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

KConFab investigators, Australian Ovarian Cancer Study Group

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - Sep 2 2016

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Neoplasms
Breast Neoplasms
Mutation
Ovarian Neoplasms
Case-Control Studies
Prostate
Prostatic Neoplasms
Population
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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PALB2, CHEK2 and ATM rare variants and cancer risk : Data from COGS. / KConFab investigators; Australian Ovarian Cancer Study Group.

In: Journal of Medical Genetics, 02.09.2016.

Research output: Contribution to journalArticle

KConFab investigators ; Australian Ovarian Cancer Study Group. / PALB2, CHEK2 and ATM rare variants and cancer risk : Data from COGS. In: Journal of Medical Genetics. 2016.
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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 = "{KConFab investigators} and {Australian Ovarian Cancer Study Group} and Southey, {Melissa C.} and Goldgar, {David E.} and Robert Winqvist and Katri Pylk{\"a}s and Couch, {Fergus J} 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 B M} 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 Olson, {Janet E} and Vachon, {Celine M} and Slager, {Susan L} and Thibodeau, {Stephen N} and Schaid, {Daniel J} and Goode, {Ellen L} and Cunningham, {Julie M}",
year = "2016",
month = "9",
day = "2",
doi = "10.1136/jmedgenet-2016-103839",
language = "English (US)",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",

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TY - JOUR

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

T2 - Data from COGS

AU - KConFab investigators

AU - Australian Ovarian Cancer Study Group

AU - Southey, Melissa C.

AU - Goldgar, David E.

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Couch, Fergus J

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 B M

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 - Olson, Janet E

AU - Vachon, Celine M

AU - Slager, Susan L

AU - Thibodeau, Stephen N

AU - Schaid, Daniel J

AU - Goode, Ellen L

AU - Cunningham, Julie M

PY - 2016/9/2

Y1 - 2016/9/2

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.

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