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 language | English |
|---|---|
| Journal | Journal of Medical Genetics |
| DOIs | |
| Publication status | Accepted/In press - Sep 2 2016 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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PALB2, CHEK2 and ATM rare variants and cancer risk : Data from COGS. / Southey, Melissa; Goldgar, David E.; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus J.; Tischkowitz, Marc; Foulkes, W. D.; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J.; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John; Dörk, Thilo; Claes, Kathleen; Reis-Filho, Jorge S.; Teo, Z. L.; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice; Dowty, James G.; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; Verhoef, S.; Carpenter, Jane; Clarke, Christine; Scott, Rodney J.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K.; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guenel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nielsen, Sune F.; Flyger, Henrik; Benitez, Javier; Zamora, M. Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Ziogas, Argyrios; Clarke, Christina A.; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon Dschun; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Spurdle, Amanda B.; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E.; Vachon, Celine; Pankratz, Vernon S.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick R.; Marchand, Loic Le; Kristensen, Vessela; Alnaes, Grethe Grenaker; Zheng, Wei; Hunter, David J.; Lindström, Sara; Hankinson, Susan E.; Kraft, Peter; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montse; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana; Rafiq, Sajjad; Tapper, William J.; Gerty, Sue M.; Hooning, Maartje J.; Martens, John W M; Collée, J. Margriet; Tilanus-Linthorst, M. M A; Hall, Per; Li, Jingmei; Brand, Judith S.; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nick; Jones, Michael E.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Grönberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G.; Weischer, Maren; Travis, Ruth C.; Neal, David E.; Donovan, J. L.; Hamdy, Freddie C.; Khaw, Kay Thee; Stanford, J. L.; Blot, William J.; Thibodeau, Stephen; Schaid, D. J.; Kelley, Joseph L.; Maier, Christiane; Kibel, Adam S.; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, R.; Batra, Jyotsna; Teixeira, Manuel R.; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, S. P.; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Nieuwenhuysen, Els Van; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A.; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E.; Friel, Grace; Lurie, G.; Killeen, Jeffrey L.; Wilkens, Lynne R.; Goodman, Marc T.; Runnebaum, I. B.; Hillemanns, Peter; Pelttari, Liisa M.; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P.; Ness, R. B.; Moysich, Kirsten B.; du Bois, A.; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y.; Walsh, Christine S.; Lester, Jenny; Jensen, Allan; Kjær, Susanne Krüger; Hogdall, Estrid; Peissel, Bernard Gilles; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L.; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie; Larson, Melissa C.; Fogarty, Zachary C.; Kalli, Kimberly R.; Liang, Dong; Lu, Karen H.; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A.; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S.; Marks, Jeffrey R.; Akushevich, Lucy; Cramer, Daniel W.; Schildkraut, Joellen M.; Terry, Kathryn L.; Poole, Elizabeth M.; Stampfer, M.; Tworoger, Shelley S.; Bandera, Elisa V.; Orlow, Irene; Olson, Sara H.; Bjorge, Line; Salvesen, Helga B.; Van Altena, Anne M.; Aben, Katja K H; Kiemeney, Lambartus; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E.; Cook, Linda S.; Le, Nhu D.; Gorski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain A.; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S.; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao Ou; Teten, Rachel T.; Sutphen, Rebecca; McLaughlin, John R.; Narod, S. A.; Phelan, Catherine M.; Monteiro, Alvaro N.; Fenstermacher, David A.; Lin, Hui Yi; Permuth, Jennifer B.; Sellers, Thomas A.; Chen, Y. Ann; Tsai, Ya Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Menon, Usha; Wu, Anna H.; Pearce, Celeste L.; Van Den Berg, David; Pike, Malcolm C.; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul D P; Song, Honglin; Winship, Ingrid M.; Chenevix-Trench, Georgia; Giles, Graham G.; Tavtigian, Sean V.; Easton, Douglas F.; Milne, Roger L.
In: Journal of Medical Genetics, 02.09.2016.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - PALB2, CHEK2 and ATM rare variants and cancer risk
T2 - Data from COGS
AU - Southey, Melissa
AU - Goldgar, David E.
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Couch, Fergus J.
AU - Tischkowitz, Marc
AU - Foulkes, W. D.
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - van Rensburg, Elizabeth J.
AU - Heikkinen, Tuomas
AU - Nevanlinna, Heli
AU - Hopper, John
AU - Dörk, Thilo
AU - Claes, Kathleen
AU - Reis-Filho, Jorge S.
AU - Teo, Z. L.
AU - Radice, Paolo
AU - Catucci, Irene
AU - Peterlongo, Paolo
AU - Tsimiklis, Helen
AU - Odefrey, Fabrice
AU - Dowty, James G.
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Hogervorst, Frans B.
AU - Verhoef, S.
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 - Burwinkel, Barbara
AU - Yang, Rongxi
AU - Guenel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
AU - Bojesen, Stig E.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Benitez, Javier
AU - Zamora, M. Pilar
AU - Perez, Jose Ignacio Arias
AU - Menéndez, Primitiva
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Ziogas, Argyrios
AU - Clarke, Christina A.
AU - Brenner, Hermann
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Brauch, Hiltrud
AU - Brüning, Thomas
AU - Ko, Yon Dschun
AU - Muranen, Taru A.
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Bogdanova, Natalia V.
AU - Antonenkova, Natalia N.
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Spurdle, Amanda B.
AU - Wauters, Els
AU - Smeets, Dominiek
AU - Beuselinck, Benoit
AU - Floris, Giuseppe
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Olson, Janet E.
AU - Vachon, Celine
AU - Pankratz, Vernon S.
AU - McLean, Catriona
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Schumacher, Fredrick R.
AU - Marchand, Loic Le
AU - Kristensen, Vessela
AU - Alnaes, Grethe Grenaker
AU - Zheng, Wei
AU - Hunter, David J.
AU - Lindström, Sara
AU - Hankinson, Susan E.
AU - Kraft, Peter
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Glendon, Gord
AU - Mulligan, Anna Marie
AU - Jukkola-Vuorinen, Arja
AU - Grip, Mervi
AU - Kauppila, Saila
AU - Devilee, Peter
AU - Tollenaar, Robert A E M
AU - Seynaeve, Caroline
AU - Hollestelle, Antoinette
AU - Garcia-Closas, Montse
AU - Figueroa, Jonine D.
AU - Chanock, Stephen J.
AU - Lissowska, Jolanta
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Eccles, Diana
AU - Rafiq, Sajjad
AU - Tapper, William J.
AU - Gerty, Sue M.
AU - Hooning, Maartje J.
AU - Martens, John W M
AU - Collée, J. Margriet
AU - Tilanus-Linthorst, M. M A
AU - Hall, Per
AU - Li, Jingmei
AU - Brand, Judith S.
AU - Humphreys, Keith
AU - Cox, Angela
AU - Reed, Malcolm W R
AU - Luccarini, Craig
AU - Baynes, Caroline
AU - Dunning, Alison
AU - Hamann, Ute
AU - Torres, Diana
AU - Ulmer, Hans Ulrich
AU - Rüdiger, Thomas
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska, Katarzyna
AU - Durda, Katarzyna
AU - Slager, Susan
AU - Toland, Amanda E.
AU - Ambrosone, Christine B.
AU - Yannoukakos, Drakoulis
AU - Swerdlow, Anthony J.
AU - Ashworth, Alan
AU - Orr, Nick
AU - Jones, Michael E.
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M. Rosario
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francois
AU - Simard, Jacques
AU - Dumont, Martine
AU - Soucy, Penny
AU - Eeles, Rosalind
AU - Muir, Kenneth
AU - Wiklund, Fredrik
AU - Grönberg, Henrik
AU - Schleutker, Johanna
AU - Nordestgaard, Børge G.
AU - Weischer, Maren
AU - Travis, Ruth C.
AU - Neal, David E.
AU - Donovan, J. L.
AU - Hamdy, Freddie C.
AU - Khaw, Kay Thee
AU - Stanford, J. L.
AU - Blot, William J.
AU - Thibodeau, Stephen
AU - Schaid, D. J.
AU - Kelley, Joseph L.
AU - Maier, Christiane
AU - Kibel, Adam S.
AU - Cybulski, Cezary
AU - Cannon-Albright, Lisa
AU - Butterbach, Katja
AU - Park, Jong
AU - Kaneva, R.
AU - Batra, Jyotsna
AU - Teixeira, Manuel R.
AU - Kote-Jarai, Zsofia
AU - Olama, Ali Amin Al
AU - Benlloch, Sara
AU - Renner, S. P.
AU - Hartmann, Arndt
AU - Hein, Alexander
AU - Ruebner, Matthias
AU - Lambrechts, Diether
AU - Nieuwenhuysen, Els Van
AU - Vergote, Ignace
AU - Lambretchs, Sandrina
AU - Doherty, Jennifer A.
AU - Rossing, Mary Anne
AU - Nickels, Stefan
AU - Eilber, Ursula
AU - Wang-Gohrke, Shan
AU - Odunsi, Kunle
AU - Sucheston-Campbell, Lara E.
AU - Friel, Grace
AU - Lurie, G.
AU - Killeen, Jeffrey L.
AU - Wilkens, Lynne R.
AU - Goodman, Marc T.
AU - Runnebaum, I. B.
AU - Hillemanns, Peter
AU - Pelttari, Liisa M.
AU - Butzow, Ralf
AU - Modugno, Francesmary
AU - Edwards, Robert P.
AU - Ness, R. B.
AU - Moysich, Kirsten B.
AU - du Bois, A.
AU - Heitz, Florian
AU - Harter, Philipp
AU - Kommoss, Stefan
AU - Karlan, Beth Y.
AU - Walsh, Christine S.
AU - Lester, Jenny
AU - Jensen, Allan
AU - Kjær, Susanne Krüger
AU - Hogdall, Estrid
AU - Peissel, Bernard Gilles
AU - Bonanni, Bernardo
AU - Bernard, Loris
AU - Goode, Ellen L.
AU - Fridley, Brooke L.
AU - Vierkant, Robert A.
AU - Cunningham, Julie
AU - Larson, Melissa C.
AU - Fogarty, Zachary C.
AU - Kalli, Kimberly R.
AU - Liang, Dong
AU - Lu, Karen H.
AU - Hildebrandt, Michelle A T
AU - Wu, Xifeng
AU - Levine, Douglas A.
AU - Dao, Fanny
AU - Bisogna, Maria
AU - Berchuck, Andrew
AU - Iversen, Edwin S.
AU - Marks, Jeffrey R.
AU - Akushevich, Lucy
AU - Cramer, Daniel W.
AU - Schildkraut, Joellen M.
AU - Terry, Kathryn L.
AU - Poole, Elizabeth M.
AU - Stampfer, M.
AU - Tworoger, Shelley S.
AU - Bandera, Elisa V.
AU - Orlow, Irene
AU - Olson, Sara H.
AU - Bjorge, Line
AU - Salvesen, Helga B.
AU - Van Altena, Anne M.
AU - Aben, Katja K H
AU - Kiemeney, Lambartus
AU - Massuger, Leon F A G
AU - Pejovic, Tanja
AU - Bean, Yukie
AU - Brooks-Wilson, Angela
AU - Kelemen, Linda E.
AU - Cook, Linda S.
AU - Le, Nhu D.
AU - Gorski, Bohdan
AU - Gronwald, Jacek
AU - Menkiszak, Janusz
AU - Hogdall, Claus
AU - Lundvall, Lene
AU - Nedergaard, Lotte
AU - Engelholm, Svend Aage
AU - Dicks, Ed
AU - Tyrer, Jonathan
AU - Campbell, Ian
AU - McNeish, Iain A.
AU - Paul, James
AU - Siddiqui, Nadeem
AU - Glasspool, Rosalind
AU - Whittemore, Alice S.
AU - Rothstein, Joseph H.
AU - McGuire, Valerie
AU - Sieh, Weiva
AU - Cai, Hui
AU - Shu, Xiao Ou
AU - Teten, Rachel T.
AU - Sutphen, Rebecca
AU - McLaughlin, John R.
AU - Narod, S. A.
AU - Phelan, Catherine M.
AU - Monteiro, Alvaro N.
AU - Fenstermacher, David A.
AU - Lin, Hui Yi
AU - Permuth, Jennifer B.
AU - Sellers, Thomas A.
AU - Chen, Y. Ann
AU - Tsai, Ya Yu
AU - Chen, Zhihua
AU - Gentry-Maharaj, Aleksandra
AU - Gayther, Simon A.
AU - Ramus, Susan J.
AU - Menon, Usha
AU - Wu, Anna H.
AU - Pearce, Celeste L.
AU - Van Den Berg, David
AU - Pike, Malcolm C.
AU - Dansonka-Mieszkowska, Agnieszka
AU - Plisiecka-Halasa, Joanna
AU - Moes-Sosnowska, Joanna
AU - Kupryjanczyk, Jolanta
AU - Pharoah, Paul D P
AU - Song, Honglin
AU - Winship, Ingrid M.
AU - Chenevix-Trench, Georgia
AU - Giles, Graham G.
AU - Tavtigian, Sean V.
AU - Easton, Douglas F.
AU - Milne, Roger L.
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.
UR - http://www.scopus.com/inward/record.url?scp=84986246968&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84986246968&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2016-103839
DO - 10.1136/jmedgenet-2016-103839
M3 - Article
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
ER -