PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
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DOI：
10.1136/jmedgenet-2016-103839
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发表时间：
2016-12
影响因子：
4
通讯作者：
Milne RL
中科院分区：
文献类型：
--
作者：
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;Burwinkel B;Yang R;Guénel P;Truong T;Menegaux F;Sanchez M;Bojesen S;Nielsen SF;Flyger H;Benitez J;Zamora MP;Perez JI;Menéndez P;Anton-Culver H;Neuhausen S;Ziogas A;Clarke CA;Brenner H;Arndt V;Stegmaier C;Brauch H;Brüning T;Ko YD;Muranen TA;Aittomäki K;Blomqvist C;Bogdanova NV;Antonenkova NN;Lindblom A;Margolin S;Mannermaa A;Kataja V;Kosma VM;Hartikainen JM;Spurdle AB;Investigators K;Australian Ovarian Cancer Study Group;Wauters E;Smeets D;Beuselinck B;Floris G;Chang-Claude J;Rudolph A;Seibold P;Flesch-Janys D;Olson JE;Vachon C;Pankratz VS;McLean C;Haiman CA;Henderson BE;Schumacher F;Le Marchand L;Kristensen V;Alnæs GG;Zheng W;Hunter DJ;Lindstrom S;Hankinson SE;Kraft P;Andrulis I;Knight JA;Glendon G;Mulligan AM;Jukkola-Vuorinen A;Grip M;Kauppila S;Devilee P;Tollenaar RA;Seynaeve C;Hollestelle A;Garcia-Closas M;Figueroa J;Chanock SJ;Lissowska J;Czene K;Darabi H;Eriksson M;Eccles DM;Rafiq S;Tapper WJ;Gerty SM;Hooning MJ;Martens JW;Collée JM;Tilanus-Linthorst M;Hall P;Li J;Brand JS;Humphreys K;Cox A;Reed MW;Luccarini C;Baynes C;Dunning AM;Hamann U;Torres D;Ulmer HU;Rüdiger T;Jakubowska A;Lubinski J;Jaworska K;Durda K;Slager S;Toland AE;Ambrosone CB;Yannoukakos D;Swerdlow A;Ashworth A;Orr N;Jones M;González-Neira A;Pita G;Alonso MR;Álvarez N;Herrero D;Tessier DC;Vincent D;Bacot F;Simard J;Dumont M;Soucy P;Eeles R;Muir K;Wiklund F;Gronberg H;Schleutker J;Nordestgaard BG;Weischer M;Travis RC;Neal D;Donovan JL;Hamdy FC;Khaw KT;Stanford JL;Blot WJ;Thibodeau S;Schaid DJ;Kelley JL;Maier C;Kibel AS;Cybulski C;Cannon-Albright L;Butterbach K;Park J;Kaneva R;Batra J;Teixeira MR;Kote-Jarai Z;Olama AA;Benlloch S;Renner SP;Hartmann A;Hein A;Ruebner M;Lambrechts D;Van Nieuwenhuysen E;Vergote I;Lambretchs S;Doherty JA;Rossing MA;Nickels S;Eilber U;Wang-Gohrke S;Odunsi K;Sucheston-Campbell LE;Friel G;Lurie G;Killeen JL;Wilkens LR;Goodman MT;Runnebaum I;Hillemanns PA;Pelttari LM;Butzow R;Modugno F;Edwards RP;Ness RB;Moysich KB;du Bois A;Heitz F;Harter P;Kommoss S;Karlan BY;Walsh C;Lester J;Jensen A;Kjaer SK;Høgdall E;Peissel B;Bonanni B;Bernard L;Goode EL;Fridley BL;Vierkant RA;Cunningham JM;Larson MC;Fogarty ZC;Kalli KR;Liang D;Lu KH;Hildebrandt MA;Wu X;Levine DA;Dao F;Bisogna M;Berchuck A;Iversen ES;Marks JR;Akushevich L;Cramer DW;Schildkraut J;Terry KL;Poole EM;Stampfer M;Tworoger SS;Bandera EV;Orlow I;Olson SH;Bjorge L;Salvesen HB;van Altena AM;Aben KK;Kiemeney LA;Massuger LF;Pejovic T;Bean Y;Brooks-Wilson A;Kelemen LE;Cook LS;Le ND;Górski B;Gronwald J;Menkiszak J;Høgdall CK;Lundvall L;Nedergaard L;Engelholm SA;Dicks E;Tyrer J;Campbell I;McNeish I;Paul J;Siddiqui N;Glasspool R;Whittemore AS;Rothstein JH;McGuire V;Sieh W;Cai H;Shu XO;Teten RT;Sutphen R;McLaughlin JR;Narod SA;Phelan CM;Monteiro AN;Fenstermacher D;Lin HY;Permuth JB;Sellers TA;Chen YA;Tsai YY;Chen Z;Gentry-Maharaj A;Gayther SA;Ramus SJ;Menon U;Wu AH;Pearce CL;Van Den Berg D;Pike MC;Dansonka-Mieszkowska A;Plisiecka-Halasa J;Moes-Sosnowska J;Kupryjanczyk J;Pharoah PD;Song H;Winship I;Chenevix-Trench G;Giles GG;Tavtigian SV;Easton DF;Milne RL
PALB2、CHEK2和ATM突变的罕见性使得精确估计相关的癌症风险变得困难。基于人群的家庭研究提供的证据表明，至少其中一些突变与乳腺癌风险相关，与罕见的BRCA2突变相关的风险一样高。我们的目的是通过一项多中心病例对照研究来估计PALB2、CHEK2和ATM中特定罕见变异的相关风险。我们使用定制的iCOGS阵列对10个罕见突变进行基因分型：PALB2 c.1592delT、c.2816T>G和c.3113G>A、CHEK2 c.349A>G、c.538C>T、c.715G>A、c.1036C>T、c.1312G>T、c.1343T>G和ATM c.7271T>G。我们评估了每个变异与乳腺癌（42 671例和42 164例对照）、前列腺癌（22 301例和22 320例对照）和卵巢癌（14 542例和23 491例对照）风险的相关性。对于欧洲女性，PALB2 c.1592delT OR为3.44 (95% CI 1.39 - 8.52, p=7.1×10−5),PALB2 c.3113G>A OR为4.21 （95% CI 1.84 - 9.60, p=6.9×10−8）和ATM c.7271T>G OR为11.0 （95% CI 1.42 - 85.7, p=0.0012）与乳腺癌风险相关。我们还发现三种CHEK2变异与乳腺癌风险相关的证据，c.349A>G OR 2.26 (95% CI 1.29至3.95),c.1036C>T OR 5.06 （95% CI 1.09至23.5）和c.538C>T OR 1.33 (95% CI 1.05至1.67)（p≤0.017）。非洲男性的CHEK2 c.1343T b> T OR为3.03 (95% CI 1.53 ~ 6.03, p=0.0006)，欧洲男性的CHEK2 c.1312G b> T OR为2.21 (95% CI 1.06 ~ 4.63, p=0.030)，存在前列腺癌风险的证据。没有证据表明这些变异与卵巢癌有关。该报告进一步证明，至少这些基因中的某些变异与乳腺癌风险增加有关，这在临床上具有重要意义。
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. 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. 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. 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.