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Br J Cancer. 2016 Apr 12;114(8):945-52.

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.

Collaborators (692)

Abbasi Z, Abdul-Hamid MA, Abel PD, Abrams PH, Adab FA, Adamson A, Adeyoju A, Afzal N, Ahiaku EK, Ahmed M, Al Sudani ML, Alcock C, Ali Z, Almond DJ, Alonzi R, Al-Samarraie AS, Al-Singary W, Al-Sudani, Anderson J, Andrews S, Andrews H, Anjum I, Anson K, Anyamene NA, Apakama I, Aparcia F, Archbold JA, Ash D, Ashford RF, Azzabi A, Badenoch D, Bahl A, Bailey MJ, Bailey K, Ball AJ, Banerjee G, Barber N, Barber J, Barnes DG, Bashir J, Basu P, Bates CA, Bax NA, Baxter-Smith D, Bdesha A, Beacock CJ, Beaney RP, Beard R, Beatty JD, Beck R, Beese G, Beesley S, Bell CR, Bellringer J, Benson R, Beresford, Bevis CR, Bhana R, Bhanot S, Bhatnagar A, Bhatt RI, Birch B, Birtle A, Bishop M, Biyani CS, Blacklock AR, Blades R, Bliss P, Bloomfield DJ, Boddy S, Booth CM, Bose P, Bott MC, Bottomley D, Boucher NR, Bowen J, Bower M, Bowsher WG, Boyd PJ, Bramble FJ, Brewster SF, Briggs T, Brock C, Brock S, Bromage S, Brough R, Brown R, Brown S, Brown R, Browning TJ, Bryan N, Burgess NA, Burns-Cox N, Butterworth PC, Cahill D, Callaghan PS, Calleary J, Calleja M, Calman F, Camilleri P, Campbell A, Cannon A, Carnell DM, Carr TW, Carter S, Carter CJ, Carter AC, Castle M, Chadwick D, Chahal R, Chakraborti P, Charig C, Chetiyawardana AD, Chilton C, Chinegwundoh FI, Chong I, Choudhury A, Chow WM, Christmas TJ, Churn MJ, Clarke NW, Clavijo-Eisele J, Coe M, Cohen NP, Coker C, Cole T, Cole DJ, Cole O, Collins G, Collinson M, Conn I, Connell C, Cook A, Cooke P, Cooksey G, Coombs L, Copland RF, Cornaby AJ, Cornford PA, Corolis, Corr J, Costello CB, Coull MN, Cowan R, Cox R, Coyle C, Crew J, Crisp JC, Cross W, Cross W, Cruger D, Crundwell M, Cummings, Dahar N, Daniel FN, Darrad J, Daruwala P, Das G, Datta S, Davidson S, Davies J, Davison OW, Dawkins G, Dawson C, De Bolla AR, Dearnaley D, Desai KM, Deutsch GP, Dick J, Dickinson AJ, Dickson J, Dinneen M, Dixit S, Dobbs HJ, Doble A, Dodds D, Doherty A, Donaldson P, Dooldeniya M, Douglas SF, Drake, Duchesne GM, Duffy P, Dunn M, Dunsmuir WD, Durrani SK, Eaton AC, Eccles D, Eddy B, Eden CD, Edwards J, Elkabir J, Elliott PT, Ellis BW, Ellis R, El-Modir A, Elves AW, Elwell C, Emberton M, Emmerson L, England RC, Errington RD, Evans DG, Falconer A, Fawcett D, Featherston C, Featherstone CJ, Feggetter J, Ferguson C, Fermont D, Ferro M, Fletcher M, Folkes A, Ford TF, Foster PW, Franks KN, Frim O, Gale J, Gallegos C, Gelister JS, Ghana, Gibbs S, Gilbert H, Gillatt D, Glaholm J, Glass JM, Glenister J, Goode TD, Gordon EM, Gower RL, Graham J, Green D, Greenland J, Grieve R, Griffiths TR, Gujral S, Gupta N, Gurun RM, Guy PJ, Haldar N, Halder N, Hamdy FC, Hamilton C, Hammonds J, Hampson SJ, Hanbury DC, Hardman PD, Harland SJ, Harney JM, Harper P, Harris S, Harris D, Harrison GS, Harriss DR, Harvey-Hills N, Hawkyard S, Heath CM, Hehir M, Hellawell GO, Hendry D, Henley M, Henry A, Hetherington J, Hickish T, Hicks JA, Hilman S, Hindley R, Hindmarsh JR, Hines J, Hingorani M, Ho ET, Hodgson S, Hoffman U, Holden D, Hollingdale A, Hollins GW, Holmes SA, Horan G, Horwich A, Hoskin P, Howell GP, Hrouda D, Huddart R, Hudson L, Hughes R, Hughes M, Hughes O, Humber C, Iacovou JW, Ibrahim A, Inglis JA, Irving S, Irwin C, Izatt L, Izegbu V, Jameel B, James MJ, James N, James RL, Javle P, Jenkins P, Jhavar S, Jones G, Jones CR, Jones DA, Joseph J, Joss S, Kaisary A, Kaliski AL, Kapur G, Karim O, Karp SJ, Keeley FX, Kelkar AR, Kelleher JP, Kelly J, Kenwrick S, Khan F, Khoo V, Kimber RM, Kinder R, Kirby RS, Kirk D, Kirkbride P, Kirollos MM, Kockelbergh R, Koenig PC, Kooiman GG, Koreich O, Koupparis A, Kourah M, Kraus S, Kujawa ML, Kulkarni R, Kumar M, Kunkler IH, Kynaston H, Lachlan KL, Laing R, Lalloo F, Lancashire M, Langley SE, Laniado M, Larner TR, Lau MW, Lawrence WT, Lawson A, Roux PJ, Leader M, Lee JO, Lee L, Lee A, Lemburger RJ, Leone P, Lester J, Leung H, Lewis J, Lewis DC, Liston T, Livsey J, Lloyd S, Locke I, Lodge R, Logue J, Longmuir M, Lucas MG, Luscombe CJ, Lydon A, Lynch M, Lynn NN, MacDermott JP, Macdonagh RP, Macdonald, Madaan S, Madhava KR, Maguire J, Maher ER, Mahmood R, Mair GH, Malone PR, Mangar SA, Mantle M, Mark I, Mason R, Mason MD, Matanhelia, Matenhelia S, Matthews PN, McAleese J, McBride D, McFarlane J, McGrath, McIlhenny C, McInerney P, McIntosh G, McKinna F, McLaren D, McLarty E, McMenemin R, McNeill A, McNicholas TA, Meddings RN, Mee AD, Melcher L, Memon, Menzes P, Miller M, Mills R, Mitchell S, Mithal N, Mitra A, Mobb GE, Moffat LE, Mokete, Money-Kyrle J, Montgomery B, Moody MP, Morley R, Morris SB, Morrison P, Mort D, Mostafid AH, Motiwala H, Mufti G, Muir G, Mumtaz F, Murphy M, Murray KW, Murray A, Murrell S, Muthukumar D, Naerger H, Namasivayam S, Nargund V, Mr Nawrocki, Neilson D, Nethersell A, Barwell J, Newby JC, Newman H, Newton R, Oakley N, O'Boyle PJ, O'Brien J, O'Brien TS, O'Donnell H, O'Donoghue N, O'Donoghue E, Ogden C, Ohja H, Oliver T, Ong EK, O'Reilly P, O'Rourke JS, Osborn D, Ostler P, O'Sullivan J, Owen J, Palfrey E, Panades M, Panakis N, Pancharatnam M, Pantelides ML, Panwar U, Parikh O, Parker C, Parker CH, Parys BT, Pascoe S, Patel A, Paterson J, Pathack S, Pati J, Patterson H, Paul A, Payne H, Peake D, Pedley I, Pengelly A, Peracha AM, Perry M, Persad R, Peters J, Philp NH, Philp T, Pickering LM, Pigott K, Plail R, Plowman PN, Pocock RD, Pope AJ, Popert R, Porter T, Potter JM, Powell C, Powles TB, Prasad K, Prasad SS, Prejbisz JW, Prescott S, Protheroe A, Qureshi KN, Raby N, Ragavan N, Raju PG, Ramachandra PB, Raman R, Rane A, Rankin J, Rao Y, Ratan HL, Ravi R, Ravishankar K, Reddy PJ, Rimington PR, Ritchie PA, Roberts JT, Robertson A, Robinson A, Robinson AC, Robinson LQ, Rochester MA, Rogers PB, Rosenbaum TP, Rothwell N, Rowbotham C, Rowe, Rowley K, Ruddy D, Rundle J, Russell JM, Ryan PG, Sabharwal A, Saggar AK, Samanci A, Sangar VK, Saxby MF, Schwaibold H, Scoble JE, Scrase C, Selim, Sells H, Sethia KK, Shackley DC, Shaffer, Shah N, Shakespeare D, Shanley S, Sharma NK, Sheehan DJ, Sherwin E, Shum PL, LucySide, Sidek N, Sikora K, Simcock R, Sinclair AM, Singh P, Siva M, Smith MF, Smith J, Sokal M, Sole GM, Speakman MJ, Spiers A, Sreenivasan T, Srihari NN, Srinivasan, Sriram R, Staffurth JN, Stewart D, Stockdale A, Stott MA, Stower MJ, Strachan JR, Stuart NS, Sugden E, Summerton D, Sundar S, Sundaram SK, Suresh G, Susnerwala S, Swami KS, Symons SJ, Syndikus I, Tahir S, Tanquay J, Taylor JW, Taylor JW, Terry T, Thomas RJ, Thomas SA, Thompson A, Thomson AH, Thurston A, Tilsley O, Tindall SF, Tipples K, Tong, Toussi H, Toy EW, Trembath RC, Tulloch DN, Turner KJ, Tweedle J, Tyrell CJ, Umez-Eronini N, Urwin GH, Vale JA, Van As N, Vasanthan S, Vesey S, Vilarino-Varela M, Violet J, Virdi J, Wade R, Waite K, Walker EM, Walker R, Wallace DM, Watkin NA, Watson ME, Waxman JH, Waymont B, Weaver A, Webb RJ, Wedderburn A, Wells P, Wemyss-Holden GD, Weston PM, Wheatley D, Whelan P, Whillis D, Wilde AD, Wiles V, Wilkins M, Williams JH, Williams S, Willis M, Wills MI, Wilson R, Wilson JR, Winkler MH, Wise M, Woodhams S, Woodhouse C, Woodward C, Woolf, Woolfenden KA, Worlding J, Wright M, Wylie JP, Wynne C, Zang A, Zarkar A, Cox A, Brown PM, George A, Marsden G, Lane A, Bollina P, Davis M, Bonnington S, Bradshaw L, Catto J, Cooper D, Down L, Doble A, Doherty A, Durkan G, Elliott E, Gillatt D, Herbert P, Holding P, Howson J, Jones M, Kockelbergh R, Kumar R, Kynaston H, Lane A, Lennon T, Lyons N, Leung H, Mason M, Moody H, Powell P, Paul A, Prescott S, Rosario D, O'Sullivan P, Thompson P, Tidball S.

Abstract

BACKGROUND:

Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.

METHODS:

Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.

RESULTS:

Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.

CONCLUSIONS:

MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

PMID:
26964030
PMCID:
PMC5379914
DOI:
10.1038/bjc.2016.50
[Indexed for MEDLINE]
Free PMC Article

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