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3. Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2

Author

Rajasekaran, V, primary, Harris, B. T, additional, Osborn, R. T, additional, Smillie, C, additional, Donnelly, K, additional, Bacou, M, additional, Esiri-Bloom, E, additional, Ooi, L.Y, additional, Allan, M, additional, Walker, M, additional, Reid, S, additional, Meynert, A, additional, Grimes, G, additional, Blackmur, J. P, additional, Vaughan-Shaw, P. G, additional, Law, P. J, additional, Fernandez-Rozadilla, C, additional, Tomlinson, I. P, additional, Houlston, R, additional, Myant, K. B, additional, Din, F. V, additional, Dunlop, M. G., additional, and Farrington, S. M, additional

Published
2023
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4. Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma

Author

da Silva Filho, M I, Försti, A, Weinhold, N, Meziane, I, Campo, C, Huhn, S, Nickel, J, Hoffmann, P, Nöthen, M M, Jöckel, K-H, Landi, S, Mitchell, J S, Johnson, D, Morgan, G J, Houlston, R, Goldschmidt, H, Jauch, A, Milani, P, Merlini, G, Rowcieno, D, Hawkins, P, Hegenbart, U, Palladini, G, Wechalekar, A, Schönland, S O, and Hemminki, K

Published
2017
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6. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, de Voer, RM, Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, and de Voer, RM

Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

7. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de

Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

9. A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1

Author

Vijayakrishnan, J, Kumar, R, Henrion, M YR, Moorman, A V, Rachakonda, P S, Hosen, I, da Silva Filho, M I, Holroyd, A, Dobbins, S E, Koehler, R, Thomsen, H, Irving, J A, Allan, J M, Lightfoot, T, Roman, E, Kinsey, S E, Sheridan, E, Thompson, P D, Hoffmann, P, Nöthen, M M, Heilmann-Heimbach, S, Jöckel, K H, Greaves, M, Harrison, C J, Bartram, C R, Schrappe, M, Stanulla, M, Hemminki, K, and Houlston, R S

Published
2017
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16. Common variation at 12q24.13 (OAS3) influences chronic lymphocytic leukemia risk

Author

Sava, G P, Speedy, H E, Di Bernardo, M C, Dyer, M JS, Holroyd, A, Sunter, N J, Marr, H, Mansouri, L, Deaglio, S, Karabon, L, Frydecka, I, Jamroziak, K, Woszczyk, D, Juliusson, G, Smedby, K E, Jayne, S, Majid, A, Wang, Y, Dearden, C, Hall, A G, Mainou-Fowler, T, Jackson, G H, Summerfield, G, Harris, R J, Pettitt, A R, Allsup, D J, Bailey, J R, Pratt, G, Pepper, C, Fegan, C, Rosenquist, R, Catovsky, D, Allan, J M, and Houlston, R S

Published
2015
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18. Common Susceptibility Loci for Male Breast Cancer

Author

Maguire, S, Perraki, E, Tomczyk, K, Jones, ME, Fletcher, O, Pugh, M, Winter, T, Thompson, K, Cooke, R, Trainer, A, James, P, Bojesen, S, Flyger, H, Nevanlinna, H, Mattson, J, Friedman, E, Laitman, Y, Palli, D, Masala, G, Zanna, I, Ottini, L, Silvestri, V, Hollestelle, A, Hooning, MJ, Novakovic, S, Krajc, M, Gago-Dominguez, M, Esteban Castelao, J, Olsson, H, Hedenfalk, I, Saloustros, E, Georgoulias, V, Easton, DF, Pharoah, P, Dunning, AM, Bishop, DT, Neuhausen, SL, Steele, L, Ashworth, A, Closas, MG, Houlston, R, Swerdlow, A, Orr, N, Maguire, S, Perraki, E, Tomczyk, K, Jones, ME, Fletcher, O, Pugh, M, Winter, T, Thompson, K, Cooke, R, Trainer, A, James, P, Bojesen, S, Flyger, H, Nevanlinna, H, Mattson, J, Friedman, E, Laitman, Y, Palli, D, Masala, G, Zanna, I, Ottini, L, Silvestri, V, Hollestelle, A, Hooning, MJ, Novakovic, S, Krajc, M, Gago-Dominguez, M, Esteban Castelao, J, Olsson, H, Hedenfalk, I, Saloustros, E, Georgoulias, V, Easton, DF, Pharoah, P, Dunning, AM, Bishop, DT, Neuhausen, SL, Steele, L, Ashworth, A, Closas, MG, Houlston, R, Swerdlow, A, and Orr, N

Abstract

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Published
2021

19. Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Author

Lesseur, C., Ferreiro-Iglesias, A., McKay, J. D., Bosse, Y., Johansson, M., Gaborieau, V., Landi, M. T., Christiani, D. C., Caporaso, N. C., Bojesen, S. E., Amos, C. I., Shete, S., Liu, G., Rennert, G., Albanes, D., Aldrich, M. C., Tardon, A., Chen, Chen, Triantafillos, L., Field, J. K., Teare, M. D., Kiemeney, L. A., Diergaarde, B., Ferris, R. L., Zienolddiny, S., Lam, S., Olshan, A. F., Weissler, M. C., Lacko, M., Risch, A., Bickeboller, H., Ness, A. R., Thomas, S., Le Marchand, L., Schabath, M. B., Wunsch-Filho, V., Tajara, E. H., Andrew, A. S., Clifford, G. M., Lazarus, P., Grankvist, K., Arnold, S., Melander, O., Brunnstrom, H., Boccia, S., Cadoni, G., Timens, W., Obeidat, M., Xiao, X., Houlston, R. S., Hung, R. J., Brennan, P., Liu G., Chen C., Boccia S. (ORCID:0000-0002-1864-749X), Cadoni G. (ORCID:0000-0001-8244-784X), Lesseur, C., Ferreiro-Iglesias, A., McKay, J. D., Bosse, Y., Johansson, M., Gaborieau, V., Landi, M. T., Christiani, D. C., Caporaso, N. C., Bojesen, S. E., Amos, C. I., Shete, S., Liu, G., Rennert, G., Albanes, D., Aldrich, M. C., Tardon, A., Chen, Chen, Triantafillos, L., Field, J. K., Teare, M. D., Kiemeney, L. A., Diergaarde, B., Ferris, R. L., Zienolddiny, S., Lam, S., Olshan, A. F., Weissler, M. C., Lacko, M., Risch, A., Bickeboller, H., Ness, A. R., Thomas, S., Le Marchand, L., Schabath, M. B., Wunsch-Filho, V., Tajara, E. H., Andrew, A. S., Clifford, G. M., Lazarus, P., Grankvist, K., Arnold, S., Melander, O., Brunnstrom, H., Boccia, S., Cadoni, G., Timens, W., Obeidat, M., Xiao, X., Houlston, R. S., Hung, R. J., Brennan, P., Liu G., Chen C., Boccia S. (ORCID:0000-0002-1864-749X), and Cadoni G. (ORCID:0000-0001-8244-784X)

Abstract

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

Published
2021

25. Effect of delays in the UK two-week wait cancer referral pathway during the COVID-19 pandemic on cancer survival: a modelling study

Author

Sud, A, Torr, B, Jones, M, Broggio, J, Scott, S, Loveday, C, Garrett, A, Gronthoud, F, Nicol, D, Jhanji, S, Boyce, S, Williams, M, Riboli, E, Muller, D, Kipps, E, Larkin, J, Navani, N, Swanton, C, Lyratzopoulos, G, McFerran, E, Lawler, M, Houlston, R, Turnbull, C, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
Adult, Male, Waiting Lists, CYSTECTOMY, Pneumonia, Viral, MUSCLE INVASION, DIAGNOSIS, Betacoronavirus, Neoplasms, BREAST-CANCER, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Pandemics, Referral and Consultation, Aged, Aged, 80 and over, Science & Technology, Models, Statistical, Middle Aged, Survival Analysis, TIME, Oncology, England, Female, Coronavirus Infections, Life Sciences & Biomedicine
Abstract

Background: During the COVID-19 lockdown, referrals via the 2 Week Wait (2WW) urgent pathway for suspected cancer in England are reported to have dropped by up to 84%. We aimed to examine the impact on cancer survival of different scenarios of lockdown accumulated-backlog. We also aimed to examine by tumour-referral-group and age, survival benefit per referred patient considering survival decrement from delayed referral versus risk of death from nosocomial SARS-CoV-2 infection. Methods: To construct the underlying models, we used age- and stage-stratified 10 year cancer survival estimates for England 2007-2017 for 20 common tumour-types. We applied per-day hazard ratios for cancer progression generated from observational studies of delay to-treatment. We quantified the annual numbers of cancers diagnosed via the 2WW-pathway using the 2WW age- and stage-specific breakdowns. From these, for per-patient delays of 1- 6 months, we estimated aggregate number of lives lost and life-years lost in England. Using referral-to-diagnosis conversion rates and COVID-19 case fatality rates, we also estimated the survival increment per patient referred. Findings: Per month across England in 2013-2016, on average 6,281 patients with Stage 1- 3 cancer were diagnosed via the 2WW pathway of whom 1,691 would be predicted to die within 10 years from their disease. We estimated 2WW-pathway presentational-delay from three months of lockdown will result in total in 181/361/542 attributable additional deaths (if % reduction in referrals was 25/50/75% respectively). Limited diagnostic capacity to address the backlog may result in additional delays: 401/811/1,231 attributable additional deaths are estimated if additional diagnostic capacity is delayed until months 3-8 post-lockdown. 2-month delay in 2WW investigatory referral results in average loss of life-years per-referred-patient of between 0 and 0.7, depending on age and tumour-type. Interpretation: Prompt provision of additional capacity for ‘catch-up’ in diagnostics will minimise deaths consequent from ‘diagnostic-delay’ accumulated on top of the ‘presentational-delay’. Prioritisation of patient groups for whom delay would result in most life years lost warrants consideration as an option for mitigating the aggregate burden of mortality. Funding: None

Published
2020

26. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Author

Houlston R., Choudhury P.P., Easton D.F., Milne R.L., Simard J., Hall P., Michailidou K., Dennis J., Schmidt M.K., Chang-Claude J., Gharahkhani P., Whiteman D., O'Mara T.A., Spurdle A.B., Thompson D.J., Tomlinson I., De Vivo I., Campbell P.T., Hoffmeister M., Jenkins M., Peters U., Hsu L., Gruber S.B., Casey G., Schmit S.L., Landi M.T., Law M.H., Iles M.M., Demenais F., Kumar R., MacGregor S., Bishop D.T., Ward S.V., Bondy M.L., Wiencke J.K., Melin B., Barnholtz-Sloan J., Kinnersley B., Wrensch M.R., Hung R.J., Caporaso N.E., Berndt S.I., Birmann B.M., Camp N.J., Kraft P., Rothman N., Slager S.L., Berchuck A., Pharoah P.D.P., Sellers T.A., Gayther S.A., Pearce C.L., Goode E.L., Schildkraut J.M., Moysich K.B., Amos C.I., Brennan P., McKay J., Amundadottir L.T., Jacobs E.J., Klein A.P., Petersen G.M., Risch H.A., Stolzenberg-Solomon R.Z., Wolpin B.M., Li D., Eeles R.A., Haiman C.A., Kote-Jarai Z., Schumacher F.R., Al Olama A.A., Purdue M.P., Scelo G., Dalgaard M.D., Greene M.H., Grotmol T., Kanetsky P.A., McGlynn K.A., Nathanson K.L., Turnbull C., Wiklund F., Chanock S.J., Chatterjee N., Garcia-Closas M., Zhang Y.D., Hurson A.N., Zhang H., Houlston R., Choudhury P.P., Easton D.F., Milne R.L., Simard J., Hall P., Michailidou K., Dennis J., Schmidt M.K., Chang-Claude J., Gharahkhani P., Whiteman D., O'Mara T.A., Spurdle A.B., Thompson D.J., Tomlinson I., De Vivo I., Campbell P.T., Hoffmeister M., Jenkins M., Peters U., Hsu L., Gruber S.B., Casey G., Schmit S.L., Landi M.T., Law M.H., Iles M.M., Demenais F., Kumar R., MacGregor S., Bishop D.T., Ward S.V., Bondy M.L., Wiencke J.K., Melin B., Barnholtz-Sloan J., Kinnersley B., Wrensch M.R., Hung R.J., Caporaso N.E., Berndt S.I., Birmann B.M., Camp N.J., Kraft P., Rothman N., Slager S.L., Berchuck A., Pharoah P.D.P., Sellers T.A., Gayther S.A., Pearce C.L., Goode E.L., Schildkraut J.M., Moysich K.B., Amos C.I., Brennan P., McKay J., Amundadottir L.T., Jacobs E.J., Klein A.P., Petersen G.M., Risch H.A., Stolzenberg-Solomon R.Z., Wolpin B.M., Li D., Eeles R.A., Haiman C.A., Kote-Jarai Z., Schumacher F.R., Al Olama A.A., Purdue M.P., Scelo G., Dalgaard M.D., Greene M.H., Grotmol T., Kanetsky P.A., McGlynn K.A., Nathanson K.L., Turnbull C., Wiklund F., Chanock S.J., Chatterjee N., Garcia-Closas M., Zhang Y.D., Hurson A.N., and Zhang H.

Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.Copyright © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

27. Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D

Author

Yang, X, Song, H, Leslie, G, Engel, C, Hahnen, E, Auber, B, Horvath, J, Kast, K, Niederacher, D, Turnbull, C, Houlston, R, Hanson, H, Loveday, C, Dolinsky, JS, LaDuca, H, Ramus, SJ, Menon, U, Rosenthal, AN, Jacobs, I, Gayther, SA, Dicks, E, Nevanlinna, H, Aittomaeki, K, Pelttari, LM, Ehrencrona, H, Borg, A, Kvist, A, Rivera, B, Hansen, TVO, Djursby, M, Lee, A, Dennis, J, Bowtell, DD, Traficante, N, Diez, O, Balmana, J, Gruber, SB, Chenevix-Trench, G, Jensen, A, Kjaer, SK, Hogdall, E, Castera, L, Garber, J, Janavicius, R, Osorio, A, Golmard, L, Vega, A, Couch, FJ, Robson, M, Gronwald, J, Domchek, SM, Culver, JO, de la Hoya, M, Easton, DF, Foulkes, WD, Tischkowitz, M, Meindl, A, Schmutzler, RK, Pharoah, PDP, Antoniou, AC, Yang, X, Song, H, Leslie, G, Engel, C, Hahnen, E, Auber, B, Horvath, J, Kast, K, Niederacher, D, Turnbull, C, Houlston, R, Hanson, H, Loveday, C, Dolinsky, JS, LaDuca, H, Ramus, SJ, Menon, U, Rosenthal, AN, Jacobs, I, Gayther, SA, Dicks, E, Nevanlinna, H, Aittomaeki, K, Pelttari, LM, Ehrencrona, H, Borg, A, Kvist, A, Rivera, B, Hansen, TVO, Djursby, M, Lee, A, Dennis, J, Bowtell, DD, Traficante, N, Diez, O, Balmana, J, Gruber, SB, Chenevix-Trench, G, Jensen, A, Kjaer, SK, Hogdall, E, Castera, L, Garber, J, Janavicius, R, Osorio, A, Golmard, L, Vega, A, Couch, FJ, Robson, M, Gronwald, J, Domchek, SM, Culver, JO, de la Hoya, M, Easton, DF, Foulkes, WD, Tischkowitz, M, Meindl, A, Schmutzler, RK, Pharoah, PDP, and Antoniou, AC

Abstract

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Published
2020

28. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author

Zhang, YD, Hurson, AN, Zhang, H, Choudhury, PP, Easton, DF, Milne, RL, Simard, J, Hall, P, Michailidou, K, Dennis, J, Schmidt, MK, Chang-Claude, J, Gharahkhani, P, Whiteman, D, Campbell, PT, Hoffmeister, M, Jenkins, M, Peters, U, Hsu, L, Gruber, SB, Casey, G, Schmit, SL, O'Mara, TA, Spurdle, AB, Thompson, DJ, Tomlinson, I, De Vivo, I, Landi, MT, Law, MH, Iles, MM, Demenais, F, Kumar, R, MacGregor, S, Bishop, DT, Ward, SV, Bondy, ML, Houlston, R, Wiencke, JK, Melin, B, Barnholtz-Sloan, J, Kinnersley, B, Wrensch, MR, Amos, CI, Hung, RJ, Brennan, P, McKay, J, Caporaso, NE, Berndt, SI, Birmann, BM, Camp, NJ, Kraft, P, Rothman, N, Slager, SL, Berchuck, A, Pharoah, PDP, Sellers, TA, Gayther, SA, Pearce, CL, Goode, EL, Schildkraut, JM, Moysich, KB, Amundadottir, LT, Jacobs, EJ, Klein, AP, Petersen, GM, Risch, HA, Stolzenberg-Solomon, RZ, Wolpin, BM, Li, D, Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, Al Olama, AA, Purdue, MP, Scelo, G, Dalgaard, MD, Greene, MH, Grotmol, T, Kanetsky, PA, McGlynn, KA, Nathanson, KL, Turnbull, C, Wiklund, F, Chanock, SJ, Chatterjee, N, Garcia-Closas, M, Zhang, YD, Hurson, AN, Zhang, H, Choudhury, PP, Easton, DF, Milne, RL, Simard, J, Hall, P, Michailidou, K, Dennis, J, Schmidt, MK, Chang-Claude, J, Gharahkhani, P, Whiteman, D, Campbell, PT, Hoffmeister, M, Jenkins, M, Peters, U, Hsu, L, Gruber, SB, Casey, G, Schmit, SL, O'Mara, TA, Spurdle, AB, Thompson, DJ, Tomlinson, I, De Vivo, I, Landi, MT, Law, MH, Iles, MM, Demenais, F, Kumar, R, MacGregor, S, Bishop, DT, Ward, SV, Bondy, ML, Houlston, R, Wiencke, JK, Melin, B, Barnholtz-Sloan, J, Kinnersley, B, Wrensch, MR, Amos, CI, Hung, RJ, Brennan, P, McKay, J, Caporaso, NE, Berndt, SI, Birmann, BM, Camp, NJ, Kraft, P, Rothman, N, Slager, SL, Berchuck, A, Pharoah, PDP, Sellers, TA, Gayther, SA, Pearce, CL, Goode, EL, Schildkraut, JM, Moysich, KB, Amundadottir, LT, Jacobs, EJ, Klein, AP, Petersen, GM, Risch, HA, Stolzenberg-Solomon, RZ, Wolpin, BM, Li, D, Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, Al Olama, AA, Purdue, MP, Scelo, G, Dalgaard, MD, Greene, MH, Grotmol, T, Kanetsky, PA, McGlynn, KA, Nathanson, KL, Turnbull, C, Wiklund, F, Chanock, SJ, Chatterjee, N, and Garcia-Closas, M

Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Published
2020

32. The C/C_ 13910 mismatch repairgenotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population

Author

Rasinpera, H., Forsblom, C., Enattah, N.S., Halonen, P., Salo, K., Victorzon, M., Mecklin, J-P., Jarvinen, H., Enholm, S., Sellick, G., Alazzouzi, H., Houlston, R., Robinson, J., Groop, P-H., Tomlinson, I., Schwartz, S., Jr., and Aaltonen, A.

Subjects
Lactase -- Consumption data, Lactase -- Research, Genotype -- Research, Colorectal cancer -- Risk factors, Colorectal cancer -- Nutritional aspects, Colorectal cancer -- Environmental aspects, Health
Published
2005

33. Exon 3 betacatenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome

Author

Johnson, V, Volikos, E, Halford, S E, Eftekhar Sadat, E T, Popat, S, Talbot, I, Truninger, K, Martin, J, Jass, J, Houlston, R, Atkin, W, Tomlinson, I P M, and Silver, A R J

Subjects
Genetic disorders -- Diagnosis, Genetic disorders -- Research, Genetic disorders -- Observations, Exon (Molecular genetics) -- Identification and classification, Exon (Molecular genetics) -- Observations, Colorectal cancer -- Diagnosis, Colorectal cancer -- Research, Health
Published
2005

39. Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci

Author

Labreche K., Kinnersley B., Berzero G., Di Stefano A. L., Rahimian A., Detrait I., Marie Y., Grenier-Boley B., Hoang-Xuan K., Delattre J. -Y., Idbaih A., Houlston R. S., Sanson M., Labreche, K., Kinnersley, B., Berzero, G., Di Stefano, A. L., Rahimian, A., Detrait, I., Marie, Y., Grenier-Boley, B., Hoang-Xuan, K., Delattre, J. -Y., Idbaih, A., Houlston, R. S., and Sanson, M.

Abstract

Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Most glioma risk loci showed subtype specificity: (1) the 8q24.21 SNP for triple-positive glioma; (2) 5p15.33, 9p21.3, 17p13.1 and 20q13.33 SNPs for TERT-only glioma; (3) 1q44, 2q33.3, 3p14.1, 11q21, 11q23.3, 14q12, and 15q24.2 SNPs for IDH mutated glioma. To link risk SNPs to target candidate genes we analysed Hi-C and gene expression data, highlighting the potential role of IDH1 at 2q33.3, MYC at 8q24.21 and STMN3 at 20q13.33. Our observations provide further insight into the nature of susceptibility to glioma.

Published
2018

40. Association between polymorphisms of the GPX1 gene and second primary tumours after index squamous cell cancer of the head and neck

Author

Jefferies, S., Kote-Jarai, Z., Goldgar, D., Houlston, R., Frazer-Williams, M.-J., A’Hern, R., Henk, J., Gore, M., Rhys-Evans, P., Archer, D., Bishop, K., Solomon, E., Hodgson, S., McGurk, M., Hibbert, J., O’Connell, M., Partridge, M., Chevretton, E., Calman, F., Saunders, M., Shotton, K., Brown, A., Whittaker, S., and Foulkes, W.

Published
2005
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45. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author

Jiang, X., Finucane, H.K., Schumacher, F.R., Schmit, S.L., Tyrer, J.P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K.B., Dennis, J., Conti, D.V., Casey, G., Gaudet, M.M., Huyghe, J.R., Albanes, D., Aldrich, M.C., Andrew, A.S., Andrulis, I.L., Anton-Culver, H., Antoniou, A.C., Antonenkova, N.N., Arnold, S.M., Aronson, K.J., Arun, B.K., Bandera, E.V., Barkardottir, R.B., Barnes, D.R., Batra, J., Beckmann, M.W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S.I., Bickeboller, H., Bien, S.A., Blomqvist, C., Boccia, S., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Brauch, H., Brenner, H., Brenton, J.D., Brook, M.N., Brunet, J., Brunnstrom, H., Buchanan, D.D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M.A., Campbell, I., Campbell, P.T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A.L., Chan, A.T., Chang-Claude, J., Chanock, S.J., Chen, C., Christiani, D.C., Claes, K.B.M., Claessens, F., Clements, J., Collee, J.M., Correa, M.C., Couch, F.J., Cox, A., Cunningham, J.M., Cybulski, C., Czene, K., Daly, M.B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J.L., Dork, T., Duell, E.J., Dunning, A.M., Dwek, M., Eccles, D.M., Edlund, C.K., Edwards, D.R.V., Ellberg, C., Evans, D.G., Fasching, P.A., Ferris, R.L., Liloglou, T., Figueiredo, J.C., Fletcher, O., Fortner, R.T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S.J., Ganz, P.A., Garber, J., Garcia-Saenz, J.A., Gayther, S.A., Giles, G.G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Goode, E.L., Goodman, M.T., Goodman, G., Grankvist, K., Greene, M.H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F.C., Hamilton, R.J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y.C., Hopper, J.L., Houlston, R., Hulick, P.J., Hunter, D.J., Huntsman, D.G., Idos, G., Imyanitov, E.N., Ingles, S.A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M.A., Johansson, M., John, E.M., Joshi, A.D., Kaneva, R., Karlan, B.Y., Kelemen, L.E., Kuhl, T., Khaw, K.T., Khusnutdinova, E., Kibel, A.S., Kiemeney, L.A., Kim, J., Kjaer, S.K., Knight, J.A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V.N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M.T., Lazarus, P., N.D. le, Lee, E., Lejbkowicz, F., Lenz, H.J., Leslie, G., Lessel, D., Lester, J., Levine, D.A., Li, L., Li, C.I., Lindblom, A., Lindor, N.M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R.L., MacInnis, R.J., Modugno, F., Montagna, M., Moreno, V., Moysich, K.B., Mucci, L., Muir, K., Mulligan, A.M., Nathanson, K.L., Neal, D.E., Ness, A.R., Neuhausen, S.L., Nevanlinna, H., Newcomb, P.A., Newcomb, L.F., Nielsen, F.C., Nikitina-Zake, L., Nordestgaard, B.G., Nussbaum, R.L., Offit, K., Olah, E., Olama, A.A. al, Olopade, O.I., Olshan, A.F., Olsson, H., Osorio, A., Pandha, H., Park, J.Y., Pashayan, N., Parsons, M.T., Pejovic, T., Penney, K.L., Peters, W.H.M., Phelan, C.M., Phipps, A.I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S.J., Raskin, L., Rennert, G., Rennert, H.S., Rensburg, E.J., Riggan, M.J., Risch, H.A., Risch, A., Roobol, M.J., Rosenstein, B.S., Rossing, M.A., Ruyck, K., Saloustros, E., Sandler, D.P., Sawyer, E.J., Schabath, M.B., Schleutker, J., Schmidt, M.K., Setiawan, V.W., Shen, H.B., Siegel, E.M., Sieh, W., Singer, C.F., Slattery, M.L., Sorensen, K.D., Southey, M.C., Spurdle, A.B., Stanford, J.L., Stevens, V.L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A.J., Tajara, E.H., Tangen, C.M., Tardon, A., Taylor, J.A., Teare, M.D., Teixeira, M.R., Terry, M.B., Terry, K.L., Thibodeau, S.N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A.E., Torres, D., Townsend, P.A., Travis, R.C., Tung, N., and Tworoger

Published
2019

46. International cancer seminars:a focus on colorectal cancer

Author

Gunter, MJ, Alhomoud, S, Arnold, M, Brenner, H, Burn, J, Casey, G, Chain, AT, Cross, AJ, Giovannucci, E, Hoover, R, Houlston, R, Jenkins, M, Laurent-Puig, P, Peters, U, Ransohoff, D, Riboli, E, Sinha, R, Stadler, ZK, Brennan, P, Chanock, SJ, and Imperial College Trust

Subjects
Oncology & Carcinogenesis, 1112 Oncology And Carcinogenesis
Abstract

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Published
2019

50. STK11 status and intussusception risk in Peutz-Jeghers syndrome

Author

Hearle, N, Schumacher, V, Menko, F H, Olschwang, S, Boardman, L A, Gille, J J P, Keller, J J, Westerman, A M, Scott, R J, Lim, W, Trimbath, J D, Giardiello, F M, Gruber, S B, Offerhaus, G J A, Rooij, F W M D E, Wilson, J H P, Hansmann, A, Möslein, G, Royer-Pokora, B, Vogel, T, Phillips, R K S, Spigelman, A D, and Houlston, R S

Published
2006

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