Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

O. Fletcher; N. Johnson; Andreá Lema Da Silva; N. Orr; A. Ashworth; H. Nevanlinna; T. Heikkinen; K. Aittomaki; C. Blomqvist; B. Burwinkel; C.R. Bartram; A. Meindl; R.K. Schmutzler; A. Cox; I. Brock; George Arthur Elliott; Brandon Reed Travis; M.C. Southey; L. Smith; A.B. Spurdle; J.L. Hopper; F.J. Couch; J.E. Olson; X.S. Wang; Z. Fredericksen; P. Schurmann; R. Waltes; M. Bremer; T. Dork; P. Devilee; C.J. van Asperen; R.A.E.M. Tollenaar; C. Seynaeve; Katrine Blædel Pinholt Hall; K. Czene; K. Humphreys; J.J. Liu; S. Ahmed; A.M. Dunning; M. Maranian; P.D.P. Pharoah; G. Chenevix-Trench; J. Beesley; N.V. Bogdanova; N.N. Antonenkova; I.V. Zalutsky; H. Anton-Culver; A. Ziogas; H. Brauch; Y.D. Ko; U. Hamann; P.A. Fasching; R. Strick; A.B. Ekici; M.W. Beckmann; Giles Gaubert; G. Severi; L. Baglietto; D.R. English; R.L. Milne; J. Benitez; J.I. Arias; G. Pita; B.G. Nordestgaard; S.E. Bojesen; H. Flyger; D. Kang; Marie Sofie Yoo Larsen; D.Y. Noh; A. Mannermaa; V. Kataja; V.M. Kosma; M. Garcia-Closas; S. Chanock; J. Lissowska; L.A. Brinton; J. Chang-Claude; S. Wang-Gohrke; A. Broeks; M.K. Schmidt; F.E. van Leeuwen; L.J. Van't Veer; S. Margolin; Anne Lindblom Hansen; M.K. Humphreys; Ann Judith Morrison; R. Platte; D.F. Easton; J. Peto

Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

O. Fletcher, N. Johnson, Andreá Lema Da Silva, N. Orr, A. Ashworth, H. Nevanlinna, T. Heikkinen, K. Aittomaki, C. Blomqvist, B. Burwinkel, C.R. Bartram, A. Meindl, R.K. Schmutzler, A. Cox, I. Brock, George Arthur Elliott, Brandon Reed Travis, M.C. Southey, L. Smith, A.B. SpurdleJ.L. Hopper, F.J. Couch, J.E. Olson, X.S. Wang, Z. Fredericksen, P. Schurmann, R. Waltes, M. Bremer, T. Dork, P. Devilee, C.J. van Asperen, R.A.E.M. Tollenaar, C. Seynaeve, Katrine Blædel Pinholt Hall, K. Czene, K. Humphreys, J.J. Liu, S. Ahmed, A.M. Dunning, M. Maranian, P.D.P. Pharoah, G. Chenevix-Trench, J. Beesley, N.V. Bogdanova, N.N. Antonenkova, I.V. Zalutsky, H. Anton-Culver, A. Ziogas, H. Brauch, Y.D. Ko, U. Hamann, P.A. Fasching, R. Strick, A.B. Ekici, M.W. Beckmann, Giles Gaubert, G. Severi, L. Baglietto, D.R. English, R.L. Milne, J. Benitez, J.I. Arias, G. Pita, B.G. Nordestgaard, S.E. Bojesen, H. Flyger, D. Kang, Marie Sofie Yoo Larsen, D.Y. Noh, A. Mannermaa, V. Kataja, V.M. Kosma, M. Garcia-Closas, S. Chanock, J. Lissowska, L.A. Brinton, J. Chang-Claude, S. Wang-Gohrke, A. Broeks, M.K. Schmidt, F.E. van Leeuwen, L.J. Van't Veer, S. Margolin, Anne Lindblom Hansen, M.K. Humphreys, Ann Judith Morrison, R. Platte, D.F. Easton, J. Peto

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Abstract

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P_trend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P_trend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.

Original language	English
Journal	Cancer Epidemiology, Biomarkers & Prevention
Volume	19
Issue number	9
Pages (from-to)	2143-2151
Number of pages	9
ISSN	1055-9965
Publication status	Published - Sept 2010

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Fletcher, O., Johnson, N., Silva, A. L. D., Orr, N., Ashworth, A., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Burwinkel, B., Bartram, C. R., Meindl, A., Schmutzler, R. K., Cox, A., Brock, I., Elliott, G. A., Travis, B. R., Southey, M. C., Smith, L., ... Peto, J. (2010). Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls. Cancer Epidemiology, Biomarkers & Prevention, 19(9), 2143-2151.

Fletcher, O, Johnson, N, Silva, ALD, Orr, N, Ashworth, A, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Burwinkel, B, Bartram, CR, Meindl, A, Schmutzler, RK, Cox, A, Brock, I, Elliott, GA, Travis, BR, Southey, MC, Smith, L, Spurdle, AB, Hopper, JL, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Schurmann, P, Waltes, R, Bremer, M, Dork, T, Devilee, P, van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Hall, KBP, Czene, K, Humphreys, K, Liu, JJ, Ahmed, S, Dunning, AM, Maranian, M, Pharoah, PDP, Chenevix-Trench, G, Beesley, J, Bogdanova, NV, Antonenkova, NN, Zalutsky, IV, Anton-Culver, H, Ziogas, A, Brauch, H, Ko, YD, Hamann, U, Fasching, PA, Strick, R, Ekici, AB, Beckmann, MW, Gaubert, G, Severi, G, Baglietto, L, English, DR, Milne, RL, Benitez, J, Arias, JI, Pita, G, Nordestgaard, BG , Bojesen, SE, Flyger, H, Kang, D, Larsen, MSY, Noh, DY, Mannermaa, A, Kataja, V, Kosma, VM, Garcia-Closas, M, Chanock, S, Lissowska, J, Brinton, LA, Chang-Claude, J, Wang-Gohrke, S, Broeks, A, Schmidt, MK, van Leeuwen, FE, Van't Veer, LJ, Margolin, S, Hansen, AL, Humphreys, MK, Morrison, AJ, Platte, R, Easton, DF & Peto, J 2010, 'Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls', Cancer Epidemiology, Biomarkers & Prevention, vol. 19, no. 9, pp. 2143-2151.

@article{4da56cbfd3cf428187a3a9867862cf9e,

title = "Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls",

abstract = "Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.",

author = "O. Fletcher and N. Johnson and Silva, {Andre{\'a} Lema Da} and N. Orr and A. Ashworth and H. Nevanlinna and T. Heikkinen and K. Aittomaki and C. Blomqvist and B. Burwinkel and C.R. Bartram and A. Meindl and R.K. Schmutzler and A. Cox and I. Brock and Elliott, {George Arthur} and Travis, {Brandon Reed} and M.C. Southey and L. Smith and A.B. Spurdle and J.L. Hopper and F.J. Couch and J.E. Olson and X.S. Wang and Z. Fredericksen and P. Schurmann and R. Waltes and M. Bremer and T. Dork and P. Devilee and {van Asperen}, C.J. and R.A.E.M. Tollenaar and C. Seynaeve and Hall, {Katrine Bl{\ae}del Pinholt} and K. Czene and K. Humphreys and J.J. Liu and S. Ahmed and A.M. Dunning and M. Maranian and P.D.P. Pharoah and G. Chenevix-Trench and J. Beesley and N.V. Bogdanova and N.N. Antonenkova and I.V. Zalutsky and H. Anton-Culver and A. Ziogas and H. Brauch and Y.D. Ko and U. Hamann and P.A. Fasching and R. Strick and A.B. Ekici and M.W. Beckmann and Giles Gaubert and G. Severi and L. Baglietto and D.R. English and R.L. Milne and J. Benitez and J.I. Arias and G. Pita and B.G. Nordestgaard and S.E. Bojesen and H. Flyger and D. Kang and Larsen, {Marie Sofie Yoo} and D.Y. Noh and A. Mannermaa and V. Kataja and V.M. Kosma and M. Garcia-Closas and S. Chanock and J. Lissowska and L.A. Brinton and J. Chang-Claude and S. Wang-Gohrke and A. Broeks and M.K. Schmidt and {van Leeuwen}, F.E. and {Van't Veer}, L.J. and S. Margolin and Hansen, {Anne Lindblom} and M.K. Humphreys and Morrison, {Ann Judith} and R. Platte and D.F. Easton and J. Peto",

year = "2010",

month = sep,

language = "English",

volume = "19",

pages = "2143--2151",

journal = "Cancer Epidemiology, Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "9",

}

TY - JOUR

T1 - Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

AU - Fletcher, O.

AU - Johnson, N.

AU - Silva, Andreá Lema Da

AU - Orr, N.

AU - Ashworth, A.

AU - Nevanlinna, H.

AU - Heikkinen, T.

AU - Aittomaki, K.

AU - Blomqvist, C.

AU - Burwinkel, B.

AU - Bartram, C.R.

AU - Meindl, A.

AU - Schmutzler, R.K.

AU - Cox, A.

AU - Brock, I.

AU - Elliott, George Arthur

AU - Travis, Brandon Reed

AU - Southey, M.C.

AU - Smith, L.

AU - Spurdle, A.B.

AU - Hopper, J.L.

AU - Couch, F.J.

AU - Olson, J.E.

AU - Wang, X.S.

AU - Fredericksen, Z.

AU - Schurmann, P.

AU - Waltes, R.

AU - Bremer, M.

AU - Dork, T.

AU - Devilee, P.

AU - van Asperen, C.J.

AU - Tollenaar, R.A.E.M.

AU - Seynaeve, C.

AU - Hall, Katrine Blædel Pinholt

AU - Czene, K.

AU - Humphreys, K.

AU - Liu, J.J.

AU - Ahmed, S.

AU - Dunning, A.M.

AU - Maranian, M.

AU - Pharoah, P.D.P.

AU - Chenevix-Trench, G.

AU - Beesley, J.

AU - Bogdanova, N.V.

AU - Antonenkova, N.N.

AU - Zalutsky, I.V.

AU - Anton-Culver, H.

AU - Ziogas, A.

AU - Brauch, H.

AU - Ko, Y.D.

AU - Hamann, U.

AU - Fasching, P.A.

AU - Strick, R.

AU - Ekici, A.B.

AU - Beckmann, M.W.

AU - Gaubert, Giles

AU - Severi, G.

AU - Baglietto, L.

AU - English, D.R.

AU - Milne, R.L.

AU - Benitez, J.

AU - Arias, J.I.

AU - Pita, G.

AU - Nordestgaard, B.G.

AU - Bojesen, S.E.

AU - Flyger, H.

AU - Kang, D.

AU - Larsen, Marie Sofie Yoo

AU - Noh, D.Y.

AU - Mannermaa, A.

AU - Kataja, V.

AU - Kosma, V.M.

AU - Garcia-Closas, M.

AU - Chanock, S.

AU - Lissowska, J.

AU - Brinton, L.A.

AU - Chang-Claude, J.

AU - Wang-Gohrke, S.

AU - Broeks, A.

AU - Schmidt, M.K.

AU - van Leeuwen, F.E.

AU - Van't Veer, L.J.

AU - Margolin, S.

AU - Hansen, Anne Lindblom

AU - Humphreys, M.K.

AU - Morrison, Ann Judith

AU - Platte, R.

AU - Easton, D.F.

AU - Peto, J.

PY - 2010/9

Y1 - 2010/9

N2 - Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.

AB - Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.

M3 - Journal article

SN - 1055-9965

VL - 19

SP - 2143

EP - 2151

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

IS - 9

ER -

Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

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