PALB2、CHEK2和ATM罕见变异与癌症风险：来自癌症遗传协会（COGS）的数据
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
作者信息
Southey Melissa C, Goldgar David E, Winqvist Robert, Pylkäs Katri, Couch Fergus, Tischkowitz Marc, Foulkes William D, Dennis Joe, Michailidou Kyriaki, van Rensburg Elizabeth J, Heikkinen Tuomas, Nevanlinna Heli, Hopper John L, Dörk Thilo, Claes Kathleen Bm, Reis-Filho Jorge, Teo Zhi Ling, Radice Paolo, Catucci Irene, Peterlongo Paolo, Tsimiklis Helen, Odefrey Fabrice A, Dowty James G, Schmidt Marjanka K, Broeks Annegien, Hogervorst Frans B, Verhoef Senno, 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, Guénel Pascal, Truong Thérèse, Menegaux Florence, Sanchez Marie, Bojesen Stig, Nielsen Sune F, Flyger Henrik, Benitez Javier, Zamora M Pilar, Perez Jose Ignacio Arias, Menéndez Primitiva, Anton-Culver Hoda, Neuhausen Susan, 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, Investigators kConFab, 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, Le Marchand Loic, Kristensen Vessela, Alnæs Grethe Grenaker, Zheng Wei, Hunter David J, Lindstrom Sara, Hankinson Susan E, Kraft Peter, Andrulis Irene, 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 Montserrat, Figueroa Jonine, Chanock Stephen J, Lissowska Jolanta, Czene Kamila, Darabi Hatef, Eriksson Mikael, Eccles Diana M, Rafiq Sajjad, Tapper William J, Gerty Sue M, Hooning Maartje J, Martens John W M, Collée J Margriet, Tilanus-Linthorst Madeleine, Hall Per, Li Jingmei, Brand Judith S, Humphreys Keith, Cox Angela, Reed Malcolm W R, Luccarini Craig, Baynes Caroline, Dunning Alison M, 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, Ashworth Alan, Orr Nick, Jones Michael, 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, Gronberg Henrik, Schleutker Johanna, Nordestgaard Børge G, Weischer Maren, Travis Ruth C, Neal David, Donovan Jenny L, Hamdy Freddie C, Khaw Kay-Tee, Stanford Janet L, Blot William J, Thibodeau Stephen, Schaid Daniel J, Kelley Joseph L, Maier Christiane, Kibel Adam S, Cybulski Cezary, Cannon-Albright Lisa, Butterbach Katja, Park Jong, Kaneva Radka, Batra Jyotsna, Teixeira Manuel R, Kote-Jarai Zsofia, Olama Ali Amin Al, Benlloch Sara, Renner Stefan P, Hartmann Arndt, Hein Alexander, Ruebner Matthias, Lambrechts Diether, Van Nieuwenhuysen Els, 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 Galina, Killeen Jeffrey L, Wilkens Lynne R, Goodman Marc T, Runnebaum Ingo, Hillemanns Peter A, Pelttari Liisa M, Butzow Ralf, Modugno Francesmary, Edwards Robert P, Ness Roberta B, Moysich Kirsten B, du Bois Andreas, Heitz Florian, Harter Philipp, Kommoss Stefan, Karlan Beth Y, Walsh Christine, Lester Jenny, Jensen Allan, Kjaer Susanne Krüger, Høgdall Estrid, Peissel Bernard, Bonanni Bernardo, Bernard Loris, Goode Ellen L, Fridley Brooke L, Vierkant Robert A, Cunningham Julie M, 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, Terry Kathryn L, Poole Elizabeth M, Stampfer Meir, 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 Lambertus A, Massuger Leon F A G, Pejovic Tanja, Bean Yukie, Brooks-Wilson Angela, Kelemen Linda E, Cook Linda S, Le Nhu D, Górski Bohdan, Gronwald Jacek, Menkiszak Janusz, Høgdall Claus K, Lundvall Lene, Nedergaard Lotte, Engelholm Svend Aage, Dicks Ed, Tyrer Jonathan, Campbell Ian, McNeish Iain, 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 Steven A, Phelan Catherine M, Monteiro Alvaro N, Fenstermacher David, 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 Dp, Song Honglin, Winship Ingrid, Chenevix-Trench Georgia, Giles Graham G, Tavtigian Sean V, Easton Doug F, Milne Roger L
机构信息
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
Huntsman Cancer Institute, Salt Lake City, UT, USA.
出版信息
J Med Genet. 2016 Dec;53(12):800-811. doi: 10.1136/jmedgenet-2016-103839. Epub 2016 Sep 5.
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), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10) 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.
背景
PALB2、CHEK2和ATM基因中的突变较为罕见，因此难以精确估计与之相关的癌症风险。基于人群的家族研究已提供证据表明，这些突变中至少有一些与乳腺癌风险相关，其风险程度与罕见的BRCA2突变相关的风险相当。我们旨在通过一项多中心病例对照研究来估计与PALB2、CHEK2和ATM基因中特定罕见变异相关的相对风险。
方法
我们使用定制的iCOGS芯片对10种罕见突变进行基因分型：PALB2基因的c.1592delT、c.2816T>G和c.3113G>A，CHEK2基因的c.349A>G、c.538C>T、c.715G>A、c.1036C>T、c.1312G>T和c.1343T>G，以及ATM基因的c.7271T>G。我们评估了每种变异与乳腺癌风险（42671例病例和42164例对照）、前列腺癌风险（22301例病例和22320例对照）以及卵巢癌风险（14542例病例和23491例对照）之间的关联。
结果
对于欧洲女性，观察到PALB2基因的c.1592delT（比值比[OR]3.44，95%置信区间[CI]1.39至8.52，p = 7.1×10）、PALB2基因的c.3113G>A（OR 4.21，95%CI 1.84至9.60，p = 6.9×10）和ATM基因的c.
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