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

O Fletcher; N Johnson; ID Silva; N Orr; A Ashworth; H Nevanlinna; T Heikkinen; K Aittomaki; C Blomqvist; B Burwinkel; CR Bartram; A Meindl; RK Schmutzler; A Cox; I Brock; G Elliott; MWR Reed; MC Southey; L (Letitia) Smith; AB Spurdle; JL Hopper; FJ Couch; JE Olson; XS Wang; Z Fredericksen; P Schurmann; R Waltes; M Bremer; T Dork; P Devilee; CJ van Asperen; RAEM Tollenaar; Caroline Seynaeve; P Hall; K Czene; K Humphreys; JJ Liu; S (Shahana) Ahmed; AM Dunning; M Maranian; PDP Pharoah; G Chenevix-Trench; J Beesley; NV Bogdanova; NN Antonenkova; IV Zalutsky; H Anton-Culver; A Ziogas; H Brauch; YD Ko; U Hamann; PA Fasching; R Strick; AB Ekici; MW Beckmann; GG Giles; G Severi; L Baglietto; DR English; RL Milne; J Benitez; JI Arias; G Pita; BG Nordestgaard; SE Bojesen; H Flyger; D Kang; KY Yoo; DY Noh; A Mannermaa; V Kataja; VM Kosma; M Garcia-Closas; S Chanock; J Lissowska; LA Brinton; J Chang-Claude; S Wang-Gohrke; A Broeks; Marjanka K Schmidt; FE van Leeuwen; LJ (Laura) van 't Veer; S Margolin; A Lindblom; MK Humphreys; J Morrison; R Platte; DF Easton; J Peto

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

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

O Fletcher, N Johnson, ID Silva, N Orr, A Ashworth, H Nevanlinna, T Heikkinen, K Aittomaki, C Blomqvist, B Burwinkel, CR Bartram, A Meindl, RK Schmutzler, A Cox, I Brock, G Elliott, MWR Reed, MC Southey, L (Letitia) Smith, AB SpurdleJL Hopper, FJ Couch, JE Olson, XS Wang, Z Fredericksen, P Schurmann, R Waltes, M Bremer, T Dork, P Devilee, CJ van Asperen, RAEM Tollenaar, Caroline Seynaeve, P Hall, K Czene, K Humphreys, JJ Liu, S (Shahana) Ahmed, AM Dunning, M Maranian, PDP Pharoah, G Chenevix-Trench, J Beesley, NV Bogdanova, NN Antonenkova, IV Zalutsky, H Anton-Culver, A Ziogas, H Brauch, YD Ko, U Hamann, PA Fasching, R Strick, AB Ekici, MW Beckmann, GG Giles, G Severi, L Baglietto, DR English, RL Milne, J Benitez, JI Arias, G Pita, BG Nordestgaard, SE Bojesen, H Flyger, D Kang, KY Yoo, DY Noh, A Mannermaa, V Kataja, VM Kosma, M Garcia-Closas, S Chanock, J Lissowska, LA Brinton, J Chang-Claude, S Wang-Gohrke, A Broeks, Marjanka K Schmidt, FE van Leeuwen, LJ (Laura) van 't Veer, S Margolin, A Lindblom, MK Humphreys, J Morrison, R Platte, DF Easton, J Peto

Research output: Contribution to journal › Article › Academic › peer-review

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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. Cancer Epidemiol Biomarkers Prev; 19(9); 2143-51. (C) 2010 AACR.

Original language	Undefined/Unknown
Pages (from-to)	2143-2151
Number of pages	9
Journal	Cancer Epidemiology Biomarkers & Prevention
Volume	19
Issue number	9
DOIs	https://doi.org/10.1158/1055-9965.EPI-10-0374
Publication status	Published - 2010

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10.1158/1055-9965.EPI-10-0374

http://hdl.handle.net/1765/28248

Cite this

Fletcher, O., Johnson, N., Silva, ID., 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, G., Reed, MWR., Southey, MC., 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. 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 (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. Cancer Epidemiol Biomarkers Prev; 19(9); 2143-51. (C) 2010 AACR.",

author = "O Fletcher and N Johnson and ID Silva and N Orr and A Ashworth and H Nevanlinna and T Heikkinen and K Aittomaki and C Blomqvist and B Burwinkel and CR Bartram and A Meindl and RK Schmutzler and A Cox and I Brock and G Elliott and MWR Reed and MC Southey and Smith, {L (Letitia)} and AB Spurdle and JL Hopper and FJ Couch and JE Olson and XS Wang and Z Fredericksen and P Schurmann and R Waltes and M Bremer and T Dork and P Devilee and {van Asperen}, CJ and RAEM Tollenaar and Caroline Seynaeve and P Hall and K Czene and K Humphreys and JJ Liu and Ahmed, {S (Shahana)} and AM Dunning and M Maranian and PDP Pharoah and G Chenevix-Trench and J Beesley and NV Bogdanova and NN Antonenkova and IV Zalutsky and H Anton-Culver and A Ziogas and H Brauch and YD Ko and U Hamann and PA Fasching and R Strick and AB Ekici and MW Beckmann and GG Giles and G Severi and L Baglietto and DR English and RL Milne and J Benitez and JI Arias and G Pita and BG Nordestgaard and SE Bojesen and H Flyger and D Kang and KY Yoo and DY Noh and A Mannermaa and V Kataja and VM Kosma and M Garcia-Closas and S Chanock and J Lissowska and LA Brinton and J Chang-Claude and S Wang-Gohrke and A Broeks and Schmidt, {Marjanka K} and {van Leeuwen}, FE and {van 't Veer}, {LJ (Laura)} and S Margolin and A Lindblom and MK Humphreys and J Morrison and R Platte and DF Easton and J Peto",

year = "2010",

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

language = "Undefined/Unknown",

volume = "19",

pages = "2143--2151",

journal = "Cancer Epidemiology Biomarkers & Prevention",

issn = "1055-9965",

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

number = "9",

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Fletcher, O, Johnson, N, Silva, ID, 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, G, Reed, MWR, 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, P, 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, Giles, GG, Severi, G, Baglietto, L, English, DR, Milne, RL, Benitez, J, Arias, JI, Pita, G, Nordestgaard, BG, Bojesen, SE, Flyger, H, Kang, D, Yoo, KY, 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, 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 & Prevention, vol. 19, no. 9, pp. 2143-2151. https://doi.org/10.1158/1055-9965.EPI-10-0374

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, ID

AU - Orr, N

AU - Ashworth, A

AU - Nevanlinna, H

AU - Heikkinen, T

AU - Aittomaki, K

AU - Blomqvist, C

AU - Burwinkel, B

AU - Bartram, CR

AU - Meindl, A

AU - Schmutzler, RK

AU - Cox, A

AU - Brock, I

AU - Elliott, G

AU - Reed, MWR

AU - Southey, MC

AU - Smith, L (Letitia)

AU - Spurdle, AB

AU - Hopper, JL

AU - Couch, FJ

AU - Olson, JE

AU - Wang, XS

AU - Fredericksen, Z

AU - Schurmann, P

AU - Waltes, R

AU - Bremer, M

AU - Dork, T

AU - Devilee, P

AU - van Asperen, CJ

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - Hall, P

AU - Czene, K

AU - Humphreys, K

AU - Liu, JJ

AU - Ahmed, S (Shahana)

AU - Dunning, AM

AU - Maranian, M

AU - Pharoah, PDP

AU - Chenevix-Trench, G

AU - Beesley, J

AU - Bogdanova, NV

AU - Antonenkova, NN

AU - Zalutsky, IV

AU - Anton-Culver, H

AU - Ziogas, A

AU - Brauch, H

AU - Ko, YD

AU - Hamann, U

AU - Fasching, PA

AU - Strick, R

AU - Ekici, AB

AU - Beckmann, MW

AU - Giles, GG

AU - Severi, G

AU - Baglietto, L

AU - English, DR

AU - Milne, RL

AU - Benitez, J

AU - Arias, JI

AU - Pita, G

AU - Nordestgaard, BG

AU - Bojesen, SE

AU - Flyger, H

AU - Kang, D

AU - Yoo, KY

AU - Noh, DY

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Garcia-Closas, M

AU - Chanock, S

AU - Lissowska, J

AU - Brinton, LA

AU - Chang-Claude, J

AU - Wang-Gohrke, S

AU - Broeks, A

AU - Schmidt, Marjanka K

AU - van Leeuwen, FE

AU - van 't Veer, LJ (Laura)

AU - Margolin, S

AU - Lindblom, A

AU - Humphreys, MK

AU - Morrison, J

AU - Platte, R

AU - Easton, DF

AU - Peto, J

PY - 2010

Y1 - 2010

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 (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. Cancer Epidemiol Biomarkers Prev; 19(9); 2143-51. (C) 2010 AACR.

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 (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. Cancer Epidemiol Biomarkers Prev; 19(9); 2143-51. (C) 2010 AACR.

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

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

M3 - Article

C2 - 20826828

SN - 1055-9965

VL - 19

SP - 2143

EP - 2151

JO - Cancer Epidemiology Biomarkers & Prevention

JF - Cancer Epidemiology Biomarkers & Prevention

IS - 9

ER -