PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
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Authors
Southey, MC
Goldgar, DE
Winqvist, R
Pylkäs, K
Couch, F
Tischkowitz, M
Foulkes, WD
Dennis, J
Michailidou, K
van Rensburg, EJ
Heikkinen, T
Nevanlinna, H
Hopper, JL
Dörk, T
Claes, KB
Reis-Filho, 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, R
Guénel, P
Truong, T
Menegaux, F
Sanchez, M
Bojesen, S
Nielsen, SF
Flyger, H
Benitez, J
Zamora, MP
Perez, JIA
Menéndez, P
Anton-Culver, H
Neuhausen, S
Ziogas, A
Clarke, CA
Brenner, H
Arndt, V
Stegmaier, C
Brauch, H
Brüning, T
Ko, Y-D
Muranen, TA
Aittomäki, K
Blomqvist, C
Bogdanova, NV
Antonenkova, NN
Lindblom, A
Margolin, S
Mannermaa, A
Kataja, V
Kosma, V-M
Hartikainen, JM
Spurdle, AB
Investigators, K
Australian Ovarian Cancer Study Group,
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
Alnæs, 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, MJ
Martens, JWM
Collée, JM
Tilanus-Linthorst, M
Hall, P
Li, J
Brand, JS
Humphreys, K
Cox, A
Reed, MWR
Luccarini, C
Baynes, C
Dunning, AM
Hamann, U
Torres, D
Ulmer, HU
Rüdiger, 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
González-Neira, A
Pita, G
Alonso, MR
Álvarez, 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, K-T
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
Olama, AAA
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
Høgdall, 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, X
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
Górski, B
Gronwald, J
Menkiszak, J
Høgdall, 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, X-O
Teten, RT
Sutphen, R
McLaughlin, JR
Narod, SA
Phelan, CM
Monteiro, AN
Fenstermacher, D
Lin, H-Y
Permuth, JB
Sellers, TA
Chen, YA
Tsai, Y-Y
Chen, Z
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, PD
Song, H
Winship, I
Chenevix-Trench, G
Giles, GG
Tavtigian, SV
Easton, DF
Milne, RL
Goldgar, DE
Winqvist, R
Pylkäs, K
Couch, F
Tischkowitz, M
Foulkes, WD
Dennis, J
Michailidou, K
van Rensburg, EJ
Heikkinen, T
Nevanlinna, H
Hopper, JL
Dörk, T
Claes, KB
Reis-Filho, 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, R
Guénel, P
Truong, T
Menegaux, F
Sanchez, M
Bojesen, S
Nielsen, SF
Flyger, H
Benitez, J
Zamora, MP
Perez, JIA
Menéndez, P
Anton-Culver, H
Neuhausen, S
Ziogas, A
Clarke, CA
Brenner, H
Arndt, V
Stegmaier, C
Brauch, H
Brüning, T
Ko, Y-D
Muranen, TA
Aittomäki, K
Blomqvist, C
Bogdanova, NV
Antonenkova, NN
Lindblom, A
Margolin, S
Mannermaa, A
Kataja, V
Kosma, V-M
Hartikainen, JM
Spurdle, AB
Investigators, K
Australian Ovarian Cancer Study Group,
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
Alnæs, 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, MJ
Martens, JWM
Collée, JM
Tilanus-Linthorst, M
Hall, P
Li, J
Brand, JS
Humphreys, K
Cox, A
Reed, MWR
Luccarini, C
Baynes, C
Dunning, AM
Hamann, U
Torres, D
Ulmer, HU
Rüdiger, 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
González-Neira, A
Pita, G
Alonso, MR
Álvarez, 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, K-T
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
Olama, AAA
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
Høgdall, 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, X
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
Górski, B
Gronwald, J
Menkiszak, J
Høgdall, 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, X-O
Teten, RT
Sutphen, R
McLaughlin, JR
Narod, SA
Phelan, CM
Monteiro, AN
Fenstermacher, D
Lin, H-Y
Permuth, JB
Sellers, TA
Chen, YA
Tsai, Y-Y
Chen, Z
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, PD
Song, H
Winship, I
Chenevix-Trench, G
Giles, GG
Tavtigian, SV
Easton, DF
Milne, RL
Document Type
Journal Article
Date
2016-12-01
Date Accepted
2016-06-21
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=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) 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.
Citation
Journal of medical genetics, 2016, 53 (12), pp. 800 - 811
Source Title
Publisher
BMJ PUBLISHING GROUP
ISSN
0022-2593
eISSN
1468-6244
Collections
Research Team
Complex Trait Genetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Oncogenetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Oncogenetics