Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Olivia Fletcher; Nichola Johnson; Isabel Dos Santos Silva; Alan Ashworth; Heli Nevanlinna; Tuomas Heikkinen; Kristiina Aittomäki; Carl Blomqvist; Barbara Burwinkel; Claus R. Bartram; Alfons Meindl; Rita K. Schmutzler; Angela Cox; Ian Brock; Graeme Elliott; Malcolm W.R. Reed; Melissa C. Southey; Letitia Smith; Amanda B. Spurdle; John L. Hopper; Fergus J. Couch; Janet E. Olson; Xianshu Wang; Zachary Fredericksen; Peter Schürmann; Regina Waltes; Michael Bremer; Thilo Dörk; Peter Devilee; Christie J. Van Asperen; Rob A.E.M. Tollenaar; Caroline Seynaeve; Per Hall; Kamila Czene; Keith Humphreys; Jianjun Liu; Shahana Ahmed; Alison M. Dunning; Melanie Maranian; Paul D.P. Pharoah; Georgia Chenevix-Trench; Jonathan Beesley; Natalia V. Bogdanova; Natalia N. Antonenkova; Iosif V. Zalutsky; Hoda Anton-Culver; Argyrios Ziogas; Hiltrud Brauch; Yon Dschun Ko; Ute Hamann; Peter A. Fasching; Reiner Strick; Arif B. Ekici; Matthias W. Beckmann; Graham G. Giles; Gianluca Severi; Laura Baglietto; Dallas R. English; Roger L. Milne; Javier Benítez; José Ignacio Arias; Guillermo Pita; Børge G. Nordestgaard; Stig E. Bojesen; Henrik Flyger; Daehee Kang; Keun Young Yoo; Dong Young Noh; Arto Mannermaa; Vesa Kataja; Veli Matti Kosma; Montserrat García-Closas; Stephen Chanock; Jolanta Lissowska; Louise A. Brinton; Jenny Chang-Claude; Shan Wang-Gohrke; Annegien Broeks; Marjanka K. Schmidt; Flora E. Van Leeuwen; Laura J. Van't Veer; Sara Margolin; Annika Lindblom; Manjeet K. Humphreys; Jonathan Morrison; Radka Platte; Douglas F. Easton; Julian Peto

doi:10.1158/1055-9965.EPI-10-0374

Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Olivia Fletcher, Nichola Johnson, Isabel Dos Santos Silva, Alan Ashworth, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Barbara Burwinkel, Claus R. Bartram, Alfons Meindl, Rita K. Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W.R. Reed, Melissa C. Southey, Letitia Smith, Amanda B. Spurdle, John L. HopperFergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Peter Schürmann, Regina Waltes, Michael Bremer, Thilo Dörk, Peter Devilee, Christie J. Van Asperen, Rob A.E.M. Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Shahana Ahmed, Alison M. Dunning, Melanie Maranian, Paul D.P. Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, Natalia V. Bogdanova, Natalia N. Antonenkova, Iosif V. Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Yon Dschun Ko, Ute Hamann, Peter A. Fasching, Reiner Strick, Arif B. Ekici, Matthias W. Beckmann, Graham G. Giles, Gianluca Severi, Laura Baglietto, Dallas R. English, Roger L. Milne, Javier Benítez, José Ignacio Arias, Guillermo Pita, Børge G. Nordestgaard, Stig E. Bojesen, Henrik Flyger, Daehee Kang, Keun Young Yoo, Dong Young Noh, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Montserrat García-Closas, Stephen Chanock, Jolanta Lissowska, Louise A. Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Annegien Broeks, Marjanka K. Schmidt, Flora E. Van Leeuwen, Laura J. Van't Veer, Sara Margolin, Annika Lindblom, Manjeet K. Humphreys, Jonathan Morrison, Radka Platte, Douglas F. Easton, Julian 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 (US)
Pages (from-to)	2143-2151
Number of pages	9
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	19
Issue number	9
DOIs	https://doi.org/10.1158/1055-9965.EPI-10-0374
State	Published - Sep 2010

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General Medicine

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Fletcher, O., Johnson, N., Dos Santos Silva, I., Ashworth, A., Nevanlinna, H., Heikkinen, T., Aittomäki, K., Blomqvist, C., Burwinkel, B., Bartram, C. R., Meindl, A., Schmutzler, R. K., Cox, A., Brock, I., Elliott, G., Reed, M. W. R., Southey, M. C., Smith, L., Spurdle, A. B., ... Peto, J. (2010). Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls. Cancer Epidemiology Biomarkers and Prevention, 19(9), 2143-2151. https://doi.org/10.1158/1055-9965.EPI-10-0374

Fletcher, O, Johnson, N, Dos Santos Silva, I, Ashworth, A, Nevanlinna, H, Heikkinen, T, Aittomäki, K, Blomqvist, C, Burwinkel, B, Bartram, CR, Meindl, A, Schmutzler, RK, Cox, A, Brock, I, Elliott, G, Reed, MWR, Southey, MC, Smith, L, Spurdle, AB, Hopper, JL, Couch, FJ , Olson, JE, Wang, X, Fredericksen, Z, Schürmann, P, Waltes, R, Bremer, M, Dörk, T, Devilee, P, Van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Hall, P, Czene, K, Humphreys, K, Liu, J, 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, Giles, GG, Severi, G, Baglietto, L, English, DR, Milne, RL, Benítez, J, Arias, JI, Pita, G, Nordestgaard, BG, Bojesen, SE, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Mannermaa, A, Kataja, V, Kosma, VM, García-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, Lindblom, A, Humphreys, MK, Morrison, J, Platte, R, Easton, DF & Peto, J 2010, 'Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls', Cancer Epidemiology Biomarkers and Prevention, vol. 19, no. 9, pp. 2143-2151. https://doi.org/10.1158/1055-9965.EPI-10-0374

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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 = "Olivia Fletcher and Nichola Johnson and {Dos Santos Silva}, Isabel and Alan Ashworth and Heli Nevanlinna and Tuomas Heikkinen and Kristiina Aittom{\"a}ki and Carl Blomqvist and Barbara Burwinkel and Bartram, {Claus R.} and Alfons Meindl and Schmutzler, {Rita K.} and Angela Cox and Ian Brock and Graeme Elliott and Reed, {Malcolm W.R.} and Southey, {Melissa C.} and Letitia Smith and Spurdle, {Amanda B.} and Hopper, {John L.} and Couch, {Fergus J.} and Olson, {Janet E.} and Xianshu Wang and Zachary Fredericksen and Peter Sch{\"u}rmann and Regina Waltes and Michael Bremer and Thilo D{\"o}rk and Peter Devilee and {Van Asperen}, {Christie J.} and Tollenaar, {Rob A.E.M.} and Caroline Seynaeve and Per Hall and Kamila Czene and Keith Humphreys and Jianjun Liu and Shahana Ahmed and Dunning, {Alison M.} and Melanie Maranian and Pharoah, {Paul D.P.} and Georgia Chenevix-Trench and Jonathan Beesley and Bogdanova, {Natalia V.} and Antonenkova, {Natalia N.} and Zalutsky, {Iosif V.} and Hoda Anton-Culver and Argyrios Ziogas and Hiltrud Brauch and Ko, {Yon Dschun} and Ute Hamann and Fasching, {Peter A.} and Reiner Strick and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Giles, {Graham G.} and Gianluca Severi and Laura Baglietto and English, {Dallas R.} and Milne, {Roger L.} and Javier Ben{\'i}tez and Arias, {Jos{\'e} Ignacio} and Guillermo Pita and Nordestgaard, {B{\o}rge G.} and Bojesen, {Stig E.} and Henrik Flyger and Daehee Kang and Yoo, {Keun Young} and Noh, {Dong Young} and Arto Mannermaa and Vesa Kataja and Kosma, {Veli Matti} and Montserrat Garc{\'i}a-Closas and Stephen Chanock and Jolanta Lissowska and Brinton, {Louise A.} and Jenny Chang-Claude and Shan Wang-Gohrke and Annegien Broeks and Schmidt, {Marjanka K.} and {Van Leeuwen}, {Flora E.} and {Van't Veer}, {Laura J.} and Sara Margolin and Annika Lindblom and Humphreys, {Manjeet K.} and Jonathan Morrison and Radka Platte and Easton, {Douglas F.} and Julian Peto",

year = "2010",

month = sep,

doi = "10.1158/1055-9965.EPI-10-0374",

language = "English (US)",

volume = "19",

pages = "2143--2151",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

TY - JOUR

T1 - Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Dos Santos Silva, Isabel

AU - Ashworth, Alan

AU - Nevanlinna, Heli

AU - Heikkinen, Tuomas

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Burwinkel, Barbara

AU - Bartram, Claus R.

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Cox, Angela

AU - Brock, Ian

AU - Elliott, Graeme

AU - Reed, Malcolm W.R.

AU - Southey, Melissa C.

AU - Smith, Letitia

AU - Spurdle, Amanda B.

AU - Hopper, John L.

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Wang, Xianshu

AU - Fredericksen, Zachary

AU - Schürmann, Peter

AU - Waltes, Regina

AU - Bremer, Michael

AU - Dörk, Thilo

AU - Devilee, Peter

AU - Van Asperen, Christie J.

AU - Tollenaar, Rob A.E.M.

AU - Seynaeve, Caroline

AU - Hall, Per

AU - Czene, Kamila

AU - Humphreys, Keith

AU - Liu, Jianjun

AU - Ahmed, Shahana

AU - Dunning, Alison M.

AU - Maranian, Melanie

AU - Pharoah, Paul D.P.

AU - Chenevix-Trench, Georgia

AU - Beesley, Jonathan

AU - Bogdanova, Natalia V.

AU - Antonenkova, Natalia N.

AU - Zalutsky, Iosif V.

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Brauch, Hiltrud

AU - Ko, Yon Dschun

AU - Hamann, Ute

AU - Fasching, Peter A.

AU - Strick, Reiner

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Giles, Graham G.

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - English, Dallas R.

AU - Milne, Roger L.

AU - Benítez, Javier

AU - Arias, José Ignacio

AU - Pita, Guillermo

AU - Nordestgaard, Børge G.

AU - Bojesen, Stig E.

AU - Flyger, Henrik

AU - Kang, Daehee

AU - Yoo, Keun Young

AU - Noh, Dong Young

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli Matti

AU - García-Closas, Montserrat

AU - Chanock, Stephen

AU - Lissowska, Jolanta

AU - Brinton, Louise A.

AU - Chang-Claude, Jenny

AU - Wang-Gohrke, Shan

AU - Broeks, Annegien

AU - Schmidt, Marjanka K.

AU - Van Leeuwen, Flora E.

AU - Van't Veer, Laura J.

AU - Margolin, Sara

AU - Lindblom, Annika

AU - Humphreys, Manjeet K.

AU - Morrison, Jonathan

AU - Platte, Radka

AU - Easton, Douglas F.

AU - Peto, Julian

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.

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U2 - 10.1158/1055-9965.EPI-10-0374

DO - 10.1158/1055-9965.EPI-10-0374

M3 - Article

C2 - 20826828

AN - SCOPUS:77956497347

SN - 1055-9965

VL - 19

SP - 2143

EP - 2151

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 9

ER -

Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

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