (PrCa) by sequencing the coding region of exon 6. Two truncating mutations were found in two patients (0.4%), both treated with androgen-ablation therapy but no chemotherapy prior to blood collection. Next generation sequencing analysis showed that the truncating variants were present in 21.4% and 32.4% of the reads, indicating that they were in mosaic in WBC, something that was confirmed by its absence in a different tissue from one of these patients. Additionally, nine patients (1.95%) were found to harbor non-synonymous germline mutations, with three patients sharing the same missense variant, c.1607G > A, p.Arg536Lys. This variant was predicted to be deleterious by different in silico tools and was not found in the 293 male control subjects tested. Large cohorts and/or functional evaluation are needed to clarify the nature of the truncating mosaic mutations in PrCa patients treated with and without androgen-ablation therapy and to evaluate the contribution of the recurrent missense variant to the risk of developing PrCa. © 2016 Wiley Periodicals, Inc.

Published
2016
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5. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author

Rosalind A. Eeles, Karina Dalsgaard Sørensen, Torben F. Ørntoft, Jeri Kim, Wayne D. Tilley, Ruth C. Travis, Lorelei A. Mucci, Jenny L Donovan, Kay-Tee Khaw, Edward Giovannucci, Christopher I. Amos, Soo Hwang Teo, Claire Aukim-Hastie, Gerald L. Andriole, Linda Steele, Martin Eklund, Guomin Wang, Michael Borre, Antonio Finelli, Liesel M. FitzGerald, Thérèse Truong, Robert N. Hoover, Sandeep Singhal, Radka Kaneva, Frank Claessens, Robert Szulkin, Javier Llorca, Dominika Wokołorczyk, Esther M. John, Daniel J. Schaid, Jyotsna Batra, Kathryn L. Penney, Børge G. Nordestgaard, Catharine M L West, Hermann Brenner, Sue A. Ingles, Markus Aly, Jonathan Tyrer, Thomas J. Schnoeller, Xin Guo, Peter Iversen, Olivier Cussenot, Laurence N. Kolonel, Henrik Grönberg, Ninghan Feng, Geraldine Cancel-Tassin, Christiane Maier, David E. Neal, Marija Gamulin, Ezequiel Anokian, Christopher J. Logothetis, Shannon K. McDonnell, Lovise Maehle, Anssi Auvinen, Antonio Gómez-Caamaño, Tomislav Kuliš, Manuel Luedeke, Teuvo L.J. Tammela, Brian D. Carter, Zan Sun, Jong Y. Park, Nawaid Usmani, Ian M. Thompson, Zuxi Cui, Johanna Schleutker, Bernd Holleczek, Davor Lessel, Katarina Cuk, Eli Marie Grindedal, Milan S. Geybels, Yuan Chun Ding, Phyllis J. Goodman, Jing Ma, Paul A. Townsend, Edward J. Saunders, Melissa C. Southey, Graham G. Giles, Robert J. Hamilton, Laura Fachal, Mitchell J. Machiela, Demetrius Albanes, Gert De Meerleer, Paula Paulo, Agnieszka Michael, Yves Akoli Koudou, Janet L. Stanford, Kim De Ruyck, Thomas Van den Broeck, Tokhir Dadaev, Clara Cieza-Borrella, Sonja I. Berndt, Artitaya Lophatananon, Brian E. Henderson, Niclas Håkansson, Christopher A. Haiman, Florence Menegaux, Xueying Mao, Jan Lubinski, Elio Riboli, Paul D.P. Pharoah, David J. Hunter, Loic Le Marchand, Stephen N. Thibodeau, Fredrik Wiklund, Tobias Nordström, Thomas A. Sellers, Chee Goh, Elaine A. Ostrander, Sune F. Nielsen, Neil E. Fleshner, Neil G. Burnet, Rasmus Bisbjerg, Manuela Gago Dominguez, Csilla Sipeky, Maria Elena Martinez, Susan L. Neuhausen, Stephen J. Chanock, Hui Yi Lin, Laura E. Beane Freeman, A. Siddiq, Alicja Wolk, Gemma Castaño-Vinyals, Lisa F. Newcomb, Catherine M. Tangen, Ana Vega, Peter Kraft, Chavdar Slavov, Daniel Leongamornlert, Lisa A. Cannon-Albright, Stella Koutros, Manuel R. Teixeira, Susan M. Gapstur, Federico Canzian, Sara Lindström, Maren Weischer, Bettina F. Drake, Lisa G. Horvath, Daniel W. Lin, Jose Esteban Castelao, Yong-Jie Lu, Xin Sheng, Vanio Mitev, Ron H.N. van Schaik, Monique J. Roobol, Zsofia Kote-Jarai, Leire Moya, Alison M. Dunning, Mahbubl Ahmed, Kenneth Muir, Douglas F. Easton, Suzanne K. Chambers, Hongwei Zhang, Jianfeng Xu, Jasmine Lim, Meir J. Stampfer, Guido Jenster, Ali Amin Al Olama, Victoria L. Stevens, Sara Benlloch, Mark N. Brook, Azad Hassan Abdul Razack, Marta Cardoso, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Fredrick R. Schumacher, Martin Andreas Røder, Harry Ostrer, Judith A. Clements, Manolis Kogevinas, Barry S. Rosenstein, Steven Joniau, Richard M. Martin, Constance Turman, Mariana C. Stern, Joe Dennis, David V. Conti, Sarah L. Kerns, Adam S. Kibel, Robert J. MacInnis, Stephanie J. Weinstein, Freddie C. Hamdy, Cezary Cybulski, Nora Pashayan, Timothy J. Key, Hardev Pandha, Piet Ost, Urology, Clinical Chemistry, Imperial College Trust, Schumacher, Fredrick R [0000-0002-3073-7463], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, PREDICTION, Cancer of the Prostate in Sweden (CAPS), Genome-wide association study, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, VARIANTS, Australian Prostate Cancer BioResource (APCB), urologic and male genital diseases, DISEASE, FAMILY-HISTORY, PATHWAY, Prostate cancer, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), 11 Medical and Health Sciences, Genetics & Heredity, RISK, education.field_of_study, Profile Study, IMPACT Study, 3. Good health, prostate cancer (PrCa)-susceptibility loci, Centre for Surgical Research, BIOLOGICAL PATHWAYS, ICEP, Life Sciences & Biomedicine, Medical Genetics, Risk, medicine.medical_specialty, Genotype, Population, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, MULTIPLE LOCI, Breast and Prostate Cancer Cohort Consortium (BPC3), SDG 3 - Good Health and Well-being, Internal medicine, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Genotyping, METAANALYSIS, Medicinsk genetik, Genetic association, Canary PASS Investigators, Science & Technology, IDENTIFICATION, CONSORTIUM, Case-control study, Prostatic Neoplasms, 06 Biological Sciences, medicine.disease, GENE, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, 030104 developmental biology, Genetic Loci, Relative risk, Case-Control Studies, genotype, humans, male, Developmental Biology, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

Published
2018
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6. The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer

Author

Catarina Santos, Rui Henrique, Sofia Maia, Manuela Pinheiro, Paula Paulo, Ana Peixoto, Marta Cardoso, Carla M. A. Pinto, Manuel R. Teixeira, and Pedro Pinto

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Genotype, DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Disease, urologic and male genital diseases, Bioinformatics, MLH1, DNA Mismatch Repair, Germline, Familial prostate cancer, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Genetics, Medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Genetics (clinical), Germ-Line Mutation, business.industry, Prostatic Neoplasms, Middle Aged, medicine.disease, Lynch syndrome, MSH6, 030104 developmental biology, Oncology, MSH2, 030220 oncology & carcinogenesis, business
Abstract

Prostate cancer (PrCa) is one of the most common cancers diagnosed worldwide and 5-10 % of all cases are estimated to be associated with inherited predisposition. Even though there is strong evidence that the genetic component is significant in PrCa, the genetic etiology of familial and early-onset disease is largely unknown. Although it has been suggested that men from families with hereditary breast/ovarian cancer (HBOC) and, more recently, with Lynch syndrome may have an increased risk for PrCa, the contribution of these syndromes to PrCa predisposition in families ascertained for early-onset and/or familial PrCa, independently of the presence of other cancers in the family, is uncertain. To quantify the contribution of genes associated with HBOC and Lynch syndromes to PrCa predisposition, we have tested for germline mutations 460 early-onset and/or familial PrCa patients. All patients were screened for the six mutations that are particularly common in Portugal and 38 of them were selected for complete sequencing of BRCA1/2 and/or MLH1, MSH2 and MSH6. Two patients were found to harbor the same MSH2 mutation and a third patient carried a Portuguese BRCA2 founder mutation. None of the alterations were identified in 288 control subjects. Furthermore, we reviewed the 62 PrCa diagnoses in all HBOC (n = 161) and Lynch syndrome (n = 124) families previously diagnosed at our department, and found five other BRCA2 mutation carriers and two additional MSH2 mutation carriers. The clinicopathological characteristics of mutation carriers are in concordance with earlier data suggesting an aggressive PrCa phenotype and support the hypothesis that mutation carriers might benefit from targeted screening according to the gene mutated in the germline.

Published
2015

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