PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

MC Southey; DE Goldgar; R Winqvist; K Pylkas; F Couch; M Tischkowitz; WD Foulkes; J Dennis; K Michailidou; EJ van Rensburg; T Heikkinen; H Nevanlinna; JL Hopper; T Dork; KBM Claes; J Reis; ZL Teo; P Radice; I Catucci; P Peterlongo; H Tsimiklis; FA Odefrey; JG Dowty; MK (Marjanka) Schmidt; A Broeks; FB Hogervorst; S Verhoef; J Carpenter; C Clarke; RJ Scott; PA Fasching; L Haeberle; AB Ekici; MW Beckmann; J Peto; I dos-Santos-Silva; O Fletcher; N Johnson; MK Bolla; EJ Sawyer; I Tomlinson; MJ Kerin; N Miller; F Marme; B Burwinkel; RX Yang; P Guenel; T Truong; F Menegaux; M Sanchez; S Bojesen; SF Nielsen; H Flyger; J Benitez; MP Zamora; JIA Perez; P Menendez; H Anton-Culver; S Neuhausen; A Ziogas; CA Clarke; H Brenner; V Arndt; C Stegmaier; H Brauch; T Bruning; YD Ko; TA Muranen; K Aittomaki; C Blomqvist; NV Bogdanova; NN Antonenkova; A Lindblom; S Margolin; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; AB Spurdle; Erwin Wauters; D Smeets; B Beuselinck; G Floris; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; JE Olson; C Vachon; VS Pankratz; C McLean; CA Haiman; BE Henderson; F Schumacher; L Le Marchand; V Kristensen; GG Alnaes; W Zheng; DJ Hunter; S Lindstrom; SE Hankinson; P Kraft; I Andrulis; JA Knight; G Glendon; AM Mulligan; A Jukkola-Vuorinen; M Grip; S Kauppila; P Devilee; RAEM Tollenaar; Caroline Seynaeve; Antoinette Hollestelle; M Garcia-Closas; J Figueroa; SJ Chanock; J Lissowska; K Czene; H Darabi; M Eriksson; DM Eccles; S Rafiq; WJ Tapper; SM Gerty; Maartje Hooning; John Martens; Margriet Collee; Madeleine Tilanus - Linthorst; P Hall; JM Li; JS Brand; K Humphreys; A Cox; MWR Reed; C Luccarini; C Baynes; AM Dunning; U Hamann; D Torres; HU Ulmer; T Rudiger; A Jakubowska; J Lubinski; K Jaworska; K Durda; S Slager; AE Toland; CB Ambrosone; D Yannoukakos; A Swerdlow; A Ashworth; N Orr; M Jones; A Gonzalez-Neira; G Pita; MR Alonso; N Alvarez; D Herrero; DC Tessier; D Vincent; F Bacot; J Simard; M Dumont; P Soucy; R Eeles; K Muir; F Wiklund; H Gronberg; J Schleutker; BG Nordestgaard; M Weischer; RC Travis; D Neal; JL Donovan; FC Hamdy; KT Khaw; J L Stanford; WJ Blot; S Thibodeau; D J Schaid; JL Kelley; C Maier; AS Kibel; C Cybulski; L Cannon-Albright; K Butterbach; J (Judy) Park; R Kaneva; J Batra; MR Teixeira; Z Kote-Jarai; A A Al Olama; S Benlloch; SP Renner; A Hartmann; A Hein; M Ruebner; D Lambrechts; E Van Nieuwenhuysen; I Vergote; S Lambretchs; JA Doherty; MA Rossing; S Nickels; U Eilber; S Wang-Gohrke; K Odunsi; LE Sucheston-Campbell; G Friel; G Lurie; JL Killeen; LR Wilkens; MT Goodman; I Runnebaum; PA Hillemanns; LM Pelttari; R Butzow; F Modugno; RP Edwards; RB Ness; KB Moysich; A (Andreas) du Bois; F Heitz; P Harter; S Kommoss; BY Karlan; C Walsh; J Lester; A Jensen; SK Kjaer; E Hogdall; B Peissel; B Bonanni; L Bernard; EL Goode; BL Fridley; RA Vierkant; JM Cunningham; MC Larson; ZC Fogarty; KR Kalli; D Liang; KH Lu; MAT Hildebrandt; XF Wu; DA Levine; F Dao; M Bisogna; A Berchuck; ES Iversen; JR Marks; L Akushevich; DW Cramer; J Schildkraut; KL Terry; EM Poole; M Stampfer; SS Tworoger; EV Bandera; I Orlow; SH Olson; L Bjorge; HB Salvesen; AM van Altena; KKH Aben; LA Kiemeney; LFAG Massuger; T Pejovic; Y Bean; A Brooks-Wilson; LE Kelemen; LS Cook; ND Le; B Grski; J Gronwald; J Menkiszak; CK Hogdall; L Lundvall; L Nedergaard; SA Engelholm; E Dicks; J Tyrer; I Campbell; I McNeish; J Paul; N Siddiqui; R Glasspool; AS Whittemore; JH Rothstein; V McGuire; W Sieh; H Cai; XO Shu; RT Teten; R Sutphen; JR McLaughlin; SA Narod; CM Phelan; AN Monteiro; D Fenstermacher; HY Lin; J B Permuth; TA Sellers; Y A Chen; YY Tsai; ZH Chen; A Gentry-Maharaj; SA Gayther; SJ Ramus; U Menon; AH Wu; CL Pearce; D van den Berg; MC Pike; A Dansonka-Mieszkowska; J Plisiecka-Halasa; J Moes-Sosnowska; J Kupryjanczyk; PDP Pharoah; HL Song; I Winship; G Chenevix-Trench; GG Giles; SV Tavtigian; DF Easton; RL Milne

doi:10.1136/jmedgenet-2016-103839

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

MC Southey, DE Goldgar, R Winqvist, K Pylkas, F Couch, M Tischkowitz, WD Foulkes, J Dennis, K Michailidou, EJ van Rensburg, T Heikkinen, H Nevanlinna, JL Hopper, T Dork, KBM Claes, J Reis, ZL Teo, P Radice, I Catucci, P PeterlongoH Tsimiklis, FA Odefrey, JG Dowty, MK (Marjanka) Schmidt, A Broeks, FB Hogervorst, S Verhoef, J Carpenter, C Clarke, RJ Scott, PA Fasching, L Haeberle, AB Ekici, MW Beckmann, J Peto, I dos-Santos-Silva, O Fletcher, N Johnson, MK Bolla, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, F Marme, B Burwinkel, RX Yang, P Guenel, T Truong, F Menegaux, M Sanchez, S Bojesen, SF Nielsen, H Flyger, J Benitez, MP Zamora, JIA Perez, P Menendez, H Anton-Culver, S Neuhausen, A Ziogas, CA Clarke, H Brenner, V Arndt, C Stegmaier, H Brauch, T Bruning, YD Ko, TA Muranen, K Aittomaki, C Blomqvist, NV Bogdanova, NN Antonenkova, A Lindblom, S Margolin, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, AB Spurdle, Erwin Wauters, D Smeets, B Beuselinck, G Floris, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, JE Olson, C Vachon, VS Pankratz, C McLean, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, V Kristensen, GG Alnaes, W Zheng, DJ Hunter, S Lindstrom, SE Hankinson, P Kraft, I Andrulis, JA Knight, G Glendon, AM Mulligan, A Jukkola-Vuorinen, M Grip, S Kauppila, P Devilee, RAEM Tollenaar, Caroline Seynaeve, Antoinette Hollestelle, M Garcia-Closas, J Figueroa, SJ Chanock, J Lissowska, K Czene, H Darabi, M Eriksson, DM Eccles, S Rafiq, WJ Tapper, SM Gerty, Maartje Hooning, John Martens, Margriet Collee, Madeleine Tilanus - Linthorst, P Hall, JM Li, JS Brand, K Humphreys, A Cox, MWR Reed, C Luccarini, C Baynes, AM Dunning, U Hamann, D Torres, HU Ulmer, T Rudiger, A Jakubowska, J Lubinski, K Jaworska, K Durda, S Slager, AE Toland, CB Ambrosone, D Yannoukakos, A Swerdlow, A Ashworth, N Orr, M Jones, A Gonzalez-Neira, G Pita, MR Alonso, N Alvarez, D Herrero, DC Tessier, D Vincent, F Bacot, J Simard, M Dumont, P Soucy, R Eeles, K Muir, F Wiklund, H Gronberg, J Schleutker, BG Nordestgaard, M Weischer, RC Travis, D Neal, JL Donovan, FC Hamdy, KT Khaw, J L Stanford, WJ Blot, S Thibodeau, D J Schaid, JL Kelley, C Maier, AS Kibel, C Cybulski, L Cannon-Albright, K Butterbach, J (Judy) Park, R Kaneva, J Batra, MR Teixeira, Z Kote-Jarai, A A Al Olama, S Benlloch, SP Renner, A Hartmann, A Hein, M Ruebner, D Lambrechts, E Van Nieuwenhuysen, I Vergote, S Lambretchs, JA Doherty, MA Rossing, S Nickels, U Eilber, S Wang-Gohrke, K Odunsi, LE Sucheston-Campbell, G Friel, G Lurie, JL Killeen, LR Wilkens, MT Goodman, I Runnebaum, PA Hillemanns, LM Pelttari, R Butzow, F Modugno, RP Edwards, RB Ness, KB Moysich, A (Andreas) du Bois, F Heitz, P Harter, S Kommoss, BY Karlan, C Walsh, J Lester, A Jensen, SK Kjaer, E Hogdall, B Peissel, B Bonanni, L Bernard, EL Goode, BL Fridley, RA Vierkant, JM Cunningham, MC Larson, ZC Fogarty, KR Kalli, D Liang, KH Lu, MAT Hildebrandt, XF Wu, DA Levine, F Dao, M Bisogna, A Berchuck, ES Iversen, JR Marks, L Akushevich, DW Cramer, J Schildkraut, KL Terry, EM Poole, M Stampfer, SS Tworoger, EV Bandera, I Orlow, SH Olson, L Bjorge, HB Salvesen, AM van Altena, KKH Aben, LA Kiemeney, LFAG Massuger, T Pejovic, Y Bean, A Brooks-Wilson, LE Kelemen, LS Cook, ND Le, B Grski, J Gronwald, J Menkiszak, CK Hogdall, L Lundvall, L Nedergaard, SA Engelholm, E Dicks, J Tyrer, I Campbell, I McNeish, J Paul, N Siddiqui, R Glasspool, AS Whittemore, JH Rothstein, V McGuire, W Sieh, H Cai, XO Shu, RT Teten, R Sutphen, JR McLaughlin, SA Narod, CM Phelan, AN Monteiro, D Fenstermacher, HY Lin, J B Permuth, TA Sellers, Y A Chen, YY Tsai, ZH Chen, A Gentry-Maharaj, SA Gayther, SJ Ramus, U Menon, AH Wu, CL Pearce, D van den Berg, MC Pike, A Dansonka-Mieszkowska, J Plisiecka-Halasa, J Moes-Sosnowska, J Kupryjanczyk, PDP Pharoah, HL Song, I Winship, G Chenevix-Trench, GG Giles, SV Tavtigian, DF Easton, RL Milne

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Abstract

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Original language	Undefined/Unknown
Pages (from-to)	800-811
Number of pages	12
Journal	Journal of Medical Genetics
Volume	53
Issue number	12
DOIs	https://doi.org/10.1136/jmedgenet-2016-103839
Publication status	Published - 2016

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Cite this

Southey, MC., Goldgar, DE., Winqvist, R., Pylkas, K., Couch, F., Tischkowitz, M., Foulkes, WD., Dennis, J., Michailidou, K., van Rensburg, EJ., Heikkinen, T., Nevanlinna, H., Hopper, JL., Dork, T., Claes, KBM., Reis, J., Teo, ZL., Radice, P., Catucci, I., ... Milne, RL. (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics, 53(12), 800-811. https://doi.org/10.1136/jmedgenet-2016-103839

@article{7dde41e838054ced8de3c7f33dd356a3,

title = "PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS",

abstract = "Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.",

author = "MC Southey and DE Goldgar and R Winqvist and K Pylkas and F Couch and M Tischkowitz and WD Foulkes and J Dennis and K Michailidou and {van Rensburg}, EJ and T Heikkinen and H Nevanlinna and JL Hopper and T Dork and KBM Claes and J Reis and ZL Teo and P Radice and I Catucci and P Peterlongo and H Tsimiklis and FA Odefrey and JG Dowty and Schmidt, {MK (Marjanka)} and A Broeks and FB Hogervorst and S Verhoef and J Carpenter and C Clarke and RJ Scott and PA Fasching and L Haeberle and AB Ekici and MW Beckmann and J Peto and I dos-Santos-Silva and O Fletcher and N Johnson and MK Bolla and EJ Sawyer and I Tomlinson and MJ Kerin and N Miller and F Marme and B Burwinkel and RX Yang and P Guenel and T Truong and F Menegaux and M Sanchez and S Bojesen and SF Nielsen and H Flyger and J Benitez and MP Zamora and JIA Perez and P Menendez and H Anton-Culver and S Neuhausen and A Ziogas and CA Clarke and H Brenner and V Arndt and C Stegmaier and H Brauch and T Bruning and YD Ko and TA Muranen and K Aittomaki and C Blomqvist and NV Bogdanova and NN Antonenkova and A Lindblom and S Margolin and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and AB Spurdle and Erwin Wauters and D Smeets and B Beuselinck and G Floris and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and JE Olson and C Vachon and VS Pankratz and C McLean and CA Haiman and BE Henderson and F Schumacher and {Le Marchand}, L and V Kristensen and GG Alnaes and W Zheng and DJ Hunter and S Lindstrom and SE Hankinson and P Kraft and I Andrulis and JA Knight and G Glendon and AM Mulligan and A Jukkola-Vuorinen and M Grip and S Kauppila and P Devilee and RAEM Tollenaar and Caroline Seynaeve and Antoinette Hollestelle and M Garcia-Closas and J Figueroa and SJ Chanock and J Lissowska and K Czene and H Darabi and M Eriksson and DM Eccles and S Rafiq and WJ Tapper and SM Gerty and Maartje Hooning and John Martens and Margriet Collee and {Tilanus - Linthorst}, Madeleine and P Hall and JM Li and JS Brand and K Humphreys and A Cox and MWR Reed and C Luccarini and C Baynes and AM Dunning and U Hamann and D Torres and HU Ulmer and T Rudiger and A Jakubowska and J Lubinski and K Jaworska and K Durda and S Slager and AE Toland and CB Ambrosone and D Yannoukakos and A Swerdlow and A Ashworth and N Orr and M Jones and A Gonzalez-Neira and G Pita and MR Alonso and N Alvarez and D Herrero and DC Tessier and D Vincent and F Bacot and J Simard and M Dumont and P Soucy and R Eeles and K Muir and F Wiklund and H Gronberg and J Schleutker and BG Nordestgaard and M Weischer and RC Travis and D Neal and JL Donovan and FC Hamdy and KT Khaw and Stanford, {J L} and WJ Blot and S Thibodeau and Schaid, {D J} and JL Kelley and C Maier and AS Kibel and C Cybulski and L Cannon-Albright and K Butterbach and Park, {J (Judy)} and R Kaneva and J Batra and MR Teixeira and Z Kote-Jarai and {Al Olama}, {A A} and S Benlloch and SP Renner and A Hartmann and A Hein and M Ruebner and D Lambrechts and {Van Nieuwenhuysen}, E and I Vergote and S Lambretchs and JA Doherty and MA Rossing and S Nickels and U Eilber and S Wang-Gohrke and K Odunsi and LE Sucheston-Campbell and G Friel and G Lurie and JL Killeen and LR Wilkens and MT Goodman and I Runnebaum and PA Hillemanns and LM Pelttari and R Butzow and F Modugno and RP Edwards and RB Ness and KB Moysich and {du Bois}, {A (Andreas)} and F Heitz and P Harter and S Kommoss and BY Karlan and C Walsh and J Lester and A Jensen and SK Kjaer and E Hogdall and B Peissel and B Bonanni and L Bernard and EL Goode and BL Fridley and RA Vierkant and JM Cunningham and MC Larson and ZC Fogarty and KR Kalli and D Liang and KH Lu and MAT Hildebrandt and XF Wu and DA Levine and F Dao and M Bisogna and A Berchuck and ES Iversen and JR Marks and L Akushevich and DW Cramer and J Schildkraut and KL Terry and EM Poole and M Stampfer and SS Tworoger and EV Bandera and I Orlow and SH Olson and L Bjorge and HB Salvesen and {van Altena}, AM and KKH Aben and LA Kiemeney and LFAG Massuger and T Pejovic and Y Bean and A Brooks-Wilson and LE Kelemen and LS Cook and ND Le and B Grski and J Gronwald and J Menkiszak and CK Hogdall and L Lundvall and L Nedergaard and SA Engelholm and E Dicks and J Tyrer and I Campbell and I McNeish and J Paul and N Siddiqui and R Glasspool and AS Whittemore and JH Rothstein and V McGuire and W Sieh and H Cai and XO Shu and RT Teten and R Sutphen and JR McLaughlin and SA Narod and CM Phelan and AN Monteiro and D Fenstermacher and HY Lin and Permuth, {J B} and TA Sellers and Chen, {Y A} and YY Tsai and ZH Chen and A Gentry-Maharaj and SA Gayther and SJ Ramus and U Menon and AH Wu and CL Pearce and {van den Berg}, D and MC Pike and A Dansonka-Mieszkowska and J Plisiecka-Halasa and J Moes-Sosnowska and J Kupryjanczyk and PDP Pharoah and HL Song and I Winship and G Chenevix-Trench and GG Giles and SV Tavtigian and DF Easton and RL Milne",

year = "2016",

doi = "10.1136/jmedgenet-2016-103839",

language = "Undefined/Unknown",

volume = "53",

pages = "800--811",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "12",

}

Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Dork, T, Claes, KBM, Reis, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, RX, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruning, T, Ko, YD, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, M , Martens, J , Collee, M , Tilanus - Linthorst, M, Hall, P, Li, JM, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Rudiger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, XF, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, XO, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, HY, Permuth, JB, Sellers, TA, Chen, YA, Tsai, YY, Chen, ZH, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, HL, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF & Milne, RL 2016, 'PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS', Journal of Medical Genetics, vol. 53, no. 12, pp. 800-811. https://doi.org/10.1136/jmedgenet-2016-103839

TY - JOUR

T1 - PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

AU - Southey, MC

AU - Goldgar, DE

AU - Winqvist, R

AU - Pylkas, K

AU - Couch, F

AU - Tischkowitz, M

AU - Foulkes, WD

AU - Dennis, J

AU - Michailidou, K

AU - van Rensburg, EJ

AU - Heikkinen, T

AU - Nevanlinna, H

AU - Hopper, JL

AU - Dork, T

AU - Claes, KBM

AU - Reis, J

AU - Teo, ZL

AU - Radice, P

AU - Catucci, I

AU - Peterlongo, P

AU - Tsimiklis, H

AU - Odefrey, FA

AU - Dowty, JG

AU - Schmidt, MK (Marjanka)

AU - Broeks, A

AU - Hogervorst, FB

AU - Verhoef, S

AU - Carpenter, J

AU - Clarke, C

AU - Scott, RJ

AU - Fasching, PA

AU - Haeberle, L

AU - Ekici, AB

AU - Beckmann, MW

AU - Peto, J

AU - dos-Santos-Silva, I

AU - Fletcher, O

AU - Johnson, N

AU - Bolla, MK

AU - Sawyer, EJ

AU - Tomlinson, I

AU - Kerin, MJ

AU - Miller, N

AU - Marme, F

AU - Burwinkel, B

AU - Yang, RX

AU - Guenel, P

AU - Truong, T

AU - Menegaux, F

AU - Sanchez, M

AU - Bojesen, S

AU - Nielsen, SF

AU - Flyger, H

AU - Benitez, J

AU - Zamora, MP

AU - Perez, JIA

AU - Menendez, P

AU - Anton-Culver, H

AU - Neuhausen, S

AU - Ziogas, A

AU - Clarke, CA

AU - Brenner, H

AU - Arndt, V

AU - Stegmaier, C

AU - Brauch, H

AU - Bruning, T

AU - Ko, YD

AU - Muranen, TA

AU - Aittomaki, K

AU - Blomqvist, C

AU - Bogdanova, NV

AU - Antonenkova, NN

AU - Lindblom, A

AU - Margolin, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Spurdle, AB

AU - Wauters, Erwin

AU - Smeets, D

AU - Beuselinck, B

AU - Floris, G

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Olson, JE

AU - Vachon, C

AU - Pankratz, VS

AU - McLean, C

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, F

AU - Le Marchand, L

AU - Kristensen, V

AU - Alnaes, GG

AU - Zheng, W

AU - Hunter, DJ

AU - Lindstrom, S

AU - Hankinson, SE

AU - Kraft, P

AU - Andrulis, I

AU - Knight, JA

AU - Glendon, G

AU - Mulligan, AM

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Kauppila, S

AU - Devilee, P

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - Hollestelle, Antoinette

AU - Garcia-Closas, M

AU - Figueroa, J

AU - Chanock, SJ

AU - Lissowska, J

AU - Czene, K

AU - Darabi, H

AU - Eriksson, M

AU - Eccles, DM

AU - Rafiq, S

AU - Tapper, WJ

AU - Gerty, SM

AU - Hooning, Maartje

AU - Martens, John

AU - Collee, Margriet

AU - Tilanus - Linthorst, Madeleine

AU - Hall, P

AU - Li, JM

AU - Brand, JS

AU - Humphreys, K

AU - Cox, A

AU - Reed, MWR

AU - Luccarini, C

AU - Baynes, C

AU - Dunning, AM

AU - Hamann, U

AU - Torres, D

AU - Ulmer, HU

AU - Rudiger, T

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska, K

AU - Durda, K

AU - Slager, S

AU - Toland, AE

AU - Ambrosone, CB

AU - Yannoukakos, D

AU - Swerdlow, A

AU - Ashworth, A

AU - Orr, N

AU - Jones, M

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, MR

AU - Alvarez, N

AU - Herrero, D

AU - Tessier, DC

AU - Vincent, D

AU - Bacot, F

AU - Simard, J

AU - Dumont, M

AU - Soucy, P

AU - Eeles, R

AU - Muir, K

AU - Wiklund, F

AU - Gronberg, H

AU - Schleutker, J

AU - Nordestgaard, BG

AU - Weischer, M

AU - Travis, RC

AU - Neal, D

AU - Donovan, JL

AU - Hamdy, FC

AU - Khaw, KT

AU - Stanford, J L

AU - Blot, WJ

AU - Thibodeau, S

AU - Schaid, D J

AU - Kelley, JL

AU - Maier, C

AU - Kibel, AS

AU - Cybulski, C

AU - Cannon-Albright, L

AU - Butterbach, K

AU - Park, J (Judy)

AU - Kaneva, R

AU - Batra, J

AU - Teixeira, MR

AU - Kote-Jarai, Z

AU - Al Olama, A A

AU - Benlloch, S

AU - Renner, SP

AU - Hartmann, A

AU - Hein, A

AU - Ruebner, M

AU - Lambrechts, D

AU - Van Nieuwenhuysen, E

AU - Vergote, I

AU - Lambretchs, S

AU - Doherty, JA

AU - Rossing, MA

AU - Nickels, S

AU - Eilber, U

AU - Wang-Gohrke, S

AU - Odunsi, K

AU - Sucheston-Campbell, LE

AU - Friel, G

AU - Lurie, G

AU - Killeen, JL

AU - Wilkens, LR

AU - Goodman, MT

AU - Runnebaum, I

AU - Hillemanns, PA

AU - Pelttari, LM

AU - Butzow, R

AU - Modugno, F

AU - Edwards, RP

AU - Ness, RB

AU - Moysich, KB

AU - du Bois, A (Andreas)

AU - Heitz, F

AU - Harter, P

AU - Kommoss, S

AU - Karlan, BY

AU - Walsh, C

AU - Lester, J

AU - Jensen, A

AU - Kjaer, SK

AU - Hogdall, E

AU - Peissel, B

AU - Bonanni, B

AU - Bernard, L

AU - Goode, EL

AU - Fridley, BL

AU - Vierkant, RA

AU - Cunningham, JM

AU - Larson, MC

AU - Fogarty, ZC

AU - Kalli, KR

AU - Liang, D

AU - Lu, KH

AU - Hildebrandt, MAT

AU - Wu, XF

AU - Levine, DA

AU - Dao, F

AU - Bisogna, M

AU - Berchuck, A

AU - Iversen, ES

AU - Marks, JR

AU - Akushevich, L

AU - Cramer, DW

AU - Schildkraut, J

AU - Terry, KL

AU - Poole, EM

AU - Stampfer, M

AU - Tworoger, SS

AU - Bandera, EV

AU - Orlow, I

AU - Olson, SH

AU - Bjorge, L

AU - Salvesen, HB

AU - van Altena, AM

AU - Aben, KKH

AU - Kiemeney, LA

AU - Massuger, LFAG

AU - Pejovic, T

AU - Bean, Y

AU - Brooks-Wilson, A

AU - Kelemen, LE

AU - Cook, LS

AU - Le, ND

AU - Grski, B

AU - Gronwald, J

AU - Menkiszak, J

AU - Hogdall, CK

AU - Lundvall, L

AU - Nedergaard, L

AU - Engelholm, SA

AU - Dicks, E

AU - Tyrer, J

AU - Campbell, I

AU - McNeish, I

AU - Paul, J

AU - Siddiqui, N

AU - Glasspool, R

AU - Whittemore, AS

AU - Rothstein, JH

AU - McGuire, V

AU - Sieh, W

AU - Cai, H

AU - Shu, XO

AU - Teten, RT

AU - Sutphen, R

AU - McLaughlin, JR

AU - Narod, SA

AU - Phelan, CM

AU - Monteiro, AN

AU - Fenstermacher, D

AU - Lin, HY

AU - Permuth, J B

AU - Sellers, TA

AU - Chen, Y A

AU - Tsai, YY

AU - Chen, ZH

AU - Gentry-Maharaj, A

AU - Gayther, SA

AU - Ramus, SJ

AU - Menon, U

AU - Wu, AH

AU - Pearce, CL

AU - van den Berg, D

AU - Pike, MC

AU - Dansonka-Mieszkowska, A

AU - Plisiecka-Halasa, J

AU - Moes-Sosnowska, J

AU - Kupryjanczyk, J

AU - Pharoah, PDP

AU - Song, HL

AU - Winship, I

AU - Chenevix-Trench, G

AU - Giles, GG

AU - Tavtigian, SV

AU - Easton, DF

AU - Milne, RL

PY - 2016

Y1 - 2016

N2 - Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

AB - Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

U2 - 10.1136/jmedgenet-2016-103839

DO - 10.1136/jmedgenet-2016-103839

M3 - Article

C2 - 27595995

SN - 0022-2593

VL - 53

SP - 800

EP - 811

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 12

ER -