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1. A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.

Author

Srinivasan S, Kryza T, Bock N, Tse BWC, Sokolowski KA, Janaththani P, Fernando A, Moya L, Stephens C, Dong Y, Röhl J, Alinezhad S, Vela I, Perry-Keene JL, Buzacott K, Nica R, Gago-Dominguez M, Schleutker J, Maier C, Muir K, Tangen CM, Gronberg H, Pashayan N, Albanes D, Wolk A, Stanford JL, Berndt SI, Mucci LA, Koutros S, Cussenot O, Sorensen KD, Grindedal EM, Travis RC, Haiman CA, MacInnis RJ, Vega A, Wiklund F, Neal DE, Kogevinas M, Penney KL, Nordestgaard BG, Brenner H, John EM, Gamulin M, Claessens F, Melander O, Dahlin A, Stattin P, Hallmans G, Häggström C, Johansson R, Thysell E, Rönn AC, Li W, Brown N, Dimeski G, Shepherd B, Dadaev T, Brook MN, Spurdle AB, Stenman UH, Koistinen H, Kote-Jarai Z, Klein RJ, Lilja H, Ecker RC, Eeles R, Clements J, and Batra J

Subjects
Male, Humans, Genetic Predisposition to Disease, Aged, Animals, Chromosomes, Human, Pair 19 genetics, Middle Aged, Mice, Alleles, Cell Line, Tumor, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms mortality, Polymorphism, Single Nucleotide, Prostate-Specific Antigen blood, Prostate-Specific Antigen metabolism, Kallikreins genetics, Kallikreins metabolism
Abstract

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes., (© 2024. The Author(s).)

Published
2024
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2. A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

Author

Wang V, Geybels MS, Jordahl KM, Gerke T, Hamid A, Penney KL, Markt SC, Freedman M, Pomerantz M, Lee GM, Rana H, Börnigen D, Rebbeck TR, Huttenhower C, Eeles RA, Stanford JL, Consortium P, Berndt SI, Claessens F, Sørensen KD, Park JY, Vega A, Usmani N, Mucci L, and Sweeney CJ

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Follow-Up Studies, Humans, Male, Middle Aged, Prostatic Neoplasms diagnosis, Extracellular Matrix Proteins genetics, Genetic Association Studies methods, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Prostatic Neoplasms genetics
Abstract

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer)., Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian., Results: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years., Conclusions: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men., (© 2021 Wiley Periodicals LLC.)

Published
2021
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3. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Author

Karunamuni RA, Huynh-Le MP, Fan CC, Thompson W, Eeles RA, Kote-Jarai Z, Muir K, Lophatananon A, Schleutker J, Pashayan N, Batra J, Grönberg H, Walsh EI, Turner EL, Lane A, Martin RM, Neal DE, Donovan JL, Hamdy FC, Nordestgaard BG, Tangen CM, MacInnis RJ, Wolk A, Albanes D, Haiman CA, Travis RC, Stanford JL, Mucci LA, West CML, Nielsen SF, Kibel AS, Wiklund F, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Park JY, Ingles SA, Maier C, Hamilton RJ, Rosenstein BS, Vega A, Kogevinas M, Penney KL, Teixeira MR, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, Razack A, Newcomb LF, Gamulin M, Usmani N, Claessens F, Gago-Dominguez M, Townsend PA, Roobol MJ, Zheng W, Mills IG, Andreassen OA, Dale AM, and Seibert TM

Subjects
Adult, Aged, Follow-Up Studies, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Risk Factors, Biomarkers, Tumor genetics, Models, Statistical, Polymorphism, Single Nucleotide, Prostatic Neoplasms pathology, Risk Assessment methods
Abstract

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46)., Materials and Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy., Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer., Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Published
2021
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4. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author

Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL, Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, Hunter DJ, Imyanitov EN, Jager A, Jakubowska A, James PA, Jensen UB, John EM, Jones ME, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khusnutdinova E, Kiiski JI, Ko YD, Kosma VM, Kraft P, Kurian AW, Laitman Y, Lambrechts D, Le Marchand L, Lester J, Lesueur F, Lindstrom T, Lopez-Fernández A, Loud JT, Luccarini C, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Mebirouk N, Meindl A, Miller A, Milne RL, Montagna M, Nathanson KL, Neuhausen SL, Nevanlinna H, Nielsen FC, O'Brien KM, Olopade OI, Olson JE, Olsson H, Osorio A, Ottini L, Park-Simon TW, Parsons MT, Pedersen IS, Peshkin B, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Polley EC, Poppe B, Presneau N, Pujana MA, Punie K, Radice P, Rantala J, Rashid MU, Rennert G, Rennert HS, Robson M, Romero A, Rossing M, Saloustros E, Sandler DP, Santella R, Scheuner MT, Schmidt MK, Schmidt G, Scott C, Sharma P, Soucy P, Southey MC, Spinelli JJ, Steinsnyder Z, Stone J, Stoppa-Lyonnet D, Swerdlow A, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Teulé A, Thull DL, Tischkowitz M, Toland AE, Torres D, Trainer AH, Truong T, Tung N, Vachon CM, Vega A, Vijai J, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wolk A, Yadav S, Yang XR, Yannoukakos D, Zheng W, Ziogas A, Zorn KK, Park SK, Thomassen M, Offit K, Schmutzler RK, Couch FJ, Simard J, Chenevix-Trench G, Easton DF, Andrieu N, and Antoniou AC

Subjects
Adult, Alleles, Female, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Mutation, Quantitative Trait Loci genetics, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10 -8 , at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Published
2021
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5. Haplotype analysis of the internationally distributed BRCA1 c.3331&#95;3334delCAAG founder mutation reveals a common ancestral origin in Iberia.

Author

Tuazon AMA, Lott P, Bohórquez M, Benavides J, Ramirez C, Criollo A, Estrada-Florez A, Mateus G, Velez A, Carmona J, Olaya J, Garcia E, Polanco-Echeverry G, Stultz J, Alvarez C, Tapia T, Ashton-Prolla P, Vega A, Lazaro C, Tornero E, Martinez-Bouzas C, Infante M, De La Hoya M, Diez O, Browning BL, Rannala B, Teixeira MR, Carvallo P, Echeverry M, and Carvajal-Carmona LG

Subjects
Africa epidemiology, Brazil epidemiology, Chile epidemiology, Chromosomes, Human, Pair 17 genetics, Colombia epidemiology, Female, Founder Effect, Genome-Wide Association Study methods, Humans, Portugal epidemiology, Spain epidemiology, BRCA1 Protein genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Haplotypes, Polymorphism, Single Nucleotide
Abstract

Background: The BRCA1 c.3331&#95;3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331&#95;3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry., Methods: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331&#95;3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia., Results: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period., Conclusions: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.

Published
2020
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6. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author

Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K, Alonso MR, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Aronson KJ, Arun BK, Auber B, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Beeghly-Fadiel A, Benitez J, Bermisheva M, Białkowska K, Blanco AM, Blomqvist C, Blot W, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Bosse K, Brauch H, Brenner H, Briceno I, Brock IW, Brooks-Wilson A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldés T, Caligo MA, Camp NJ, Campbell I, Canzian F, Carroll JS, Carter BD, Castelao JE, Chiquette J, Christiansen H, Chung WK, Claes KBM, Clarke CL, Collée JM, Cornelissen S, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Domchek SM, Dörk T, Dos-Santos-Silva I, Droit A, Dubois S, Dumont M, Duran M, Durcan L, Dwek M, Eccles DM, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Floris G, Flyger H, Foretova L, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gago-Dominguez M, Gambino G, Ganz PA, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Tibiletti MG, Greene MH, Grip M, Gronwald J, Grundy A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hartikainen JM, Hartman M, He W, Healey CS, Heemskerk-Gerritsen BAM, Heyworth J, Hillemanns P, Hogervorst FBL, Hollestelle A, Hooning MJ, Hopper JL, Howell A, Huang G, Hulick PJ, Imyanitov EN, Isaacs C, Iwasaki M, Jager A, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kang D, Kapoor PM, Karlan BY, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Kirk J, Kitahara CM, Ko YD, Konstantopoulou I, Kosma VM, Koutros S, Kubelka-Sabit K, Kwong A, Kyriacou K, Laitman Y, Lambrechts D, Lee E, Leslie G, Lester J, Lesueur F, Lindblom A, Lo WY, Long J, Lophatananon A, Loud JT, Lubiński J, MacInnis RJ, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matsuo K, Maurer T, Mavroudis D, Mayes R, McGuffog L, McLean C, Mebirouk N, Meindl A, Miller A, Miller N, Montagna M, Moreno F, Muir K, Mulligan AM, Muñoz-Garzon VM, Muranen TA, Narod SA, Nassir R, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nikitina-Zake L, Norman A, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Osorio A, Pankratz VS, Papp J, Park SK, Park-Simon TW, Parsons MT, Paul J, Pedersen IS, Peissel B, Peshkin B, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Prokofyeva D, Pujana MA, Pylkäs K, Radice P, Ramus SJ, Rantala J, Rau-Murthy R, Rennert G, Risch HA, Robson M, Romero A, Rossing M, Saloustros E, Sánchez-Herrero E, Sandler DP, Santamariña M, Saunders C, Sawyer EJ, Scheuner MT, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Scott C, Scott RJ, Senter L, Seynaeve CM, Shah M, Sharma P, Shen CY, Shu XO, Singer CF, Slavin TP, Smichkoska S, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Stoppa-Lyonnet D, Sutter C, Swerdlow AJ, Tamimi RM, Tan YY, Tapper WJ, Taylor JA, Teixeira MR, Tengström M, Teo SH, Terry MB, Teulé A, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Torres-Mejía G, Troester MA, Truong T, Tung N, Tzardi M, Ulmer HU, Vachon CM, van Asperen CJ, van der Kolk LE, van Rensburg EJ, Vega A, Viel A, Vijai J, Vogel MJ, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wildiers H, Winqvist R, Wolk A, Wu AH, Yannoukakos D, Zhang Y, Zheng W, Hunter D, Pharoah PDP, Chang-Claude J, García-Closas M, Schmidt MK, Milne RL, Kristensen VN, French JD, Edwards SL, Antoniou AC, Chenevix-Trench G, Simard J, Easton DF, Kraft P, and Dunning AM

Subjects
Bayes Theorem, Female, Humans, Linkage Disequilibrium, Regulatory Sequences, Nucleic Acid, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Chromosome Mapping methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract

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

Published
2020
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7. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Author

Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, and Simard J

Subjects
Breast Neoplasms ethnology, Breast Neoplasms metabolism, Female, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study methods, Heterozygote, Humans, Receptors, Estrogen metabolism, Risk Factors, White People genetics, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mutation, Polymorphism, Single Nucleotide
Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Published
2017
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8. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

Author

Ahmed M, Dorling L, Kerns S, Fachal L, Elliott R, Partliament M, Rosenstein BS, Vega A, Gómez-Caamaño A, Barnett G, Dearnaley DP, Hall E, Sydes M, Burnet N, Pharoah PD, Eeles R, and West CM

Subjects
Aged, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Middle Aged, Principal Component Analysis, Prostatic Neoplasms ethnology, White People genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, Prostatic Neoplasms radiotherapy, Radiation Injuries epidemiology
Abstract

Background: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy., Methods: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods., Results: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity., Conclusion: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.

Published
2016
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9. Radiogenomics: radiobiology enters the era of big data and team science.

Author

Rosenstein BS, West CM, Bentzen SM, Alsner J, Andreassen CN, Azria D, Barnett GC, Baumann M, Burnet N, Chang-Claude J, Chuang EY, Coles CE, Dekker A, De Ruyck K, De Ruysscher D, Drumea K, Dunning AM, Easton D, Eeles R, Fachal L, Gutiérrez-Enríquez S, Haustermans K, Henríquez-Hernández LA, Imai T, Jones GD, Kerns SL, Liao Z, Onel K, Ostrer H, Parliament M, Pharoah PD, Rebbeck TR, Talbot CJ, Thierens H, Vega A, Witte JS, Wong P, and Zenhausern F

Subjects
Alleles, Chromosome Aberrations, Genetic Predisposition to Disease genetics, Humans, Neoplasms genetics, Radiation Tolerance genetics, Radiotherapy Dosage, Sample Size, Genome-Wide Association Study methods, Genomics methods, Genotype, Neoplasms radiotherapy, Phenotype, Polymorphism, Single Nucleotide genetics, Radiation Injuries genetics
Abstract

Competing Interests: E.Y. Chuang holds a patent on biomarkers for predicting response of esophageal cancer patients to chemoradiation therapy. The authors report no other conflict of interest.

Published
2014
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10. Association of a XRCC3 polymorphism and rectum mean dose with the risk of acute radio-induced gastrointestinal toxicity in prostate cancer patients.

Author

Fachal L, Gómez-Caamaño A, Peleteiro P, Carballo A, Calvo-Crespo P, Sánchez-García M, Lobato-Busto R, Carracedo A, and Vega A

Subjects
Aged, Aged, 80 and over, Biomarkers blood, Case-Control Studies, Follow-Up Studies, Gastrointestinal Diseases genetics, Gastrointestinal Tract radiation effects, Humans, Male, Middle Aged, Prospective Studies, Prostatectomy, Prostatic Neoplasms blood, Prostatic Neoplasms etiology, Prostatic Neoplasms surgery, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated adverse effects, Risk Factors, Time Factors, Urinary Bladder radiation effects, Urogenital System radiation effects, DNA-Binding Proteins genetics, Gastrointestinal Diseases etiology, Polymorphism, Single Nucleotide genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms radiotherapy, Radiotherapy, Conformal adverse effects, Rectum radiation effects
Abstract

Background and Purpose: We have performed a case-control study among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) in order to investigate the association between single nucleotide polymorphisms (SNPs), treatment and patient features with gastrointestinal and genitourinary acute toxicity., Material and Methods: A total of 698 patients were screened for 14 SNPs located in the ATM, ERCC2, LIG4, MLH1 and XRCC3 genes. Gastrointestinal and genitourinary toxicities were recorded prospectively using the Common Terminology Criteria for Adverse Events v3.0., Results: The XRCC3 SNP rs1799794 (G/G OR=5.65; 95% CI: 1.95-16.38; G/A OR=2.75; 95% CI: 1.25-6.05; uncorrected p-value=2.8×10(-03); corrected p-value=0.03; FDR q-value=0.06) as well as the mean dose received by the rectum (OR=1.06; 95% CI: 1.02-1.1; uncorrected p-value=2.49×10(-03); corrected p-value=0.03; FDR q-value=0.06) were significantly associated with gastrointestinal toxicity after correction for multiple testing. Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity (OR=0.38; 95% CI: 0.18-0.71; uncorrected p-value=4.95×10(-03); corrected p-value=0.03; FDR q-value=0.08). Our study excludes the possibility of a >2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP, the rs1805386 and rs1805388 LIG4 markers, as well as all the SNPs evaluated in the ERCC2, MLH1 and XRCC3 genes., Conclusions: The XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Published
2012
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11. TGFβ1 SNPs and radio-induced toxicity in prostate cancer patients.

Author

Fachal L, Gómez-Caamaño A, Sánchez-García M, Carballo A, Peleteiro P, Lobato-Busto R, Carracedo A, and Vega A

Subjects
Case-Control Studies, Haplotypes, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms radiotherapy, Radiotherapy, Conformal adverse effects, Transforming Growth Factor beta1 genetics
Abstract

Background and Purpose: We have performed a case-control study in 413 prostate cancer patients to test for association between TGFβ1 and the development of late normal-tissue toxicity among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) MATERIALS AND METHODS: Late gastrointestinal and genitourinary toxicities were assessed for at least two years after radiotherapy in 413 patients according to CTCAEvs3 scores. Codominant genotypic tests and haplotypic analyses were undertaken to evaluate the correlation between TGFβ1 SNPs rs1800469, rs1800470 and rs1800472 and radio-induced toxicity., Results: Neither the SNPs nor the haplotypes were found to be associated with the risk of late toxicity., Conclusions: We were able to exclude up to a 2-fold increase in the risk of developing late gastrointestinal and genitourinary radio-induced toxicity due to the TGFβ1 SNPs rs1800469 and rs1800470, as well as the two most frequent TGFβ1 haplotypes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Published
2012
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12. Establishment of a Radiogenomics Consortium.

Author

West C, Rosenstein BS, Alsner J, Azria D, Barnett G, Begg A, Bentzen S, Burnet N, Chang-Claude J, Chuang E, Coles C, De Ruyck K, De Ruysscher D, Dunning A, Elliott R, Fachal L, Hall J, Haustermans K, Herskind C, Hoelscher T, Imai T, Iwakawa M, Jones D, Kulich C, Langendijk JH, O'Neils P, Ozsahin M, Parliament M, Polanski A, Rosenstein B, Seminara D, Symonds P, Talbot C, Thierens H, Vega A, West C, and Yarnold J

Subjects
Genetic Predisposition to Disease genetics, Genetic Variation genetics, Humans, United Kingdom, Neoplasms radiotherapy, Polymorphism, Single Nucleotide genetics, Radiation Injuries genetics, Radiation Tolerance genetics
Published
2010
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13. Association of ESR1 gene tagging SNPs with breast cancer risk.

Author

Dunning AM, Healey CS, Baynes C, Maia AT, Scollen S, Vega A, Rodríguez R, Barbosa-Morais NL, Ponder BA, Low YL, Bingham S, Haiman CA, Le Marchand L, Broeks A, Schmidt MK, Hopper J, Southey M, Beckmann MW, Fasching PA, Peto J, Johnson N, Bojesen SE, Nordestgaard B, Milne RL, Benitez J, Hamann U, Ko Y, Schmutzler RK, Burwinkel B, Schürmann P, Dörk T, Heikkinen T, Nevanlinna H, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Chen X, Spurdle A, Change-Claude J, Flesch-Janys D, Couch FJ, Olson JE, Severi G, Baglietto L, Børresen-Dale AL, Kristensen V, Hunter DJ, Hankinson SE, Devilee P, Vreeswijk M, Lissowska J, Brinton L, Liu J, Hall P, Kang D, Yoo KY, Shen CY, Yu JC, Anton-Culver H, Ziogoas A, Sigurdson A, Struewing J, Easton DF, Garcia-Closas M, Humphreys MK, Morrison J, Pharoah PD, Pooley KA, and Chenevix-Trench G

Subjects
Breast Neoplasms pathology, Female, Haplotypes, Humans, Neoplasm Staging, RNA, Neoplasm genetics, Breast Neoplasms genetics, Estrogen Receptor alpha genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
Abstract

We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.

Published
2009
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14. Haplotype and quantitative transcript analyses of Portuguese breast/ovarian cancer families with the BRCA1 R71G founder mutation of Galician origin.

Author

Santos C, Peixoto A, Rocha P, Vega A, Soares MJ, Cerveira N, Bizarro S, Pinheiro M, Pereira D, Rodrigues H, Castro F, Henrique R, and Teixeira MR

Subjects
Alternative Splicing, Amino Acid Substitution, Arginine genetics, DNA Mutational Analysis, Genotype, Glycine genetics, Humans, Portugal, Reverse Transcriptase Polymerase Chain Reaction, BRCA1 Protein genetics, Breast Neoplasms genetics, Haplotypes, Polymorphism, Single Nucleotide
Abstract

We investigated the functional effect of the missense variant c.211A>G (R71G) localized at position -2 of exon 5 donor splice site in the BRCA1 gene and evaluated whether Portuguese and Galician families with this mutation share a common ancestry. Three unrelated Portuguese breast/ovarian cancer families carrying this variant were studied through qualitative and quantitative transcript analyses. We also evaluated the presence of loss of heterozigosity and the histopathologic characteristics of the carcinomas in those families. Informative families (two from Portugal and one from Galicia) were genotyped for polymorphic microsatellite markers flanking BRCA1 to reconstruct haplotypes. Qualitative RNA analysis revealed the presence of two alternative transcripts both in carriers of the BRCA1 R71G variant and in controls. Semi-quantitative fragment analysis and real-time RT-PCR showed a significant increase of the transcript with an out of frame deletion of the last 22nt of exon 5 (BRCA1-Delta22ntex5) and a decrease of the full-length transcript (BRCA1-ex5FL) in patients carrying the R71G mutation as compared to controls, whereas no significant differences were found for the transcript with in frame skipping of exon 5 (BRCA1-Deltaex5). One haplotype was found to segregate in the two informative Portuguese families and in the Galician family. We demonstrate that disruption of alternative transcript ratios is the mechanism causing hereditary breast/ovarian cancer associated with the BRCA1 R71G mutation. Furthermore, our findings indicate a common ancestry of the Portuguese and Galician families sharing this mutation.

Published
2009
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15. Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: a two-stage Spanish case-control study.

Author

Vega A, Salas A, Milne RL, Carracedo B, Ribas G, Ruibal A, de León AC, González-Hernández A, Benítez J, and Carracedo A

Subjects
Adult, Aged, Aged, 80 and over, Alleles, Cell Cycle Proteins genetics, Female, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Middle Aged, Breast Neoplasms genetics, Penetrance, Polymorphism, Single Nucleotide
Abstract

Objectives: A polygenic model has been proposed in order to explain the genetic susceptibility to sporadic breast cancer. According to this model, common population variants would be responsible for low to modest effects on the risk of developing the disease. We have carried out a high-throughput SNP genotyping project in order to shed some light on the complex genetic aetiology of non-familial breast cancer., Methods: Ninety-one genes have been selected because of their implications in several candidate cell pathways for breast cancer. A total of 640 SNPs in these genes were genotyped in a series of 450 consecutive cases and 448 controls from mainland Spain. Promising SNPs were then studied in an independent series of 294 cases and 299 controls from the Canary Islands., Results: In the first case-control series we identified 25 SNPs with P-values below 0.05 (under a 1 df Chi-square test), five of them with P-values below 0.01 (best=0.0008). In the stage 2 Canary Islands series, odd ratios (OR) for two SNPs in HUS1 were in a consistent direction., Conclusions: SNPs located at the gene HUS1 are good candidates for further investigation in independent association studies and functional assays.

Published
2009
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17. Evaluating HapMap SNP data transferability in a large-scale genotyping project involving 175 cancer-associated genes.

Author

Ribas G, González-Neira A, Salas A, Milne RL, Vega A, Carracedo B, González E, Barroso E, Fernández LP, Yankilevich P, Robledo M, Carracedo A, and Benítez J

Subjects
Gene Frequency, Genome, Human, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Biomarkers, Tumor analysis, Genes, Neoplasm, Polymorphism, Single Nucleotide
Abstract

One of the many potential uses of the HapMap project is its application to the investigation of complex disease aetiology among a wide range of populations. This study aims to assess the transferability of HapMap SNP data to the Spanish population in the context of cancer research. We have carried out a genotyping study in Spanish subjects involving 175 candidate cancer genes using an indirect gene-based approach and compared results with those for HapMap CEU subjects. Allele frequencies were very consistent between the two samples, with a high positive correlation (R) of 0.91 (P<<1x10(-6)). Linkage disequilibrium patterns and block structures across each gene were also very similar, with disequilibrium coefficient (r (2)) highly correlated (R=0.95, P<<1x10(-6)). We found that of the 21 genes that contained at least one block larger than 60 kb, nine (ATM, ATR, BRCA1, ERCC6, FANCC, RAD17, RAD50, RAD54B and XRCC4) belonged to the GO category "DNA repair". Haplotype frequencies per gene were also highly correlated (mean R=0.93), as was haplotype diversity (R=0.91, P<<1x10(-6)). "Yin yang" haplotypes were observed for 43% of the genes analysed and 18% of those were identical to the ancestral haplotype (identified in Chimpazee). Finally, the portability of tagSNPs identified in the HapMap CEU data using pairwise r (2) thresholds of 0.8 and 0.5 was assessed by applying these to the Spanish and current HapMap data for 66 genes. In general, the HapMap tagSNPs performed very well. Our results show generally high concordance with HapMap data in allele frequencies and haplotype distributions and confirm the applicability of HapMap SNP data to the study of complex diseases among the Spanish population.

Published
2006
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18. The variant E233G of the RAD51D gene could be a low-penetrance allele in high-risk breast cancer families without BRCA1/2 mutations.

Author

Rodríguez-López R, Osorio A, Ribas G, Pollán M, Sánchez-Pulido L, de la Hoya M, Ruibal A, Zamora P, Arias JI, Salazar R, Vega A, Martínez JI, Esteban-Cardeñosa E, Alonso C, Letón R, Urioste Azcorra M, Miner C, Armengod ME, Carracedo A, González-Sarmiento R, Caldés T, Díez O, and Benítez J

Subjects
Age of Onset, Amino Acid Substitution, Female, Gene Frequency, Humans, Middle Aged, Mutation, Mutation, Missense, Ovarian Neoplasms genetics, Polymerase Chain Reaction, Reference Values, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Genes, BRCA1, Genes, BRCA2, Polymorphism, Single Nucleotide
Abstract

Six SNPs have been detected in the DNA repair genes RAD51C and RAD51D, not previously characterized. The novel variant E233G in RAD51D is more highly represented in high-risk, site-specific, familial breast cancer cases that are not associated with the BRCA1/2 genes, with a frequency of 5.74% (n = 174) compared to a control population (n = 567) and another subset of breast cancer patients (n = 765) with a prevalence of around 2% only (comparison to controls, OR = 2.6, 95% CI 1.12-6.03; p < 0.021). We found that the immunohistochemical profile detected in available tumors from these patients differs slightly from those described in non-BRCA1/2 tumors. Finally, the structural prediction of the putative functional consequence of this change indicates that it can diminish protein stability and structure. This suggests a role for E233G as a low-penetrance susceptibility gene in the specific subgroup of high-risk familial breast cancer cases that are not related to BRCA1/2., (Copyright 2004 Wiley-Liss, Inc.)

Published
2004
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19. Over-representation of two specific haplotypes among chromosomes harbouring BRCA1 mutations.

Author

Osorio A, de la Hoya M, Rodríguez-López R, Granizo JJ, Díez O, Vega A, Durán M, Carracedo A, Baiget M, Caldés T, and Benítez J

Subjects
Humans, Linkage Disequilibrium, Microsatellite Repeats genetics, Gene Frequency genetics, Genes, BRCA1, Haplotypes genetics, Polymorphism, Single Nucleotide genetics
Abstract

The BRCA1 gene is included in a 200-400 kb region that is subjected to a recombination suppression mechanism; this region shows nearly complete linkage disequilibrium for a series of common biallelic polymorphisms, all of them with rarer allele frequency close to 0.4. These series of SNPs define two major haplotypes designated as class I and class II. In the present study, we have determined haplotype classes in the index case of 106 breast/ovarian cancer families previously screened for mutations in the BRCA genes and we have found that haplotype II (the less frequent in the control population) is over-represented among chromosomes harbouring mutations in BRCA1. In addition, we have defined a subtype of chromosomes characterized by haplotype I and one specific allele for the microsatellite marker D17S855, which are also more frequently associated with BRCA1 mutations. These findings may have important consequences for the selection of families with higher probabilities of carrying mutations in the BRCA1 gene.

Published
2003
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20. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Asona, Lui, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth R, Lophatananon, Artitaya, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Blot, William J, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L, Huff, Chad D, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Ost, Piet, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Abraham, Aswin, Claessens, Frank, Castelao, Jose Esteban, Townsend, Paul A, Crawford, Dana C, Petrovics, Gyorgy, Van Schaik, Ron HN, Parent, Marie-Élise, Hu, Jennifer J, Zheng, Wei, UKGPCS Collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee And Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, Huynh-Le, Minh-Phuong [0000-0002-5025-4709], Fan, Chun Chieh [0000-0001-9437-2128], Asona, Lui [0000-0002-0076-3492], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth R [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Pashayan, Nora [0000-0003-0843-2468], Batra, Jyotsna [0000-0003-4646-6247], Grönberg, Henrik [0000-0002-1073-2753], Nordestgaard, Børge G [0000-0002-1954-7220], Wolk, Alicja [0000-0001-7387-6845], Travis, Ruth C [0000-0002-9571-0763], West, Catharine ML [0000-0002-0839-3449], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Menegaux, Florence [0000-0003-3363-6411], Park, Jong Y [0000-0002-6384-6447], Lu, Yong-Jie [0000-0001-6174-6621], Vega, Ana [0000-0002-7416-5137], Kogevinas, Manolis [0000-0002-9605-0461], Wiklund, Fredrik [0000-0002-4623-0544], Teixeira, Manuel R [0000-0002-4896-5982], Multigner, Luc [0000-0003-3205-8568], Brenner, Hermann [0000-0002-6129-1572], Ost, Piet [0000-0002-2203-4848], Fowke, Jay H [0000-0003-3803-8162], Gamulin, Marija [0000-0003-2431-7910], Abraham, Aswin [0000-0003-0024-3339], Crawford, Dana C [0000-0002-6437-6248], Petrovics, Gyorgy [0000-0003-3732-284X], Parent, Marie-Élise [0000-0002-4196-3773], Zheng, Wei [0000-0003-1226-070X], Seibert, Tyler M [0000-0002-4089-7399], and Apollo - University of Cambridge Repository

Subjects
Male, Urologic Diseases, Aging, Oncology and Carcinogenesis, Polymorphism, Single Nucleotide, Risk Assessment, UKGPCS collaborators, Risk Factors, NC-LA PCaP Investigators, Genetics, PRACTICAL Consortium, Humans, Genetic Predisposition to Disease, Polymorphism, Early Detection of Cancer, Cancer, Canary PASS Investigators, IMPACT Study Steering Committee and Collaborators, Profile Study Steering Committee, Prevention, Prostate Cancer, APCB, Prostatic Neoplasms, Single Nucleotide, Prostate-Specific Antigen, Urology & Nephrology, Good Health and Well Being
Abstract

Funder: University of California (#C21CR2060), the Prostate Cancer Foundation, Funder: Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority, BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

21. No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

Author

Barnett, Gillian C, Kerns, Sarah L, Dorling, Leila, Fachal, Laura, Aguado-Barrera, Miguel E, Martínez-Calvo, Laura, Jandu, Harkeran K, Welsh, Ceilidh, Tyrer, Jonathan, Coles, Charlotte E, Haviland, Joanne S, Parker, Christopher, Gómez-Caamaño, Antonio, Calvo-Crespo, Patricia, Sosa-Fajardo, Paloma, Burnet, Neil G, Summersgill, Holly, Webb, Adam, De Ruysscher, Dirk, Seibold, Petra, Chang-Claude, Jenny, Talbot, Christopher J, Rattay, Tim, Parliament, Matthew, De Ruyck, Kim, Rosenstein, Barry S, Pharoah, Paul DP, Dunning, Alison M, Vega, Ana, West, Catharine ML, RGC and REQUITE Consortia, Coles, Charlotte [0000-0003-4473-8552], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Male, Biological Products, Risk Factors, Humans, Prostatic Neoplasms, Breast Neoplasms, Genetic Predisposition to Disease, Radiation Injuries, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

PURPOSE: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. METHODS AND MATERIALS: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. RESULTS: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10-5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10-5). CONCLUSIONS: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

Published
2022
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22. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research

Subjects
Male, Biochemistry & Molecular Biology, OCAC Consortium, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, Ovaris - Càncer - Aspectes genètics, Carcinoma, Ovarian Epithelial, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, GEMO Study Collaborators, Risk Factors, OPAL Study Group, Other subheadings::Other subheadings::/genetics [Other subheadings], Medicine and Health Sciences, Genetics, Ovaris - Càncer - Propensió, Humans, Genetic Predisposition to Disease, Prospective Studies, EMBRACE Collaborators, GC-HBOC Study Collaborators, Genetics (clinical), HEBON Investigators, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Medicinsk genetik, Ovarian Neoplasms, Genetics & Heredity, 0604 Genetics, Science & Technology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], 1103 Clinical Sciences, Bayes Theorem, AOCS Group, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Carcinoma, Ovarian Epithelial/genetics, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], CIMBA Consortium, 1182 Biochemistry, cell and molecular biology, Female, KConFab Investigators, Ovarian Neoplasms/epidemiology, Medical Genetics, Life Sciences & Biomedicine
Abstract

Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Published
2022
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23. Runs of homozygosity and testicular cancer risk

Author

Loveday, C, Sud, A, Litchfield, K, Levy, M, Holroyd, A, Broderick, P, Kote-Jarai, Z, Dunning, AM, Muir, K, Peto, J, Eeles, R, Easton, DF, Dudakia, D, Orr, N, Pashayan, N, Rustin, Gordon, Srihari, Narayanan N, Cole, David, Askill, Colin, Bertelli, Gianfilippo, Barber, James, Gilby, Ed, White, Jeff, Baybrooke, Jeremy, Leahy, Michael, Welch, Richard, Chakraborti, Prabir, Joffe, Johnathan, Brown, Richard, Faust, Guy, Simmonds, Peter, Mazhar, Danish, Stockdale, Andrew, Hrounda, David, Humber, Caroline, Appel, Wiebke, Hong, Anne, Howard, Grahame, Douglas, Fiona, Bloomfield, David, Butt, Mohammad, Kelly, Kay, Mehra, Rakesh, Rogers, Paul, Hatton, Matthew, Hennig, Ivo, McAteer, John, Savage, Philip, Seckl, Michael, Gale, Joanna, Clark, Peter, Woby, Steve, Rathmell, Adrian, Lamont, Alan, Sarwar, Naveed, Stuart, Nick, Chowdhury, Simon, Beesley, Sharon, Winkler, Mathius, Hamid, Abdel, Pathak, Sanjeev, Madhavan, Krishnaswamy, Highley, Martin, Money-Kryle, Julian, Brock, Cathryn, Sreenivasan, Thiagarajan, Henderson, Brian E, Haiman, Christopher A, Schumacher, Fredrick R, Al Olama, Ali Amin, Benlloch, Sara, Berndt, Sonja I, Conti, David V, Wiklund, Fredrik, Chanock, Stephen, Gapster, Susan, Stevens, Victoria L, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Geraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Ingles, Sue Ann, Rosenstein, Barry S, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Borge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Dominguez, Manuela Gago, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albrigh, Lisa, Pandha, Hardev, Thibodeau, Stephen N, Reid, A, Huddart, RA, Houlston, RS, Turnbull, C, and Urology

Subjects
Oncology, Male, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Runs of Homozygosity, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Endocrinology, testicular germ cell tumour, Risk Factors, Genotype, genetics, Andrology, 030219 obstetrics & reproductive medicine, Genome, Homozygote, Neoplasms, Germ Cell and Embryonal, Disease gene identification, homozygosity mapping, Life Sciences & Biomedicine, RECENT POSITIVE SELECTION, medicine.medical_specialty, Urology, Biology, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Testicular Neoplasms, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, cancer, Humans, Allele, GENOME-WIDE ASSOCIATION, SEX DETERMINATION, runs of homozygosity, Science & Technology, IDENTIFICATION, Cancer, recessive, medicine.disease, GERM-CELL TUMOR, CONSANGUINITY, Reproductive Medicine, Relative risk, genome-wide association studies, Genome-Wide Association Study
Abstract

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p

Published
2019
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24. Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Author

Tuazon, Anna Marie De Asis, Lott, Paul, Bohórquez, Mabel, Benavides, Jennyfer, Ramirez, Carolina, Criollo, Angel, Estrada-Florez, Ana, Mateus, Gilbert, Velez, Alejandro, Carmona, Jenny, Olaya, Justo, Garcia, Elisha, Polanco-Echeverry, Guadalupe, Stultz, Jacob, Alvarez, Carolina, Tapia, Teresa, Ashton-Prolla, Patricia, Brazilian Familial Cancer Network, Vega, Ana, Lazaro, Conxi, Tornero, Eva, Martinez-Bouzas, Cristina, Infante, Mar, De La Hoya, Miguel, Diez, Orland, Browning, Brian L, COLUMBUS Consortium, Rannala, Bruce, Teixeira, Manuel R, Carvallo, Pilar, Echeverry, Magdalena, Carvajal-Carmona, Luis G, Institut Català de la Salut, [De Asis Tuazon AM, Lott P] Genome Center, University of California Davis, Davis, CA, USA. [Bohórquez M, Benavides J, Ramirez C, Criollo A] Universidad del Tolima, Ibague, Colombia. [Diez O] Grupo de Cáncer Hereditario, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University of California, Davis, Colciencias (Colombia), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Hospital de Clínicas de Porto Alegre, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, and National Institutes of Health (US)

Subjects
Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [DISEASES], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Càncer d'ovari, Càncer - Aspectes genètics, Identity by descent, 0302 clinical medicine, Breast cancer, Mama - Càncer, Mutation Carrier, Haplotype, Chile, Cancer, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, BRCA1 Protein, Single Nucleotide, c.3331_3334delCAAG, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Founder Effect, Chromosome 17 (human), 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Brazil, Research Article, COLUMBUS Consortium, Human, Brazilian Familial Cancer Network, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Colombia, lcsh:RC254-282, Polymorphism, Single Nucleotide, Chromosomes, Càncer de mama, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::susceptibilidad a enfermedades::predisposición genética a la enfermedad [ENFERMEDADES], 03 medical and health sciences, Rare Diseases, Ovarian cancer, SNP, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Founder mutation, Germ-Line Mutation, 030304 developmental biology, Portugal, BRCA1 c.3331_3334delCAAG, Pair 17, Human Genome, Multiple Hispanic, BRCA1, Haplotypes, Spain, Africa, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

© The Author(s)., [Background]: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. [Methods]: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia., [Results]: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period., [Conclusions]: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening., AMDEA was supported with graduate Fellowships from UC Davis T32 Biotechnology Program. MB, ME, and LGC-C received funding from GSK Oncology and from “Oficina de Desarrollo a la Docencia de la Universidad del Tolima, Convocatoria 2010”. AC and AEF received funding from the Colciencias program “Becas Doctorales Nacionales, Convocatorias 528-2011 and 647-2015”. JB received funding from the Colciencias program “Formación de Capital Humano de Alto Nivel para el Departamento de Tolima- 2016, convocatoria 755”. BRCA1/2 genotyping of the Brazilian patients was performed in part with grants from CNPq (408313/2016-1), FAPERGS and Fundo de Incentivo a Pesquisa (FIPE) do Hospital de Clínicas de Porto Alegre, Brazil. AV received funding from CIBERER (grant ER17P1AC7112/2017). PC received funding from FONDEF grant #CA12I10152. CL was Supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI19/00553; PI16/00563; PI16/01898; SAF2015-68016-R and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS_MedPerCan and URDCat projects), 2017SGR1282 and 2017SGR496]. BR received funding from the National Institutes of Health (R01GM123306).

Published
2020

25. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author

Hollis, Ben, Day, Felix R., Busch, Alexander S., Thompson, Deborah J., Soares, Ana Luiza G., Timmers, Paul R.H.J., Kwong, Alex, Easton, Doug F., Joshi, Peter K., Timpson, Nicholas J., Eeles, Rosalind A., Henderson, Brian E., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Nordestgaard, Børge G., Day, Felix R [0000-0003-3789-7651], Busch, Alexander S [0000-0003-4417-569X], Thompson, Deborah J [0000-0003-1465-5799], Soares, Ana Luiza G [0000-0003-2763-4647], Timmers, Paul R H J [0000-0002-5197-1267], Kwong, Alex [0000-0003-1953-2771], Easton, Doug F [0000-0003-2444-3247], Joshi, Peter K [0000-0002-6361-5059], Timpson, Nicholas J [0000-0002-7141-9189], Ong, Ken K [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, General Physics and Astronomy, Physiology, Genome-wide association study, Genome-wide association studies, Cohort Studies, 0302 clinical medicine, Endocrinology, Genetics research, Sexual Maturation, Young adult, lcsh:Science, RISK, Multidisciplinary, Age Factors, Mendelian Randomization Analysis, Effective sample size, Multidisciplinary Sciences, Pituitary hormones, Science & Technology - Other Topics, Female, Adult, Science, Longevity, Reproductive biology, Biology, Health outcomes, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, MENARCHE, 03 medical and health sciences, Young Adult, AGE, Mendelian randomization, Humans, Hair Color, Genetic association, Menarche, Science & Technology, MUTATIONS, Puberty, General Chemistry, 030104 developmental biology, METASTASIS, PIGMENTATION, lcsh:Q, 030217 neurology & neurosurgery, SKIN, Genome-Wide Association Study
Abstract

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes., Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.

Published
2020
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26. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J, Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, Gormley, Stuart, Hamilton, Shea, Herberg, Jethro, Hourmat, Bernardo, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Bokhandi, S, Power, Sue, Barham, Heather, Pathan, N, Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S, Patel, S, McCorkell, Jenni, Davies, P, Cratev, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R, Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C, White, Sonia, Fortune, PM, Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, Martinon-Torres, Nazareth, Martinon Sanchez, Jose Maria, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero Calle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J, Palacios, Alba, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, AM Tutu, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Paulus, Stephane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Agbeko, Rachel, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngane, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumatta, Thomas, Gilleh, Antonio, Martin, Walcher, Wolfgang, Geishofer, Gotho, Klobassa, Daniela, Martin, Mueller, Pfurtscheller, Klaus, Reiter, Karl, Roedl, Siegfried, Zobel, Gerfried, Zoehrer, Bettina, Toepke, Baerbel, Fucik, Peter, Gabriel, Markwart, Penzien, Johann M, Diab, Gedeon, Miething, Robert, Deeg, KH, Hammer, Jurg, Varnholt, Verena, Schmidt, Andreas, Bindl, Lutz, Sillaber, Ursula, Huemer, Christian, Meier, Primrose, Simic-Schleicher, G, Markart, Markus, Pfau, Eberhard, Broede, Hans, Ausserer, Bernd, Kalhoff, Hermann, Arpe, Volker, Schweitzer-Krantz, Susanne, Kasper, Johannes-Martin, Loranth, Kathrin, Bittrich, Hans J, Simma, Burkhard, Klinge, Jens, Fedlmaier, Michael, Weigand, Nicola, Herting, Egbert, Grube, Regina, Fusch, Christoph, Gruber, Alois, Schimmel, Ulf, Knaufer-Schiefer, Suzanne, Laessig, Wolfgang, Hennenberger, Axel, von der Wense, Axel, Tillmann, Roland, Schwarick, Juergen, Sitzmann, Friedrich C, Streif, Werner, Mueller, Herbert, Kurnik, Peter, Groneck, Peter, Weiss, Ute, Groeblacher-Roth, Helene, Bensch, Juergen, Moser, Reinhard, Schwarz, Rudolf, Lenz, Kurt, Hofmann, Thomas, Goepel, Wolfgang, Schulz, Dietrich, Berger, Thomas, Hauser, Erwin, Foerster, Kai Martin, Peters, Jochen, Nicolai, T Homas, Kumlien, Bjoern, Beckmann, Regina, Seitz, Christiane, Hueseman, D, Schuermann, Roland, Ta, Van Hop, Weikmann, Eckart, Evert, W, Hautz, Juergen, Seidenberg, Juergen, Wocko, Lucia, Luigs, Petra, Reiter, Hans-Ludwig, Quietzach, J, Koenig, Michael, Herrmann, Johanna, Mitter, Horst, Seidler, Ekkehard, Maak, Bernhard, Sperl, Wolfgang, Zwiauer, Karl, Meissl, Manfred, Koch, Reinhard, Cremer, Manfred, Breuer, HA, Goerke, W, Nossal, Robert, Pernice, Walter, Brangenberg, Ralf, Salzer, Hans R, Koch, Hartmut, Schaller, Gerhard, Paky, Franz, Strasser, Friedrich, Eitelberger, Franz, Sontheimer, D, Lischka, Andreas, Kronberger, Martina, Dilch, Alfred, Scheibenpflug, Christian, Bruckner, Robert, Mahler, Klaus, Runge, Klaus, Kunze, Wolfgang, Schermann, Peter, Consortium, EUCLIDS, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, University of Zurich, Borghini, Lisa, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Png, Eileen [0000-0001-5586-6395], Wright, Victoria J [0000-0001-7826-1516], Schlapbach, Luregn J [0000-0003-2281-2598], Salas, Antonio [0000-0002-2336-702X], Martinon-Torres, Federico [0000-0002-9023-581X], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, AII - Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Neurology, ANS - Neuroinfection & -inflammation, Medical Microbiology and Infection Prevention, Pediatrics, Public Health, Posfay Barbe, Klara, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), APH - Aging & Later Life, Amsterdam Reproduction & Development (AR&D), and Pediatric surgery

Subjects
0301 basic medicine, Candidate gene, Hypopharyngeal Neoplasms / microbiology, Meningococcal Infections / microbiology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MathematicsofComputing_GENERAL, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], lcsh:Medicine, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, Cohort Studies, 0302 clinical medicine, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, Hypopharyngeal Neoplasms / pathology, BINDING, Tumor Cells, Cultured, lcsh:Science, Genetics, Multidisciplinary, ddc:618, Cultured, TheoryofComputation_GENERAL, High-Throughput Nucleotide Sequencing, Genomics, Phenotype, 3. Good health, ddc, Tumor Cells, Multidisciplinary Sciences, GENOME, Science & Technology - Other Topics, Neisseria meningitidis / isolation & purification, Single-nucleotide polymorphism, 610 Medicine & health, KAPPA-B, Biology, Hypopharyngeal Neoplasms / genetics, Polymorphism, Single Nucleotide, Article, Meningococcal Infections / epidemiology, 03 medical and health sciences, SEQUENCE VARIATION, Genetic predisposition, Journal Article, Humans, Meningitis, Meningococcal Infections / genetics, Genetic Predisposition to Disease, Nucleic Acid, Polymorphism, General, Gene, Genotyping, Neisseria meningitidis / genetics, Genetic Association Studies, Genetic association, Genetic association study, 1000 Multidisciplinary, Science & Technology, Hypopharyngeal Neoplasms, genetic variants, meningococcal disease, lcsh:R, Single Nucleotide, EUCLIDS consortium, Gene regulation, Meningococcal Infections, 030104 developmental biology, 10036 Medical Clinic, Case-Control Studies, lcsh:Q, Software_PROGRAMMINGLANGUAGES, Regulatory Sequences, 030217 neurology & neurosurgery
Abstract

EUCLIDS consortium., Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes., This work has been partially funded by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. The UK meningococcal cohort was established with support from Meningitis Research Foundation through grants to Imperial College London. The Research from Newcastle partners was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The ESIGEM Research group activities were supported by grants from Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2016), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and ‘fondos FEDER’ (F.M.T.). The Swiss Pediatric Sepsis study was funded by grants from the Swiss National Science Foundation (342730_153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. The Western Europe Meningococcal Study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006–9 of the Department for Science and Research of the Styrian federal government (Austria) and the non for profit association ‘In Vita’, Graz (Austria).

Published
2019
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27. Author Correction: Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Author

Sud, Amit, Thomsen, Hauke, Law, Philip J., Försti, Asta, da Silva Filho, Miguel Inacio, Holroyd, Amy, Broderick, Peter, Orlando, Giulia, Lenive, Oleg, Wright, Lauren, Cooke, Rosie, Easton, Douglas, Pharoah, Paul, Dunning, Alison, Peto, Julian, Canzian, Federico, Eeles, Rosalind, Kote-Jarai, Zsofia, Muir, Kenneth, Pashayan, Nora, Henderson, Brian E., Haiman, Christopher A., Benlloch, Sara, Schumacher, Fredrick R., Olama, Ali Amin Al, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Gago-Dominguez, Manuela, Roobol, Monique J., Menegaux, Florence, Hoffmann, Per, Nöthen, Markus M., Jöckel, Karl-Heinz, von Strandmann, Elke Pogge, Lightfoot, Tracy, Kane, Eleanor, Roman, Eve, Lake, Annette, Montgomery, Dorothy, Jarrett, Ruth F., Swerdlow, Anthony J., Engert, Andreas, Orr, Nick, Hemminki, Kari, and Houlston, Richard S.

Subjects
Science, Medizin, MEDLINE, General Physics and Astronomy, Genome-wide association study, Computational biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Disease susceptibility, immune system diseases, hemic and lymphatic diseases, Classical Hodgkin lymphoma, Humans, Genetic Predisposition to Disease, Author Correction, lcsh:Science, Alleles, HLA-DP beta-Chains, Multidisciplinary, Published Erratum, General Chemistry, Hodgkin Disease, Spelling, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Key (cryptography), lcsh:Q, Psychology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10−8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10−17), 6q23.3 (rs6928977, P = 4.62 × 10−11), 10p14 (rs3781093, P = 9.49 × 10−13), 13q34 (rs112998813, P = 4.58 × 10−8) and 16p13.13 (rs34972832, P = 2.12 × 10−8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response., Classical Hodgkin lymphoma is a cancer that originates in lymph nodes. Little is known about its genetic susceptibility. Here, the authors combined existing and new genome-wide association studies to identify risk loci for classical Hodgkin lymphoma at 6q22.33, and nodular sclerosis Hodgkin lymphoma at 3q28, 6q23.3, 10p14, 13q34, 16p13.13.

Published
2019
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28. Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer

Author

Kerns, Sarah L, Dorling, Leila, Fachal, Laura, Bentzen, Søren, Pharoah, Paul D P, Barnes, Daniel R, Gómez-Caamaño, Antonio, Carballo, Ana M, Dearnaley, David P, Peleteiro, Paula, Gulliford, Sarah L, Hall, Emma, Michailidou, Kyriaki, Carracedo, Ángel, Sia, Michael, Stock, Richard, Stone, Nelson N, Sydes, Matthew R, Tyrer, Jonathan P, Ahmed, Shahana, Parliament, Matthew, Ostrer, Harry, Rosenstein, Barry S, Vega, Ana, Burnet, Neil G, Dunning, Alison M, Barnett, Gillian C, and West, Catharine M L

Subjects
Genetic Markers, Male, Quality of life, Genome-wide association study, Genotype, LD, linkage disequilibrium, Cancer survivorship, Radiogenomics, lcsh:Medicine, EBRT, external bean radiotherapy, STAT, standardized total average toxicity, MAF, minor allele frequency, Polymorphism, Single Nucleotide, Radiation Tolerance, eQTL, expression quantitative trait locus, Cohort Studies, Radiation toxicity, GTEx, Genotype-Tissue Expression project, Odds Ratio, Humans, BED, biologic effective dose, GWAS, genome-wide association study, ENCODE, encyclopedia of DNA elements, Alleles, Aged, Neoplasm Staging, lcsh:R5-920, Prostate cancer, Manchester Cancer Research Centre, Radiotherapy, ResearchInstitutes_Networks_Beacons/mcrc, lcsh:R, Prostatic Neoplasms, TURP, transurethral resection of the prostate, Middle Aged, SNP, single nucleotide polymorphism, Combined Modality Therapy, Treatment Outcome, PCA, principle components analysis, lcsh:Medicine (General), Research Paper
Abstract

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling., Highlights • SNPs rs17599026 and rs7720298 increase risk of urinary toxicity following radiotherapy in prostate cancer patients. • Data from heterogeneous radiotherapy cohorts can be meta-analyzed to identify genetic variants associated with toxicity. • A SNP-based predictive assay could improve the therapeutic index of radiotherapy and aid in individualization of cancer treatment. Risk of radiotherapy side-effects in a minority limits doses given to the majority. A test is needed to predict risks so treatments are personalized. Recent whole-genome studies in a few hundred patients found none or one genetic variant increasing side-effect risk. Larger studies are needed, but difficult because treatments differ between centers. Our study of > 1500 prostate cancer patients from four centers found two variants. The research shows combining heterogeneous radiotherapy datasets works and larger collaborative efforts identifying enough variants for a future test are worthwhile. As nearly 50% of cancer patients have radiotherapy, our work could benefit many people.

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

Author

Schumacher, Fredrick R, Al Olama, Ali Amin, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward J, Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara, Goh, Chee, Brook, Mark N, Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine ML, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei A, Giovannucci, Edward, Andriole, Gerald L, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura E, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Stanford, Janet L, and Cybulski, Cezary

Subjects
Urologic Diseases, Risk, Male, Aging, Genotype, Breast and Prostate Cancer Cohort Consortium, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, urologic and male genital diseases, Medical and Health Sciences, Polymorphism, Single Nucleotide, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Polymorphism, Aetiology, Cancer, Canary PASS Investigators, Prostate Cancer, Human Genome, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci, Profile Study, Australian Prostate Cancer BioResource, Prostatic Neoplasms, Single Nucleotide, Biological Sciences, IMPACT Study, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, Cancer of the Prostate in Sweden, Genetic Loci, Case-Control Studies, Developmental Biology, Genome-Wide Association Study
Abstract

© 2018 The Author(s). 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

30. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Dadaev, Tokhir, Saunders, Edward J, Newcombe, Paul J, Anokian, Ezequiel, Leongamornlert, Daniel A, Brook, Mark N, Cieza-Borrella, Clara, Mijuskovic, Martina, Wakerell, Sarah, Olama, Ali Amin Al, Schumacher, Fredrick R, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Goh, Chee, Sheng, Xin, Zhang, Zhuo, Muir, Kenneth, Govindasami, Koveela, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Hakansson, Niclas, West, Catharine, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Freeman, Laura E Beane, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, and Sellers, Thomas A

Subjects
Urologic Diseases, Risk, Male, Aging, Quantitative Trait Loci, European Continental Ancestry Group, Black People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Polymorphism, Single Nucleotide, White People, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Polymorphism, Aetiology, Cancer, African Continental Ancestry Group, Prostate Cancer, Prevention, Human Genome, Prostatic Neoplasms, Chromosome Mapping, Bayes Theorem, Molecular Sequence Annotation, Single Nucleotide, Multivariate Analysis, Algorithms, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Published
2018

31. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

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

Subjects
Quantitative Trait Loci, Chromosome Mapping, Bayes Theorem, Breast Neoplasms, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

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

32. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, Hopper, John L, Horcasitas, Darling J, Hulick, Peter J, Hunter, David J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, Agnes, Jakubowska, Anna, James, Paul A, Jensen, Uffe Birk, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I, Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W, Laitman, Yael, Lambrechts, Diether, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T, Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L, Montagna, Marco, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, O'Brien, Katie M, Olopade, Olufunmilayo I, Olson, Janet E, Olsson, Håkan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Polley, Eric C, Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P, Santella, Regina, Scheuner, Maren T, Schmidt, Marjanka K, Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Terry, Mary Beth, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Trainer, Alison H, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Park, Sue K, Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K, Couch, Fergus J, Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F, Andrieu, Nadine, and Antoniou, Antonis C

Subjects
Adult, BRCA2 Protein, endocrine system diseases, Genotype, BRCA1 Protein, Quantitative Trait Loci, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Mutation, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Alleles, Genome-Wide Association Study
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

33. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

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

Subjects
Male, Risk, Quantitative Trait Loci, Black People, Chromosome Mapping, Prostatic Neoplasms, Bayes Theorem, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, White People, 3. Good health, Multivariate Analysis, Humans, Genetic Predisposition to Disease, Algorithms, Genome-Wide Association Study
Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

34. Shared heritability and functional enrichment across six solid cancers

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, DeFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, Ganz, Patricia A, Garber, Judy, García-Sáenz, José A, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, Goode, Ellen L, Goodman, Marc T, Goodman, Gary, Grankvist, Kjell, Greene, Mark H, Gronberg, Henrik, Gronwald, Jacek, Guénel, Pascal, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hamdy, Freddie C, Hamilton, Robert J, Hampe, Jochen, Haugen, Aage, Heitz, Florian, Herrero, Rolando, Hillemanns, Peter, Hoffmeister, Michael, Høgdall, Estrid, Hong, Yun-Chul, Hopper, John L, Houlston, Richard, Hulick, Peter J, Hunter, David J, Huntsman, David G, Idos, Gregory, Imyanitov, Evgeny N, Ingles, Sue Ann, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Jenkins, Mark A, Johansson, Mattias, Johansson, Mikael, John, Esther M, Joshi, Amit D, Kaneva, Radka, Karlan, Beth Y, Kelemen, Linda E, Kühl, Tabea, Khaw, Kay-Tee, Khusnutdinova, Elza, Kibel, Adam S, Kiemeney, Lambertus A, Kim, Jeri, Kjaer, Susanne K, Knight, Julia A, Kogevinas, Manolis, Kote-Jarai, Zsofia, Koutros, Stella, Kristensen, Vessela N, Kupryjanczyk, Jolanta, Lacko, Martin, Lam, Stephan, Lambrechts, Diether, Landi, Maria Teresa, Lazarus, Philip, Le, Nhu D, Lee, Eunjung, Lejbkowicz, Flavio, Lenz, Heinz-Josef, Leslie, Goska, Lessel, Davor, Lester, Jenny, Levine, Douglas A, Li, Li, Li, Christopher I, Lindblom, Annika, Lindor, Noralane M, Liu, Geoffrey, Loupakis, Fotios, Lubiński, Jan, Maehle, Lovise, Maier, Christiane, Mannermaa, Arto, Marchand, Loic Le, Margolin, Sara, May, Taymaa, McGuffog, Lesley, Meindl, Alfons, Middha, Pooja, Miller, Austin, Milne, Roger L, MacInnis, Robert J, Modugno, Francesmary, Montagna, Marco, Moreno, Victor, Moysich, Kirsten B, Mucci, Lorelei, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L, Neal, David E, Ness, Andrew R, Neuhausen, Susan L, Nevanlinna, Heli, Newcomb, Polly A, Newcomb, Lisa F, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Nordestgaard, Børge G, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olama, Ali Amin Al, Olopade, Olufunmilayo I, Olshan, Andrew F, Olsson, Håkan, Osorio, Ana, Pandha, Hardev, Park, Jong Y, Pashayan, Nora, Parsons, Michael T, Pejovic, Tanja, Penney, Kathryn L, Peters, Wilbert HM, Phelan, Catherine M, Phipps, Amanda I, Plaseska-Karanfilska, Dijana, Pring, Miranda, Prokofyeva, Darya, Radice, Paolo, Stefansson, Kari, Ramus, Susan J, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Van Rensburg, Elizabeth J, Riggan, Marjorie J, Risch, Harvey A, Risch, Angela, Roobol, Monique J, Rosenstein, Barry S, Rossing, Mary Anne, De Ruyck, Kim, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schabath, Matthew B, Schleutker, Johanna, Schmidt, Marjanka K, Setiawan, V Wendy, Shen, Hongbing, Siegel, Erin M, Sieh, Weiva, Singer, Christian F, Slattery, Martha L, Sorensen, Karina Dalsgaard, Southey, Melissa C, Spurdle, Amanda B, Stanford, Janet L, Stevens, Victoria L, Stintzing, Sebastian, Stone, Jennifer, Sundfeldt, Karin, Sutphen, Rebecca, Swerdlow, Anthony J, Tajara, Eloiza H, Tangen, Catherine M, Tardon, Adonina, Taylor, Jack A, Teare, M Dawn, Teixeira, Manuel R, Terry, Mary Beth, Terry, Kathryn L, Thibodeau, Stephen N, Thomassen, Mads, Bjørge, Line, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Townsend, Paul A, Travis, Ruth C, Tung, Nadine, Tworoger, Shelley S, Ulrich, Cornelia M, Usmani, Nawaid, Vachon, Celine M, Van Nieuwenhuysen, Els, Vega, Ana, Aguado-Barrera, Miguel Elías, Wang, Qin, Webb, Penelope M, Weinberg, Clarice R, Weinstein, Stephanie, Weissler, Mark C, Weitzel, Jeffrey N, West, Catharine ML, White, Emily, Whittemore, Alice S, Wichmann, H-Erich, Wiklund, Fredrik, Winqvist, Robert, Wolk, Alicja, Woll, Penella, Woods, Michael, Wu, Anna H, Wu, Xifeng, Yannoukakos, Drakoulis, Zheng, Wei, Zienolddiny, Shanbeh, Ziogas, Argyrios, Zorn, Kristin K, Lane, Jacqueline M, Saxena, Richa, Thomas, Duncan, Hung, Rayjean J, Diergaarde, Brenda, McKay, James, Peters, Ulrike, Hsu, Li, García-Closas, Montserrat, Eeles, Rosalind A, Chenevix-Trench, Georgia, Brennan, Paul J, Haiman, Christopher A, Simard, Jacques, Easton, Douglas F, Gruber, Stephen B, Pharoah, Paul DP, Price, Alkes L, Pasaniuc, Bogdan, Amos, Christopher I, Kraft, Peter, and Lindström, Sara

Subjects
Male, Ovarian Neoplasms, Lung Neoplasms, Mental Disorders, Smoking, Inheritance Patterns, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 3. Good health, Neoplasm Proteins, Phenotype, Head and Neck Neoplasms, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

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