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

Melissa C Southey; David E Goldgar; Robert Winqvist; Katri Pylkäs; Fergus Couch; Marc Tischkowitz; William D Foulkes; Joe Dennis; Kyriaki Michailidou; Elizabeth J van Rensburg; Tuomas Heikkinen; Heli Nevanlinna; John L Hopper; Thilo Dörk; Kathleen Bm Claes; Jorge Reis-Filho; Zhi Ling Teo; Paolo Radice; Irene Catucci; Paolo Peterlongo; Helen Tsimiklis; Fabrice A Odefrey; James G Dowty; Marjanka K Schmidt; Annegien Broeks; Frans B Hogervorst; Senno Verhoef; Jane Carpenter; Christine Clarke; Rodney J Scott; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Julian Peto; Isabel Dos-Santos-Silva; Olivia Fletcher; Nichola Johnson; Manjeet K Bolla; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Federik Marme; Stig Bojesen; Børge G Nordestgaard; Susanne Krüger Kjaer; Estrid Høgdall; Claus K Høgdall; Svend Aage Engelholm; Australian Ovarian Cancer Study Group

doi:10.1136/jmedgenet-2016-103839

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

Melissa C Southey, David E Goldgar, Robert Winqvist, Katri Pylkäs, Fergus Couch, Marc Tischkowitz, William D Foulkes, Joe Dennis, Kyriaki Michailidou, Elizabeth J van Rensburg, Tuomas Heikkinen, Heli Nevanlinna, John L Hopper, Thilo Dörk, Kathleen Bm Claes, Jorge Reis-Filho, Zhi Ling Teo, Paolo Radice, Irene Catucci, Paolo PeterlongoHelen Tsimiklis, Fabrice A Odefrey, James G Dowty, Marjanka K Schmidt, Annegien Broeks, Frans B Hogervorst, Senno Verhoef, Jane Carpenter, Christine Clarke, Rodney J Scott, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K Bolla, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federik Marme, Stig Bojesen, Børge G Nordestgaard, Susanne Krüger Kjaer, Estrid Høgdall, Claus K Høgdall, Svend Aage Engelholm, Australian Ovarian Cancer Study Group

Institut for Klinisk Medicin

106 Citationer (Scopus)

127 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medical Genetics
Vol/bind	53
Udgave nummer	12
Sider (fra-til)	800-811
ISSN	0022-2593
DOI	https://doi.org/10.1136/jmedgenet-2016-103839
Status	Udgivet - 1 dec. 2016

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10.1136/jmedgenet-2016-103839Licens: CC BY

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGSForlagets udgivne version, 455 KBLicens: CC BY

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Southey, M. C., Goldgar, D. E., Winqvist, R., Pylkäs, K., Couch, F., Tischkowitz, M., Foulkes, W. D., Dennis, J., Michailidou, K., van Rensburg, E. J., Heikkinen, T., Nevanlinna, H., Hopper, J. L., Dörk, T., Claes, K. B., Reis-Filho, J., Teo, Z. L., Radice, P., Catucci, I., ... Australian Ovarian Cancer Study Group (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

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, Bojesen, S , Nordestgaard, BG , Kjaer, SK , Høgdall, E , Høgdall, CK, Engelholm, SA & Australian Ovarian Cancer Study Group 2016, 'PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS', Journal of Medical Genetics, bind 53, nr. 12, s. 800-811. https://doi.org/10.1136/jmedgenet-2016-103839

@article{c491878fe6fd4d8b9d67eec8fb9031f5,

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=7.1×10(-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.",

author = "Southey, {Melissa C} and Goldgar, {David E} and Robert Winqvist and Katri Pylk{\"a}s and Fergus Couch and Marc Tischkowitz and Foulkes, {William D} and Joe Dennis and Kyriaki Michailidou and {van Rensburg}, {Elizabeth J} and Tuomas Heikkinen and Heli Nevanlinna and Hopper, {John L} and Thilo D{\"o}rk and Claes, {Kathleen Bm} and Jorge Reis-Filho and Teo, {Zhi Ling} and Paolo Radice and Irene Catucci and Paolo Peterlongo and Helen Tsimiklis and Odefrey, {Fabrice A} and Dowty, {James G} and Schmidt, {Marjanka K} and Annegien Broeks and Hogervorst, {Frans B} and Senno Verhoef and Jane Carpenter and Christine Clarke and Scott, {Rodney J} and Fasching, {Peter A} and Lothar Haeberle and Ekici, {Arif B} and Beckmann, {Matthias W} and Julian Peto and Isabel Dos-Santos-Silva and Olivia Fletcher and Nichola Johnson and Bolla, {Manjeet K} and Sawyer, {Elinor J} and Ian Tomlinson and Kerin, {Michael J} and Nicola Miller and Federik Marme and Stig Bojesen and Nordestgaard, {B{\o}rge G} and Kjaer, {Susanne Kr{\"u}ger} and Estrid H{\o}gdall and H{\o}gdall, {Claus K} and Engelholm, {Svend Aage} and {Australian Ovarian Cancer Study Group}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

month = dec,

day = "1",

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

language = "English",

volume = "53",

pages = "800--811",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J Group",

number = "12",

}

TY - JOUR

T1 - PALB2, CHEK2 and ATM rare variants and cancer risk

T2 - data from COGS

AU - Southey, Melissa C

AU - Goldgar, David E

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Couch, Fergus

AU - Tischkowitz, Marc

AU - Foulkes, William D

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - van Rensburg, Elizabeth J

AU - Heikkinen, Tuomas

AU - Nevanlinna, Heli

AU - Hopper, John L

AU - Dörk, Thilo

AU - Claes, Kathleen Bm

AU - Reis-Filho, Jorge

AU - Teo, Zhi Ling

AU - Radice, Paolo

AU - Catucci, Irene

AU - Peterlongo, Paolo

AU - Tsimiklis, Helen

AU - Odefrey, Fabrice A

AU - Dowty, James G

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Hogervorst, Frans B

AU - Verhoef, Senno

AU - Carpenter, Jane

AU - Clarke, Christine

AU - Scott, Rodney J

AU - Fasching, Peter A

AU - Haeberle, Lothar

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Bolla, Manjeet K

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Kerin, Michael J

AU - Miller, Nicola

AU - Marme, Federik

AU - Bojesen, Stig

AU - Nordestgaard, Børge G

AU - Kjaer, Susanne Krüger

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Engelholm, Svend Aage

AU - Australian Ovarian Cancer Study Group

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/12/1

Y1 - 2016/12/1

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=7.1×10(-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.

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=7.1×10(-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.

U2 - 10.1136/jmedgenet-2016-103839

DO - 10.1136/jmedgenet-2016-103839

M3 - Journal 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 -

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

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