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

ORIGINAL ARTICLE PALB2,CHEK2 and ATM a e a ian s and cance isk: da a om COGS ▸Addi ional ma e ial is published online only. To iew please isi he jou nal online (h p://dx.doi.o g/10.1136/ jmedgene -2016-103839). Fo numbe ed a filia ions see end o a icle. Co espondence o P o esso Melissa C. Sou hey, Gene ic Epidemiology Labo a o y, Depa men o Pa hology, The Uni e si y o Melbou ne, Melbou ne, Vic o ia 3010, Aus alia; msou he[email p o ec ed] Recei ed 29 Ma ch 2016 Re ised 1 June 2016 Accep ed 21 June 2016 Published Online Fi s 5 Sep embe 2016 To ci e: Sou hey MC, Goldga DE, Winq is R, e al.J Med Gene 2016;53:800–811. Melissa C Sou hey, 1 Da id E Goldga , 2 Robe Winq is , 3 Ka i Pylkäs, 3 Fe gus Couch, 4 Ma c Tischkowi z, 5 William D Foulkes, 6 Joe Dennis, 7 Ky iaki Michailidou, 7 Elizabe h J an Rensbu g, 8 Tuomas Heikkinen, 9 Heli Ne anlinna, 9 John L Hoppe , 10 Thilo Dö k, 11 Ka hleen BM Claes, 12 Jo ge Reis-Filho, 13 Zhi Ling Teo, 1 Paolo Radice, 14 I ene Ca ucci, 15 Paolo Pe e longo, 15 Helen Tsimiklis, 1 Fab ice A Ode ey, 1 James G Dow y, 10 Ma janka K Schmid , 16 Annegien B oeks, 16 F ans B Hoge o s , 16 Senno Ve hoe , 16 Jane Ca pen e , 17 Ch is ine Cla ke, 18 Rodney J Sco , 19 Pe e A Fasching, 20,21 Lo ha Haebe le, 20,22 A i B Ekici, 23 Ma hias W Beckmann, 20 Julian Pe o, 24 Isabel dos-San os-Sil a, 24 Oli ia Fle che , 25 Nichola Johnson, 25 Manjee K Bolla, 7 Elino J Sawye , 26 Ian Tomlinson, 27 Michael J Ke in, 28 Nicola Mille , 28 Fede ik Ma me, 29,30 Ba ba a Bu winkel, 29,31 Rongxi Yang, 29,31 Pascal Guénel, 32,33 Thé èse T uong, 32,33 Flo ence Menegaux, 32,33 Ma ie Sanchez, 32,33 S ig Bojesen, 34,35 Sune F Nielsen, 34,35 Hen ik Flyge , 36 Ja ie Beni ez, 37,38 M Pila Zamo a, 39 Jose Ignacio A ias Pe ez, 40 P imi i a Menéndez, 41 Hoda An on-Cul e , 42 Susan Neuhausen, 43 A gy ios Ziogas, 44 Ch is ina A Cla ke, 45 He mann B enne , 46,47,48 Volke A nd , 46 Ch is a S egmaie , 49 Hil ud B auch, 48,50,51 Thomas B üning, 52 Yon-Dschun Ko, 53 Ta u A Mu anen, 54 K is iina Ai omäki, 55 Ca l Blomq is , 56 Na alia V Bogdano a, 11,57 Na alia N An onenko a, 58 Annika Lindblom, 59 Sa a Ma golin, 60 A o Manne maa, 61,62 Vesa Ka aja, 63,64 Veli-Ma i Kosma, 61,62 Jaana M Ha ikainen, 61,62 Amanda B Spu dle, 65 kConFab In es iga o s, 66 Aus alian O a ian Cance S udy G oup 65,66 Els Wau e s, 67,68 Dominiek Smee s, 67,68 Benoi Beuselinck, 69 Giuseppe Flo is, 69 Jenny Chang-Claude, 70 Anja Rudolph, 70 Pe a Seibold, 70 Die e Flesch-Janys, 71 Jane E Olson, 72 Celine Vachon, 72 Ve non S Pank a z, 72 Ca iona McLean, 73 Ch is ophe A Haiman, 74 B ian E Hende son, 74 F ed ick Schumache , 74 Loic Le Ma chand, 75 Vessela K is ensen, 76,77 G e he G enake Alnæs, 76 Wei Zheng, 78 Da id J Hun e , 79,80 Sa a Linds om, 79,80 Susan E Hankinson, 80,81 Pe e K a , 79,80 I ene And ulis, 82,83 Julia A Knigh , 84,85 Go d Glendon, 82 Anna Ma ie Mulligan, 86,87 A ja Jukkola-Vuo inen, 88 Me i G ip, 89 Saila Kauppila, 90 Pe e De ilee, 91 Robe A E M Tollenaa , 91 Ca oline Seynae e, 92,98 An oine e Holles elle, 92,98 Mon se a Ga cia-Closas, 93 Jonine Figue oa, 94 S ephen J Chanock, 94 Jolan a Lissowska, 95 Kamila Czene, 96 Ha e Da abi, 96 Mikael E iksson, 96 Diana M Eccles, 97 Sajjad Rafiq, 97 William J Tappe , 97 Sue M Ge y, 97 Maa je J Hooning, 98 John W M Ma ens, 98 J Ma g ie Collée, 99 Madeleine Tilanus-Lin ho s , 100 Pe Hall, 101 Jingmei Li, 102 Judi h S B and, 101 Kei h Humph eys, 101 Angela Cox, 103 Malcolm W R Reed, 103 C aig Lucca ini, 104 Ca oline Baynes, 104 Alison M Dunning, 104 U e Hamann, 105 Diana To es, 105,106 Hans Ul ich Ulme , 107 Thomas Rüdige , 108 Anna Jakubowska, 109 Jan Lubinski, 109 Ka a zyna Jawo ska, 109,110 Ka a zyna Du da, 109 Susan Slage , 72 Amanda E Toland, 111 Ch is ine B Amb osone, 112 D akoulis Yannoukakos, 113 An hony Swe dlow, 114,115 Alan Ashwo h, 93 Nick O , 93 Michael Jones, 114 Anna González-Nei a, 37 Guille mo Pi a, 37 M Rosa io Alonso, 37 Nu ia Ál a ez, 37 Daniel He e o, 37 800 Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om Daniel C Tessie , 116 Daniel Vincen , 117 F ancois Baco , 117 Jacques Sima d, 118 Ma ine Dumon , 118 Penny Soucy, 118 Rosalind Eeles, 119,120 Kenne h Mui , 121 F ed ik Wiklund, 122 Hen ik G onbe g, 122 Johanna Schleu ke , 123,124 Bø ge G No des gaa d, 125 Ma en Weische , 126 Ru h C T a is, 127 Da id Neal, 128 Jenny L Dono an, 129 F eddie C Hamdy, 130 Kay-Tee Khaw, 131 Jane L S an o d, 132,133 William J Blo , 134 S ephen Thibodeau, 4 Daniel J Schaid, 72 Joseph L Kelley, 135 Ch is iane Maie , 136,137 Adam S Kibel, 138,139 Ceza y Cybulski, 140 Lisa Cannon-Alb igh , 141 Ka ja Bu e bach, 46 Jong Pa k, 142 Radka Kane a, 143 Jyo sna Ba a, 144 Manuel R Teixei a, 145 Zsofia Ko e-Ja ai, 119 Ali Amin Al Olama, 7 Sa a Benlloch, 7 S e an P Renne , 146 A nd Ha mann, 147 Alexande Hein, 146 Ma hias Ruebne , 146 Die he Lamb ech s, 148,149 Els Van Nieuwenhuysen, 150 Ignace Ve go e, 150 Sand ina Lamb e chs, 150 Jenni e A Dohe y, 151 Ma y Anne Rossing, 152,153 S e an Nickels, 154 U sula Eilbe , 154 Shan Wang-Goh ke, 155 Kunle Odunsi, 156 La a E Suches on-Campbell, 156 G ace F iel, 156 Galina Lu ie, 157 Je ey L Killeen, 158 Lynne R Wilkens, 157 Ma c T Goodman, 159,160 Ingo Runnebaum, 161 Pe e A Hillemanns, 162 Liisa M Pel a i, 9 Ral Bu zow, 163 F ancesma y Modugno, 164,165 Robe P Edwa ds, 135 Robe a B Ness, 166 Ki s en B Moysich, 167 And eas du Bois, 168,169 Flo ian Hei z, 168,169 Philipp Ha e , 168,169 S e an Kommoss, 169,170 Be h Y Ka lan, 171 Ch is ine Walsh, 171 Jenny Les e , 171 Allan Jensen, 172 Susanne K üge Kjae , 172,173 Es id Høgdall, 172,174 Be na d Peissel, 175 Be na do Bonanni, 176 Lo is Be na d, 177 Ellen L Goode, 72 B ooke L F idley, 178 Robe A Vie kan , 72 Julie M Cunningham, 4 Melissa C La son, 72 Zacha y C Foga y, 72 Kimbe ly R Kalli, 179 Dong Liang, 180 Ka en H Lu, 181 Michelle A T Hildeb and , 182 Xi eng Wu, 182 Douglas A Le ine, 183 Fanny Dao, 183 Ma ia Bisogna, 183 And ew Be chuck, 184 Edwin S I e sen, 185 Je ey R Ma ks, 186 Lucy Akushe ich, 187 Daniel W C ame , 188 Joellen Schildk au , 187 Ka h yn L Te y, 188 Elizabe h M Poole, 189,190 Mei S amp e , 80,189 Shelley S Two oge , 189,190 Elisa V Bande a, 191 I ene O low, 192 Sa a H Olson, 192 Line Bjo ge, 193,194 Helga B Sal esen, 193,194 Anne M an Al ena, 195 Ka ja K H Aben, 196,197,198 Lambe us A Kiemeney, 196 Leon F A G Massuge , 195 Tanja Pejo ic, 199 Yukie Bean, 199 Angela B ooks-Wilson, 200,201 Linda E Kelemen, 202,203 Linda S Cook, 204 Nhu D Le, 205 Bohdan Gó ski, 206 Jacek G onwald, 206 Janusz Menkiszak, 207 Claus K Høgdall, 173 Lene Lund all, 208 Lo e Nede gaa d, 209 S end Aage Engelholm, 210 Ed Dicks, 211 Jona han Ty e , 211 Ian Campbell, 212 Iain McNeish, 213 James Paul, 214 Nadeem Siddiqui, 215 Rosalind Glasspool, 215 Alice S Whi emo e, 216 Joseph H Ro hs ein, 216 Vale ie McGui e, 216 Wei a Sieh, 216 Hui Cai, 78 Xiao-Ou Shu, 78 Rachel T Te en, 217 Rebecca Su phen, 217 John R McLaughlin, 218 S e en A Na od, 219 Ca he ine M Phelan, 220 Al a o N Mon ei o, 220 Da id Fens e mache , 221 Hui-Yi Lin, 221 Jenni e B Pe mu h, 220 Thomas A Selle s, 220 Y Ann Chen, 221 Ya-Yu Tsai, 220 Zhihua Chen, 221 Aleksand a Gen y-Maha aj, 222 Simon A Gay he , 223 Susan J Ramus, 223 Usha Menon, 222 Anna H Wu, 223 Celes e L Pea ce, 223 Da id Van Den Be g, 223 Malcolm C Pike, 223,224 Agnieszka Dansonka-Mieszkowska, 225 Joanna Plisiecka-Halasa, 225 Joanna Moes-Sosnowska, 225 Jolan a Kup yjanczyk, 225 Paul DP Pha oah, 211 Honglin Song, 211 Ing id Winship, 226,227 Geo gia Chene ix-T ench, 65 G aham G Giles, 10,228 Sean V Ta igian, 2 Doug F Eas on, 7 Roge L Milne 10,228 ABSTRACT Backg ound The a i y o mu a ions in PALB2,CHEK2 and ATM make i di ficul o es ima e p ecisely associa ed cance isks. Popula ion-based amily s udies ha e p o ided e idence ha a leas some o hese mu a ions a e associa ed wi h b eas cance isk as high as hose associa ed wi h a e BRCA2 mu a ions. We aimed o es ima e he ela i e isks associa ed wi h specific a e a ian s in PALB2, CHEK2 and ATM ia a mul icen e case-con ol s udy. Me hods We geno yped 10 a e mu a ions using he cus om iCOGS a ay: 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 associa ions wi h b eas cance isk (42 671 cases and 42 164 con ols), as well as p os a e (22 301 cases and 22 320 con ols) and o a ian (14 542 cases and 23 491 con ols) cance isk, o each a ian . Resul s Fo Eu opean women, s ong e idence o associa ion wi h b eas cance isk was obse ed o PALB2 c.1592delT OR 3.44 (95% CI 1.39 o 8.52, p=7.1×10 −5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 o 9.60, p=6.9×10 −8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 o 85.7, p=0.0012). We also ound e idence o associa ion wi h b eas cance isk o h ee a ian s in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 o 3.95), c.1036C>T OR 5.06 (95% CI 1.09 o 23.5) and c.538C>T OR 1.33 (95% CI 1.05 o 1.67) (p≤0.017). E idence o p os a e cance isk was obse ed o CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 o 6.03, p=0.0006) o A ican men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 o 4.63, p=0.030) o Eu opean Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 801 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om men. No e idence o associa ion wi h o a ian cance was ound o any o hese a ian s. Conclusions This epo adds o accumula ing e idence ha a leas some a ian s in hese genes a e associa ed wi h an inc eased isk o b eas cance ha is clinically impo an . INTRODUCTION The apid in oduc ion o massi e pa allel sequencing (MPS) in o clinical gene ics se ices is enabling he sc eening o mul- iple b eas cance suscep ibili y genes in one assay a educed cos o women who a e a inc eased isk o b eas (and o he ) cance . These gene panels now ypically include he so-called ‘mode a e- isk’b eas cance suscep ibili y genes, including PALB2,CHEK2 and ATM. 1–3 Howe e , mu a ions in hese genes a e indi idually ex emely a e and limi ed da a a e a ail- able wi h which o accu a ely es ima e he isk o cance asso- cia ed wi h hem. Es ima ion o he age-specific cumula i e isk (pene ance) o b eas cance associa ed wi h specific mu a ions in hese h ee genes has been limi ed o hose ha ha e been obse ed mo e equen ly, such as PALB2 c.1592delT (a Finnish ounde mu a- ion), PALB2 c.3113G>A and ATM c.7271T>G. These mu a- ions ha e been es ima ed o be associa ed wi h a 40% (95% CI 17% o 77%), 91% (95% CI 44% o 100%) and 52% (95% CI 28% o 80%) cumula i e isk o b eas cance o he age o 70 yea s, espec i ely. 4–7 These findings, based on seg ega ion analyses in amilies o popula ion-based case se ies, indica e ha a leas some mu a ions in hese ‘mode a e- isk’genes a e asso- cia ed wi h a b eas cance isk compa able o ha o he a e age pa hogenic mu a ion in BRCA2: 45% (95% CI 31% o 56%). 8 Howe e , such es ima es a e imp ecise and, mo eo e , may be con ounded by modi ying gene ic a ian s o o he amilial isk ac o s. Case-con ol s udies p o ide an al e na i e app oach o es ima ing cance isks associa ed wi h specific a ian s. This design can es ima e he ela i e isk di ec ly, wi hou making assump ions abou he modi ying e ec s o o he isk ac o s. Howe e , because hese a ian s a e a e, such s udies need o be ex emely la ge o p o ide p ecise es ima es. The clea es e idence o associa ion, and he mos p ecise b eas cance isk es ima es, o a e a ian s in PALB2, CHEK2 and ATM ela e o p o ein unca ing and splice-junc ion a - ian s. 910 Howe e , s udies based on mu a ion sc eening in case- con ol s udies, combined wi h s a ifica ion o a ian s by hei e olu iona y likelihood sugges ha a leas some e olu iona ily unlikely missense subs i u ions a e associa ed wi h a simila isk o hose con e ed by unca ing mu a ions. 11–13 Fo example, Ta igian e al 12 es ima ed an OR o 2.85 (95% CI 0.83 o 4.86) o e olu iona ily unlikely missense subs i u ions in he 30 hi d o ATM, which is compa able o ha o unca ing a - ian s. Specifically, ATM c.7271C>G has been associa ed wi h a mo e subs an ial b eas cance isk in se e al s udies. 713 Le Cal ez-Kelm e al, 11 es ima ed ha he ORs associa ed wi h a e mu a ions in CHEK2 om simila ly designed s udies we e 6.18 (95% CI 1.76 o 21.8) o a e p o ein- unca ing and splice- junc ion a ian s and 8.75 (95% CI 1.06 o 72.2) o e olu ion- a ily unlikely missense subs i u ions. 11 I is plausible ha monoallelic mu a ions in PALB2,CHEK2 and ATM could be associa ed wi h inc eased isk o cance s o he han b eas cance , as has been obse ed o BRCA1 and BRCA2 and bo h o a ian and p os a e cance s. 14–17 Howe e , wi h he excep ion o panc ea ic cance in PALB2 ca ie s, he e is li le e idence o suppo o e u e he exis ence o such associa ions, al hough a ew indi idually s iking pedig ees ha e been obse ed. 4818–20 In his s udy we selec ed a e gene ic a ian s on he basis ha hey had been obse ed in b eas cance candida e gene case-con ol sc eening p ojec s in ol ing PALB2,CHEK2 o ATM. These included h ee a e a ian s in PALB2: he p o ein unca ing a ian s c.1592delT (p.Leu531Cys s) 4 and c.3113 G>A (p.T p1038*) 6 and he missense a ian c.2816T>G, (p. Leu939T p), six a e missense a ian s in CHEK2: c.349A>G (p.A g117Gly) and c.1036C>T (p.A g346Cys) p edic ed o be dele e ious on he basis o e olu iona y conse a ion, 11 c.538C>T (p.A g180Cys), c.715G>A (p.Glu239Lys), c.1312G>T (p.Asp438Ty ) and c.1343T>G (p.Ile448Se ) and ATM c.7271T>G (p.Val2424Gly). 7 We assessed he associa ion o hese a ian s wi h b eas , o a ian and p os a e isk by case- con ol analyses in h ee la ge conso ia pa icipa ing in he Collabo a i e Oncological Gene-en i onmen S udy. 21 22 METHODS Pa icipan s Pa icipan s we e d awn om s udies pa icipa ing in h ee con- so ia as ollows: The B eas Cance Associa ion Conso ium (BCAC), in ol ing a o al o 48 s udies: 37 o women om popula ions wi h p edominan ly Eu opean ances y (42 671 cases and 42 164 con ols), 9 o Asian women (5795 cases and 6624 con ols) and 2 o A ican-Ame ican women (1046 cases and 932 con- ols). All cases had in asi e b eas cance . The majo i y o s udies we e popula ion-based o hospi al-based case-con ol s udies, bu some s udies o Eu opean women o e sampled cases wi h a amily his o y o wi h bila e al disease (see online supplemen a y able S1). O e all, 79% o BCAC cases wi h known Es ogen Recp o (ER) s a us (23% missing) a e ER- posi i e. The p opo ion o cases selec ed by amily his o y ha a e ER-posi i e is 78% (38% missing). The P os a e Cance Associa ion G oup o In es iga e Cance Associa ed Al e a ions in he Genome (PRACTICAL) in ol ing a o al o 26 s udies: 25 included men wi h Eu opean ances y (22 301 cases and 22 320 con ols) and 3 included A ican- Ame ican men (623 cases and 569 con ols). The majo i y o s udies we e popula ion-based o hospi al-based case-con ol s udies (see online supplemen a y able S2). The O a ian Cance Associa ion Conso ium (OCAC), in- ol ing a o al o 46 s udies. Some s udies we e case-only and hei da a we e combined wi h case-con ol s udies om he same geog aphical egion (lea ing 36 s udy g oupings). O hese g oupings, 33 included women om popula ions wi h p edomin- an ly Eu opean ances y (16 287 cases (14 542 wi h in asi e disease) and 23 491 con ols), 25 included Asian women (813 cases (720 wi h in asi e disease) and 1574 con ols), 17 included A ican-Ame ican women (186 cases (150 wi h in asi e disease) and 200 con ols) and 29 included women o o he e hnic o igin (893 cases (709 wi h in asi e disease) and 864 con ols). The majo i y o s udies we e popula ion-based o hospi al-based case- con ol s udies (see online supplemen a y able S3). De ails ega ding sample quali y con ol ha e been published p e iously. 22 23 All s udy pa icipan s ga e in o med consen and all s udies we e app o ed by he co esponding local e hics commi ees (see online supplemen a y ables S1–S3). Va ian selec ion We selec ed o geno yping 13 a e mu a ions ha had been obse ed in popula ion-based case-con ol mu a ion sc eening s udies. These a ian s we e PALB2 (c.1592delT, p. 802 Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om Leu531Cys s; 4510 c.2323C>T p.Gln775*; 20 c.2816T>G, p. Leu939T p; 220 c.3113G>A, p.T p1038*; 2620 c.3116delA, p. Asn1039IIe s; 2620 c.3549C>G, p.Ty 1183* 2 ), CHEK2 (c.349A>G, p.A gR117Gly; c.538C>T, p.A g180Cys; c.715G>A p.Glu239Lys; c.1036C>T, p.A g346Cys; c.1312G>T, p.Asp438Ty ; c.1343T>G, p.Ile448Se ) 11 and ATM (c.7271T>G, p.Val2424Gly) 71324 see able 1. A DNA sample ca ying each o hese a ian s was included in a pla e o con ol DNAs ha was dis ibu ed o each geno yping cen e o assis wi h quali y con ol and geno ype calling. Geno yping Th ee PALB2 a ian s c.2323C>T (p.Gln775*), c.3116delA (p.Asn1039IIe s) and c.3549C>G (p.Ty 1183*) we e unable o be designed o measu emen on he cus om Illumina iSelec geno yping a ay and we e no conside ed u he ( able 1). Geno yping was conduc ed using a cus om Illumina Infinium a ay (iCOGS) in ou cen es, as pa o a mul iconso ia collab- o a ion as desc ibed p e iously. 22 Geno ypes we e called using Illumina’s p op ie a y GenCall algo i hm and hen, o he da a gene a ed om he a e a ian p obes, manually confi med wi h e e ence o he posi i e con ol sample. Two pe cen o samples we e p o ided in duplica e by all s udies and 270 HapMap2 samples we e geno yped in all ou geno yping cen es. Subjec s wi h an o e all call a e <95% we e excluded. Pla es wi h call a es <90% we e excluded on a a ian -by- a ian basis. Clus e plo s gene a ed o all o he 10 a e a - ian s we e manually checked o confi m au oma ed calls (see online supplemen a y figu e S1). S a is ical me hods The associa ion o each a ian wi h b eas , p os a e and o a ian cance isk was assessed using uncondi ional logis ic eg ession o es ima e ORs o ca ie s e sus non-ca ie s, adjus ing o s udy (ca ego ical). p Values we e de e mined by he likelihood a io es compa ing models wi h and wi hou ca ie s a us as a co a ia e. We also applied condi ional logis ic eg ession, defin- ing isk se s by s udy, and ound ha his made no di e ence o he OR es ima es, CIs o p alues o wo significan figu es; since model con e gence was a p oblem o his la e eg ession analysis, all subsequen analyses we e based on uncondi ional logis ic eg ession. Fo he main analyses o b eas cance isk in Eu opean women, we also included as co a ia es he fi s six p incipal componen s, oge he wi h a se en h componen spe- cific o one s udy (Leu en Mul idisciplina y B eas Cen e (LMBC)) o which he e was subs an ial infla ion no accoun ed o by he componen s de i ed om he analysis o all s udies. Addi ion o u he p incipal componen s did no educe infla- ion u he . Da a om all b eas cance s udies we e included o assess s a is ical significance. Da a om cases selec ed o inclusion based on pe sonal o amily his o y o b eas cance we e excluded in o de o ob ain unbiased OR es ima es o he gene al popula ion o whi e Eu opean women (lea ing 37 039 cases and 38 260 con ols om 32 s udies). Mul iple es ing was adjus ed o using he Benjamini-Hochbe g p ocedu e o con ol he alse disco e y a e, wi h a significance h eshold o 0.05. 25 Repo ed p alues a e unadjus ed unless o he wise s a ed. Repo ed CIs a e all nominal. We included wo ace-specific p incipal componen s in each o he main b eas cance analyses o Asian and A ican-Ame ican women. Simila analyses we e conduc ed using he da a om PRACTICAL and OCAC, consis - en wi h hose used p e iously. 23 26 All analyses we e ca ied ou using S a a: Release V.10 (S a aCo p, 2008). RESULTS PALB2 In BCAC, PALB2 c.1592delT (Leu531Cys s) was only obse ed in 35 cases and 6 con ols, all om ou s udies om Sweden and Finland (Helsinki B eas Cance S udy (HEBCS), Kuopio B eas Cance P ojec (KBCP), Oulu B eas Cance S udy (OBCS) and Ka olinska Mammog aphy P ojec o Risk P edic ion B eas Cance (pKARMA); see online supplemen a y Table 1 Ra e gene ic a ian s included in he iCOGS a ay. Gene Va ian * Amino acid* dbSNP s B eas cance isk es ima es Align-GVGD Re e ence(s) Designed‡Geno ypedOR (95% CI) Pene ance† (95% CI) PALB2 c.1592delT p.Leu531Cys s s180177102 3.94 (1.5-12.1)§ 40% (17–77) na 4,5,10 Yes Yes c.2323C>T p.Gln775* s180177111 na 25,26 No No c.2816T>G p.Leu939T p s45478192 C55 20 Yes Yes c.3113G>A p.T p1038* s180177132 95% (44–100) na 2,6,20 Yes Yes c.3116delA p.Asn1039Ile s s180177133 na 2 No No c.3549C>G p.Ty 1183* s118203998 na 2 No No CHEK2 c.349A>G p.A g117Gly s28909982 8.75 (1.06–72.2)¶ C65 11 Yes Yes c.538C>T p.A g180Cys s77130927 2.47 (0.45–13.49)** C25 11 Yes Yes c.715G>A p.Glu239Lys s121908702 1.82 (0.62–5.34)†† C15 11 Yes Yes c.1036C>T p.A g346Cys na 8.75 (1.06–72.2)¶ C65 11 Yes Yes c.1312G>T p.Asp438Ty na 2.47 (0.45–13.49)** C25 11 Yes Yes c.1343T>G p.Ile448Se s17886163 1.82 (0.62–5.34)†† C15 11 Yes Yes ATM c.7271T>G p.Val2424Gly s28904921 52% (28–80) C65 7,13,23,27 Yes Yes *Human Genome Va ia ion Socie y (HGVS); e e ence sequences PALB2, NM_024675.3, NP_078951.2; CHEK2, NM_007194.3, NP_009125.1; ATM, NM_000051.3, NP_000042.3. †Age-speci ic cumula i e isk o b eas cance o age 70 yea s. 5–7 ‡Able o be designed o measu emen on he cus om Illumina iSelec geno yping a ay. 21 22 §B eas cance cases unselec ed o amily his o y o b eas cance . 4 ¶OR es ima ed in a combined g oup o C65 CHEK2 a ian s. 11 **OR es ima ed in a combined g oup o C25 CHEK2 a ian s. 11 ††OR es ima ed in a combined g oup o C15 CHEK2 a ian s. 11 na, no a ailable. Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 803 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om able S1), gi ing s ong e idence o associa ion wi h b eas cance isk (p=7.1×10 −5 ); he OR es ima e was 4.52 (95% CI 1.90 o 10.8) based on all s udies and 3.44 (95% CI 1.39 o 8.52) based on unselec ed cases and con ols ( able 2). We also ound e idence o he e ogenei y by ER s a us (p=0.0023), he associa ion being s onge o ER-nega i e disease (OR 6.49 (95% CI 2.17 o 19.4) e sus 2.24 (95% CI 1.05 o 7.24) o ER-posi i e disease). PALB2 c.3113G>A (p.T p1038*) was iden ified in 44 cases and 8 con ols om nine BCAC s udies. Only one ca ie o he a ian was o non-Eu opean o igin. S ong e idence o associ- a ion wi h b eas cance isk was obse ed (p=6.9×10 −8 ), wi h an es ima ed OR o 5.93 (95% CI 2.77 o 12.7) based on all s udies and 4.21 (95% CI 1.85 o 9.61) based on unselec ed cases and con ols. The e was no e idence o a di e en ial asso- cia ion by ER s a us (p=0.15). Based on unselec ed cases, he es ima ed OR associa ed wi h ca ying ei he o hese PALB2 a ian s (c.1592delT o c.3113G>A) was 3.85 (95% CI 2.09 o 7.09). PALB2 c.2816T>G (p.Leu939T p) was iden ified in 150 cases and 145 con ols and he e was no e idence o associa ion wi h isk o b eas cance . The e was no e idence o associa ion wi h isk o p os a e o o a ian cance o any o he h ee PALB2 a ian s (see ables 3 and 4). Table 2 Summa y esul s om B eas Cance Associa ion Conso ium s udies o whi e Eu opeans (42 671 in asi e b eas cance cases and 42 164 con ols) Va ian F equency* Con ols F equency* Cases OR (95% CI) LRT p Value OR†(95% CI) LRT p Value† PALB2§ c.1592delT (p.Leu531Cys s) 0.00014 0.00082 4.52 (1.90 o 10.8) 7.1×10 −5 3.44 (1.39 o 8.52) 0.003 c.2816T>G (p.Leu939T p) 0.00342 0.00352 1.05 (0.83 o 1.32) 0.70 1.03 (0.80 o 1.32) 0.82 c.3113G>A (p.T p1038*) 0.00019 0.00101 5.93 (2.77 o 12.7) 6.9×10 −8 4.21 (1.84 o 9.60) 1.2×10 −4 CHEK2 c.349A>G (p.A g117Gly) 0.00043 0.00103 2.26 (1.29 o 3.95) 0.003 2.03 (1.10 o 3.73) 0.020 c.538C>T (p.A g180Cys) 0.00337 0.00370 1.33 (1.05 o 1.67) 0.016 1.34 (1.06 o 1.70) 0.015 c.715G>A (p.Glu239Lys) 0.00021 0.00035 1.70 (0.73 o 3.93) 0.210 1.47 (0.60 o 3.64) 0.40 c.1036C>T (p.A g346Cys) 0.00005 0.00021 5.06 (1.09 o 23.5) 0.017 3.39 (0.68 o 16.9) 0.11 c.1312G>T (p.Asp438Ty ) 0.00078 0.00082 1.03 (0.62 o 1.71) 0.910 0.87 (0.49 o 1.52) 0.62 c.1343T>G (p.Ile448Se )‡0.00002 0 –––– ATM c.7271T>G (p.Val2424Gly) 0.00002 0.00028 11.6 (1.50 o 89.9) 0.0012 11.0 (1.42 o 85.7) 0.0019 *P opo ion o subjec s ca ying he a ian . †Excluding women om i e s udies ha selec ed all cases based on amily his o y o bila e al disease and he subse o selec ed cases om o he s udies (based on 34 488 unselec ed cases and 34 059 con ols). ‡CHEK2 c.1343T>G (p.Ile448Se ) was only obse ed in one con ol and no cases o whi e Eu opean o igin. §PALB2 c.3113G>A (p.T p1038*) only obse ed in he UK, Aus alia, he USA and Canada. PALB2 c.1592delT (p.Leu531Cys s) only obse ed in Finland and Sweden. LRT, likelihood a io es ; OR, OR o ca ie s o he a ian e sus common-allele homozygo es, adjus ed o s udy and se en p incipal componen s. Table 3 Summa y esul s om he P os a e Cance Associa ion G oup o In es iga e Cance Associa ed Al e a ions in he Genome s udies o whi e Eu opean men* (22 301 p os a e cance cases and 22 320 con ols) Va ian F equency† Con ols F equency† Cases OR (95% CI) LRT p Value PALB2 c.1592delT (p.Leu531Cys s) 0.00018 0.00031 2.06 (0.59 o 7.11) 0.24 c.2816T>G (p.Leu939T p) 0.00354 0.00381 0.95 (0.69 o 1.29) 0.73 c.3113G>A (p.T p1038*) 0.00045 0.00027 0.49 (0.18 o 1.36) 0.16 CHEK2‡ c.349A>G (p.A g117Gly) 0.00063 0.00081 1.46 (0.71 o 3.02) 0.30 c.538C>T (p.A g180Cys) 0.00341 0.00296 1.02 (0.73 o 1.44) 0.90 c.715G>A (p.Glu239Lys) 0.00018 0.00027 1.47 (0.41 o 5.35) 0.55 c.1036C>T (p.A g346Cys) 0.00018 0.00022 1.07 (0.28 o 4.07) 0.93 c.1312G>T (p.Asp438Ty ) 0.00049 0.00103 2.21 (1.06 o 4.63) 0.03 c.1343T>G (p.Ile448Se ) 0 0.00009 –– c.1343T>G (A icans§) 0.019 0.057 3.03 (1.53 o 6.03) 0.001 ATM c.7271T>G (p.Val2424Gly) 0.00004 0.00027 4.37 (0.52 o 36.4) 0.17 *Fo whi e Eu opean men, unless o he wise indica ed. †P opo ion o subjec s ca ying he a ian . ‡CHEK2 c.1343T>G (p.Ile448Se ) was he only CHEK2 a ian obse ed in A ican men and was iden i ied in wo cases and no con ols o whi e Eu opean o igin. §Based on da a om 623 and 569 A ican-Ame ican cases and con ols, espec i ely. LRT, likelihood a io es ; OR, OR o ca ie s o he a ian e sus common-allele homozygo es, adjus ed o s udy and se en p incipal componen s. 804 Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om CHEK2 CHEK2 c.349A>G (p.A g117Gly) was iden ified in 44 cases and 18 con ols in s udies pa icipa ing in BCAC; all o hese women we e o Eu opean o igin. We ound e idence o associa ion wi h b eas cance (p=0.003), wi h li le change in he OR a e exclud- ing selec ed cases (OR 2.03 (95% CI 1.10 o 3.73)). CHEK2 c.538C>T (p.A g180Cys) was iden ified in 158 b eas cance cases and 142 con ols in s udies o whi e Eu opeans. E idence o associa ion wi h b eas cance isk (p=0.016) was obse ed, wi h an unbiased OR es ima e o 1.34 (95% CI 1.06 o 1.70). A consis en OR es ima e was obse ed o Asian women, based on 45 case and 45 con ol ca ie s (OR 1.16 (95% CI 0.75 o 1.76)). CHEK2 c.715G>A (p.Glu239Lys) mu a ions we e iden ified in 15 cases and 9 con ols, all Eu opean women pa icipa ing in BCAC and no e idence o associa ion wi h isk o b eas cance was obse ed (p=0.21). CHEK2 c.1036C>T (p.A g346Cys) was iden ified in nine cases om se en s udies and wo con ols om wo di e en s udies in BCAC (nei he con ol ca ie was om a s udy ha had case ca ie s), all o Eu opean o igin. We ound e idence o associ- a ion wi h b eas cance isk (p=0.017) wi h educed OR es ima e o 3.39 (95% CI 0.68 o 16.9) a e excluding selec ed cases. None o he abo e ou CHEK2 a ian s (CHEK2 c.349A>G (p.A g117Gly); c.538C>T (p.A g180Cys); c.715G>A (p. Glu239Lys) and c.1036C>T (p.A g346Cys)) we e ound o be associa ed wi h an inc eased isk o p os a e o o a ian cance ( ables 3 and 4). CHEK2 a ian c.1312G>T (p.Asp438Ty ) was no associa ed wi h isk o b eas cance o Eu opean women (p=0.91). Va ian c.1343T>G (p.Ile448Se ) was no obse ed in any b eas cance cases o Eu opean o Asian o igin. I was de ec ed in 48 cases and 29 con ols o A ican o igin, gi ing weak e idence o associa ion (OR 1.52 (95% CI 0.95 o 2.43, p=0.083)). CHEK2 c.1312G>T (p.Asp438Ty ) was iden i- fied in 23 cases and 11 con ols om PRACTICAL, all Eu opean, p o iding e idence o associa ion wi h p os a e cance isk (OR 2.21 (95% CI 1.06 o 4.63, p=0.030)). CHEK2 c.1343T>G (p. Ile448Se ) was obse ed in 35 cases and 11 con ols, all A ican, pa icipa ing in PRACTICAL and was also associa ed wi h an inc eased isk o p os a e cance (OR 3.03 (95% CI 1.53 o 6.03, p=0.00059)). The e was no e idence ha hese CHEK2 a ian s we e associa ed wi h isk o o a ian cance ( able 4). ATM ATM c.7271T>G (p.Val2424Gly) was iden ified in 12 cases and 1 con ol in s udies pa icipa ing in BCAC, all o Eu opean o igin, gi ing e idence o associa ion wi h b eas cance isk (p=0.0012). The OR es ima e based on unselec ed s udies was 11.0 (95% CI 1.42 o 85.7). The e was no e idence o associ- a ion o his a ian wi h p os a e o o a ian cance isk (see ables 3 and 4). DISCUSSION The p esen epo adds o an accumula ing body o e idence ha a leas some a e a ian s in so-called ‘mode a e- isk’genes a e associa ed wi h an inc eased isk o b eas cance ha is o clinical ele ance. These findings a e p esen ed a a ime when de ailed in o ma- ion abou a ian s in hese genes is becoming mo e eadily a ail- able ia he ansla ion o diagnos ic gene ic es ing om Sange sequencing-based es ing pla o ms o MPS pla o ms ha es panels o genes in single assays. 27–29 The as majo i y o in o - ma ion abou PALB2,CHEK2 and ATM, a ian s gene a ed om hese new es ing pla o ms is no being used in clinical gene ics se ices due o lack o eliable es ima es o he cance isk asso- cia ed wi h indi idual a ian s, o g oups o a ian s, in each gene. P e ious analyses ha e been la gely based on selec ed am- ilies, elying on da a on he seg ega ion o he a ian . The p esen s udy is by a he la ges o ake a case-con ol app oach. Consis en wi h p e ious epo s, 5–7911–13 PALB2 c.3113G>A (p.T p1038*), PALB2 c.1592delT (p.Leu531Cys s) and ATM c.7271T>G (p.Val2424Gly) we e ound o be associa ed wi h subs an ially inc eased isk o b eas cance all wi h associa ed ela i e isk es ima es o 3.44 o g ea e . The es ima es o he wo loss-o - unc ion PALB2 a ian s (c.1592delT and c.3113G<A) we e consis en wi h each o he and wi h es ima es based on seg ega ion analysis. 569 We ound no e idence o associa ion wi h b eas cance o PALB2 c.2816T>G (p.Leu939T p), wi h an uppe 95% confidence limi excluding an OR >1.5 which is no able gi en he Table 4 Summa y esul s om he O a ian Cance Associa ion Conso ium s udies o whi e Eu opean women (14 542 in asi e o a ian cance cases and 23 491 con ols) Va ian F equency* Con ols F equency* Cases OR (95% CI) LRT p Value PALB2 c.1592delT (p.Leu531Cys s) 0.00004 0.00012 2.50 (0.21 o 29.1) 0.45 c.2816T>G (p.Leu939T p) 0.00413 0.00399 0.96 (0.69 o 1.34) 0.81 c.3113G>A (p.T p1038*) 0.00034 0.00031 1.34 (0.36 o 4.97) 0.66 CHEK2 c.349A>G (p.A g117Gly) 0.00038 0.00031 1.07 (0.32 o 3.60) 0.92 c.538C>T (p.A g180Cys) 0.00128 0.00160 1.49 (0.83 o 2.67) 0.18 c.715G>A (p.Glu239Lys) 0.00021 0.00037 1.47 (0.42 o 5.22) 0.54 c.1036C>T (p.A g346Cys)‡00–– c.1312G>T (p.Asp438Ty ) 0.00081 0.00074 0.92 (0.42 o 1.99) 0.83 c.1343T>G (p.Ile448Se ) 0.00009 0 –– ATM c.7271T>G (p.Val2424Gly) 0 0.00012 –– *P opo ion o subjec s ca ying he a ian . ‡c.1036C>T (p.A g346Cys) was no obse ed in any sample. LRT, likelihood a io es ; OR, OR o ca ie s o he a ian e sus common-allele homozygo es, adjus ed o s udy and se en p incipal componen s. Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 805 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om Align-G an ham Va ia ion G an han De ia ion (Align-GVGD) sco e and he obse ed impac on p o ein unc ion. 30 The es ima e o ATM c.7271T>G (p.Val2424Gly) was also consis en wi h ha ound by seg ega ion analysis. 713 The sub- s an ial inc eased isk o b eas cance associa ed wi h ATM c.7271T>G (p.Val2424Gly) could be due o he educ ion in kinase ac i i y (wi h nea -no mal p o ein le els) obse ed o ATM p.Val2424Gly, 31 hus his a ian is likely o be ac ing as a dominan nega i e mu a ion. 32 In con as , we ound no e idence o an associa ion wi h isk o p os a e o o a ian cance wi h any o hese h ee a ian s: howe e , he confidence limi s we e wide; based on he uppe 95% confidence limi we could exclude an OR o >1.4 o p os a e cance o he loss-o - unc ion PALB2 c.3113G>A and 1.9 o c.1592delT and c.3113G>A combined. We analysed six a e missense a ian s in CHEK2. Two o hese (CHEK2 c.349A>G (p.A g117Gly; s28909982) and c.1036C>T (p.A g346Cys)) had e idence o a significan impac on he p o ein based on in silico p edic ion. We p o- posed hese a ian s o inclusion in he iCOGS design as hey had been iden ified in 3/1242 cases and 1/1089 con ols and 3/1242 cases and 0/1089 con ols, espec i ely, in a popula ion- based case-con ol mu a ion sc eening s udy o CHEK2. 11 In ha s udy, Le Cal ez-Kelm e al, es ima ed an OR o 8.75 (95% CI 1.06 o 72.2) o a ian s wi h an Align-GVGD sco e C65 (based on nine cases and one con ol). The cu en analysis p o- ides confi ma o y e idence o his associa ion in a much la ge sample (OR 2.18 (95% CI 1.23 o 3.85)) including 40 unse- lec ed case and 18 con ol ca ie s. The e idence ha CHEK2 is a b eas cance suscep ibili y gene is la gely based on s udies o p o ein unca ing a ian s, in pa icula CHEK2 1100delC. 33 Repo s o he associa ion o he missense a ian I157T, (C15) and b eas cance isk ha e been conflic ing bu a la ge me a-analysis in ol ing 15 985 b eas cance cases and 18 609 con ols es ima ed a modes OR o 1.58 (95% CI 1.42 o 1.75). 34 We also ound e idence (p=0.015) o an associa ion o c.538C>T (Align-GVGD C25); OR 1.34 (95% CI 1.06 o 1.70), a isk compa able o I157T. The p alues epo ed abo e ha e no been adjus ed o mul- iple es ing. This was no conside ed app op ia e o he asso- cia ions wi h b eas cance isk o PALB2 c.1592delT, c.3113G>A and ATM c.7271T>G because hese associa ions had p e iously been epo ed; ou aim was o mo e p ecisely es ima e he associa ed ela i e isks. All h ee associa ions wi h b eas cance isk epo ed o CHEK2 a ian s emained s a is- ically significan a e adjus ing o he o he es s conduc ed in ela ion o b eas cance isk, bu no a e co ec ing o all es s o all cance s. Ne e heless, he findings o CHEK2 c.349A>G and c.1036C>T confi med hose epo ed p e i- ously, al hough collec i ely. The associa ion obse ed wi h CHEK2 c.538C>T equi es independen eplica ion. Do his app oach and new da a ha e an impac on clinical ecommenda ions o women and amilies ca ying hese a e gene ic a ian s? Al hough age-specific cumula e isks o cance a e mo e in o ma i e o gene ic counselling and clinical man- agemen o ca ie s, ou s udy p o ides in o ma ion ha is ele- an o clinical ecommenda ions. As discussed in Eas on e al, 35 a ela i e isk o 4 will place a woman in a ‘high- isk’ca ego y (in he absence o any o he isk ac o ) and a ela i e isk be ween 2 and 4 will place a woman in his ca ego y i o he isk ac o s a e p esen . Thus, se e al o he a ian s included in his epo (PALB2 c.1592delT; c.3113G>A ATM c.7271T>G) would place he ca ie in a high- isk g oup, especially i o he isk ac o s, such as a amily his o y, a e p esen . The high le el o b eas cance isk associa ed wi h PALB2 c.1592delT and c.3113G>A epo ed he e is consis en wi h he pene ance es ima e epo ed o a g oup o loss-o - unc ion mu a ions in PALB2 9 and has an ad an age in e ms o clinical u ili y ha he es ima es in his s udy ha e been made a a mu a ion-specific le el. The e o e, his wo k p o ides impo an in o ma ion o isk educ ion ecom- menda ions (such as p ophylac ic mas ec omy and po en ially salpingo-oopho ec omy) o ca ie s o hese a ian s. Howe e , u he p ospec i e esea ch is equi ed o cha ac e ise hese isks and o unde s and he po en ial o o he isk- educing s a egies such as salpingo-oopho ec omy and chemop e en ion. The consis ency o he ela i e isk es ima es wi h hose de i ed h ough amily based s udies suppo s he hypo hesis ha hese a ian s combine mul iplica i ely wi h o he gene ic loci and amilial isk ac o s; his in o ma ion is c i ical o de i ing com- p ehensi e isk models. E en wi h e y la ge sample sizes such as hose s udied he e, howe e , i is s ill only possible o de i e indi- idual isk es ima es o a limi ed se o a ian s, and e en o hese a ian s he es ima es a e s ill imp ecise. This in e na ionally collabo a i e app oach also has limi ed capaci y o imp o e isk es ima es o a e a ian s ha a e only obse ed in specificpopu- la ions. Ine i ably, he e o e, isk models will depend on combin- ing da a ac oss mul iple a ian s, using imp o ed in silico p edic ions and po en ially biochemical/ unc ional e idence o syn hesise hese es ima es e ficien ly. I will also be necessa y de elop counselling and pa ien managemen s a egies ha can accommoda e a mul i ac o ial app oach o a ian classifica ion. Au ho a filia ions 1 Gene ic Epidemiology Labo a o y, Depa men o Pa hology, The Uni e si y o Melbou ne, Melbou ne, Aus alia 2 Hun sman Cance Ins i u e, Sal Lake Ci y, UT, USA 3 Labo a o y o Cance Gene ics and Tumo Biology, Cance and T ansla ional Medicine Resea ch Uni and Biocen e Oulu, Uni e si y o Oulu, No dlab Oulu, Oulu, Finland 4 Depa men o Labo a o y Medicine and Pa hology, Mayo Clinic, Roches e , MN, USA 5 Depa men o Medical Gene ics and Na ional Ins i u e o Heal h Resea ch Camb idge Biomedical Resea ch Cen e, Uni e si y o Camb idge, and he Depa men o Clinical Gene ics, Eas Anglian Regional Gene ics Se ice, Addenb ooke’s Hospi al 6 P og am in Cance Gene ics, Depa men o Human Gene ics and Oncology, Lady Da is Ins i u e, and Resea ch Ins i u e, McGill Uni e si y Heal h Cen e, McGill Uni e si y, Mon eal, Canada, 7 Cen e o Cance Gene ic Epidemiology, Depa men o Public Heal h and P ima y Ca e, Uni e si y o Camb idge, S angeways Labo a o y, Wo s Causeway, Camb idge, UK 8 Depa men o Gene ics, Uni e si y o P e o ia, Sou h A ica 9 Depa men o Obs e ics and Gynecology, Uni e si y o Helsinki and Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland 10 Cen e o Epidemiology and Bios a is ics, School o Popula ion and Global Heal h, The Uni e si y o Melbou ne, Melbou ne, Aus alia, 11 Gynaecology Resea ch Uni , Hanno e Medical School, Hanno e , Ge many 12 Cen e o Medical Gene ics, Ghen Uni e si y Hospi al, De Pin elaan 185, 9000 Ghen , Belgium, 13 Depa men o Pa hology and Human Oncology and Pa hogenesis P og am, Memo ial Sloan-Ke e ing Cance Cen e , New Yo k, New Yo k, USA 14 Uni o Molecula Bases o Gene ic Risk and Gene ic Tes ing, Depa men o P e en i e and P edic i e Medicine, Fondazione IRCCS Is i u o Nazionale dei Tumo i (INT), Milan, I aly 15 IFOM, he FIRC Ins i u e o Molecula Oncology, Milan, I aly 16 Ne he lands Cance Ins i u e, An oni an Leeuwenhoek hospi al, Ams e dam, The Ne he lands 17 Aus alian B eas Cance Tissue Bank, Uni e si y o Sydney a he Wes mead Ins i u e o Medical Resea ch, NSW, Aus alia 18 Cen e o Cance Resea ch, Uni e si y o Sydney a he Wes mead Ins i u e o Medical Resea ch, NSW, Aus alia 19 Di ision o Molecula Medicine, Pa hology No h, Newcas le and Uni e si y o Newcas le, NSW, Aus alia 20 Uni e si y B eas Cen e F anconia, Depa men o Gynecology and Obs e ics, Uni e si y Hospi al E langen, F ied ich-Alexande Uni e si y E langen-Nu embe g, Comp ehensi e Cance Cen e E langen-EMN, E langen, Ge many 806 Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om 21 Da id Ge en School o Medicine, Depa men o Medicine Di ision o Hema ology and Oncology, Uni e si y o Cali o nia a Los Angeles, CA, USA 22 Uni o Bios a is ics, Depa men o Gynecology and Obs e ics, Uni e si y Hospi al E langen, F ied ich-Alexande Uni e si y E langen-Nu embe g, E langen, Ge many 23 Ins i u e o Human Gene ics, Uni e si y Hospi al E langen, F ied ich Alexande Uni e si y E langen-Nu embe g, E langen, Ge many 24 Non-communicable Disease Epidemiology Depa men , London School o Hygiene and T opical Medicine, London, UK 25 B eak h ough B eas Cance Resea ch Cen e, The Ins i u e o Cance Resea ch, London, UK 26 Di ision o Cance S udies, NIHR Comp ehensi e Biomedical Resea ch Cen e, Guy’s & S . Thomas’NHS Founda ion T us in pa ne ship wi h King’s College London, London, UK 27 Wellcome T us Cen e o Human Gene ics and Ox o d Biomedical Resea ch Cen e, Uni e si y o Ox o d, UK and Ox o d NIHR Biomedical Resea ch Cen e, Heading on, OX3 7LE 28 Su ge y, Lambe Ins i u e o T ansla ional Science, NUIGalway, Uni e si y Hospi al Galway, Galway, I eland 29 Depa men o Obs e ics and Gynecology, Uni e si y o Heidelbe g, Heidelbe g, Ge many 30 Na ional Cen e o Tumo Diseases, Uni e si y o Heidelbe g, Heidelbe g, Ge many 31 Molecula Epidemiology G oup, Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 32 Inse m (Na ional Ins i u e o Heal h and Medical Resea ch), CESP (Cen e o Resea ch in Epidemiology and Popula ion Heal h), U1018, En i onmen al Epidemiology o Cance , Villejui , F ance 33 Uni e si y Pa is-Sud, UMRS 1018, Villejui , F ance 34 Copenhagen Gene al Popula ion S udy, He le Hospi al, Copenhagen Uni e si y Hospi al, Uni e si y o Copenhagen, Copenhagen, Denma k 35 Depa men o Clinical Biochemis y, He le Hospi al, Copenhagen Uni e si y Hospi al, Uni e si y o Copenhagen, Copenhagen, Denma k 36 Depa men o B eas Su ge y, He le Hospi al, Copenhagen Uni e si y Hospi al, Copenhagen, Denma k 37 Human Gene ics G oup, Human Cance Gene ics P og am, Spanish Na ional Cance Resea ch Cen e (CNIO), Mad id, Spain 38 Cen o de In es igación en Red de En e medades Ra as (CIBERER), Valencia, Spain 39 Se icio de Oncología Médica, Hospi al Uni e si a io La Paz, Mad id, Spain 40 Se icio de Ci ugía Gene al y Especialidades, Hospi al Mon e Na anco, O iedo, Spain 41 Se icio de Ana omía Pa ológica, Hospi al Mon e Na anco, O iedo, Spain 42 Depa men o Epidemiology, Uni e si y o Cali o nia I ine, I ine, Cali o nia, USA 43 Beckman Resea ch Ins i u e o Ci y o Hope, Dua e, Cali o nia, USA 44 Depa men o Epidemiology, Uni e si y o Cali o nia I ine, I ine, Cali o nia, USA 45 Cance P e en ion Ins i u e o Cali o nia, F emon , Cali o nia, USA 46 Di ision o Clinical Epidemiology and Aging Resea ch, Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 47 Di ision o P e en i e Oncology, Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 48 Ge man Cance Conso ium (DKTK), Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 49 Saa land Cance Regis y, Saa b ücken, Ge many 50 D . Ma ga e e Fische -Bosch-Ins i u e o Clinical Pha macology, S u ga 51 Uni e si y o Tübingen, Tübingen, Ge many 52 Ins i u e o P e en ion and Occupa ional Medicine o he Ge man Social Acciden Insu ance, Ins i u e o he Ruh Uni e si y, Bochum (IPA), Ge many 53 Depa men o In e nal Medicine, E angelische Kliniken Bonn gGmbH, Johanni e K ankenhaus, Bonn, Ge many 54 Depa men o Obs e ics and Gynecology, Uni e si y o Helsinki and Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland 55 Depa men o Clinical Gene ics, Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland 56 Depa men o Oncology, Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland 57 Depa men o Radia ion Oncology, Hanno e Medical School, Hanno e , Ge many 58 N.N. Alexand o Resea ch Ins i u e o Oncology and Medical Radiology, Minsk, Bela us 59 Depa men o Molecula Medicine and Su ge y, Ka olinska Ins i u e , S ockholm, Sweden 60 Depa men o Oncology –Pa hology, Ka olinska Ins i u e , S ockholm, Sweden 61 School o Medicine, Ins i u e o Clinical Medicine, Pa hology and Fo ensic Medicine, and Cance Cen e o Eas e n Finland, Uni e si y o Eas e n Finland, Kuopio, Finland 62 Imaging Cen e , Depa men o Clinical Pa hology, Kuopio Uni e si y Hospi al, Kuopio, Finland 63 School o Medicine, Ins i u e o Clinical Medicine, Oncology, Uni e si y o Eas e n Finland, Kuopio, Finland 64 Biocen e Kuopio, Cance Cen e o Eas e n Finland, Kuopio Uni e si y Hospi al, Kuopio, Finland 65 QIMR Be gho e Medical Resea ch Ins i u e, B isbane, Aus alia 66 Resea ch Depa men , Pe e MacCallum Cance Cen e and The Si Pe e MacCallum Depa men o Oncology, Uni e si y o Melbou ne, Vic o ia, Aus alia 67 Vesalius Resea ch Cen e (VRC), VIB, Leu en, Belgium 68 Labo a o y o T ansla ional Gene ics, Depa men o Oncology, Uni e si y o Leu en, Leu en, Belgium 69 Uni e si y Hospi al Gas huisbe g, Leu en, Belgium 70 Di ision o Cance Epidemiology, Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 71 Depa men o Cance Epidemiology/Clinical Cance Regis y and Ins i u e o Medical Biome ics and Epidemiology, Uni e si y Clinic Hambu g-Eppendo , Hambu g, Ge many 72 Depa men o Heal h Sciences Resea ch, Mayo Clinic, Roches e , MN, USA 73 Ana omical Pa hology, The Al ed Hospi al, Melbou ne, Aus alia 74 Depa men o P e en i e Medicine, Keck School o Medicine, Uni e si y o Sou he n Cali o nia, Los Angeles, CA, USA 75 Epidemiology P og am, Cance Resea ch Cen e , Uni e si y o Hawaii, Honolulu, HI, USA 76 Depa men o Gene ics, Ins i u e o Cance Resea ch, Oslo Uni e si y Hospi al, Radiumhospi ale , Oslo, No way 77 Facul y o Medicine (Facul y Di ision Ahus), Uni e si y o Oslo (UiO), No way 78 Di ision o Epidemiology, Depa men o Medicine, Vande bil Epidemiology Cen e , Vande bil -Ing am Cance Cen e , Vande bil Uni e si y School o Medicine, Nash ille, TN, USA 79 P og am in Molecula and Gene ic Epidemiology, Ha a d School o Public Heal h, Bos on, MA, USA 80 Depa men o Epidemiology, Ha a d School o Public Heal h, Bos on, MA, USA 81 Channing Labo a o y, Depa men o Medicine, B igham and Women’sHospi aland Ha a d Medical School, Bos on, MA, USA 82 On a io Cance Gene ics Ne wo k, Lunen eld-Tanenbaum Resea ch Ins i u e o Moun Sinai Hospi al, To on o, On a io, Canada 83 Depa men o Molecula Gene ics, Uni e si y o To on o, To on o, On a io, Canada 84 P osse man Cen e o Heal h Resea ch, Lunen eld-Tanenbaum Resea ch Ins i u e o Moun Sinai Hospi al, To on o, On a io, Canada 85 Di ision o Epidemiology, Dalla Lana School o Public Heal h, Uni e si y o To on o, To on o, On a io, Canada 86 Depa men o Labo a o y Medicine and Pa hobiology, Uni e si y o To on o, To on o, ON, Canada 87 Labo a o y Medicine P og am, Uni e si y Heal h Ne wo k, To on o, On a io; Depa men o Labo a o y Medicine and Pa hobiology, Uni e si y o To on o, To on o, ON, Canada 88 Depa men o Oncology, Oulu Uni e si y Hospi al, Uni e si y o Oulu, Oulu, Finland 89 Depa men o Su ge y, Oulu Uni e si y Hospi al, Uni e si y o Oulu, Oulu, Finland 90 Depa men o Pa hology, Oulu Uni e si y Hospi al, Uni e si y o Oulu, Oulu, Finland 91 Depa men o Su gical Oncology, Leiden Uni e si y Medical Cen e , 2300 RC Leiden, The Ne he lands 92 Family Cance Clinic, Depa men o Medical Oncology, E asmus MC-Daniel den Hoed Cance Cen e, Ro e dam, The Ne he lands 93 The B eas Cance Now Toby Robins Resea ch Cen e, The Ins i u e o Cance Resea ch, London, SW3 6JB, UK 94 Di ision o Cance Epidemiology and Gene ics, Na ional Cance Ins i u e, Rock ille, Ma yland, USA 95 Depa men o Cance Epidemiology and P e en ion, M. Sklodowska-Cu ie Memo ial Cance Cen e & Ins i u e o Oncology, Wa saw, Poland 96 Depa men o Medical Epidemiology and Bios a is ics, Ka olinska Ins i u e , S ockholm 17177, Sweden 97 Facul y o Medicine, Uni e si y o Sou hamp on (UoS), Sou hamp on UK 98 Depa men o Medical Oncology, Family Cance Clinic, E asmus MC Cance Ins i u e, Ro e dam, The Ne he lands 99 Depa men o Clinical Gene ics, Family Cance Clinic, E asmus Uni e si y Medical Cen e , Ro e dam, The Ne he lands 100 Depa men o Su gical Oncology, Family Cance Clinic, E asmus Uni e si y Medical Cen e , Ro e dam, The Ne he lands 101 Depa men o Medical Epidemiology and Bios a is ics, Ka olinska Ins i u e , S ockholm 17177, Sweden 102 Human Gene ics Di ision, Genome Ins i u e o Singapo e, Singapo e 138672, Singapo e 103 She field Cance Resea ch, Depa men o Oncology, Uni e si y o She field, She field, UK 104 Cen e o Cance Gene ic Epidemiology, Depa men o Oncology, Uni e si y o Camb idge, Camb idge, UK 105 Molecula Gene ics o B eas Cance , Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many 106 Ins i u e o Human Gene ics, Pon ificia Uni e sidad Ja e iana, Bogo a, Colombia 107 F auenklinik de S ad klinik Baden-Baden, Baden-Baden, Ge many 108 Ins i u e o Pa hology, S äd isches Klinikum Ka ls uhe, Ka ls uhe, Ge many 109 Depa men o Gene ics and Pa hology, Pome anian Medical Uni e si y, Szczecin, Poland 110 Pos g adua e School o Molecula Medicine, Wa saw Medical Uni e si y, Wa saw, Poland Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 807 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om 111 Depa men o Molecula Vi ology, Immunology and Medical Gene ics, Comp ehensi e Cance Cen e , The Ohio S a e Uni e si y, Columbus, OH, USA 112 Roswell Pa k Cance Ins i u e, Bu alo, New Yo k, USA 113 Molecula Diagnos ics Labo a o y, IRRP, Na ional Cen e o Scien ific Resea ch "Demok i os", Aghia Pa aske i A ikis, A hens, G eece 114 Di ision o Gene ics and Epidemiology, Ins i u e o Cance Resea ch, London, UK 115 Di ision o B eas Cance Resea ch, Ins i u e o Cance Resea ch, London, UK 116 Cen e d’inno a ion Genome Quebec e Uni e si y McGill Mon eal Quebec, Canada 117 McGill Uni e si y, Mon eal, Quebec, Canada 118 Cance Genomics Labo a o y, Cen e Hospi alie Uni e si ai e de Quebec Resea ch Cen e . La al Uni e si y, Quebec, Canada 119 The Ins i u e o Cance Resea ch, London, SM2 5NG, UK 120 Royal Ma sden NHS Founda ion T us , Fulham, London, SW3 6JJ, UK 121 Uni e si y o Wa wick, Co en y, UK 122 Depa men o Medical Epidemiology and Bios a is ics, Ka olinska Ins i u e, S ockholm, Sweden 123 Depa men o Medical Biochemis y and Gene ics, Uni e si y o Tu ku, and Tyks Mic obiology and Gene ics, Depa men o Medical Gene ics, Tu ku Uni e si y Hospi al, Tu ku, Finland 124 Ins i u e o Biomedical Technology/BioMediTech, Uni e si y o Tampe e, Tampe e, Finland 125 Depa men o Clinical Biochemis y, He le Hospi al, Copenhagen Uni e si y Hospi al, He le Ring ej 75, DK-2730 He le , Denma k 126 Depa men o Human Gene ics Uni e si y o U ah, Sal Lake Ci y, UT, USA and Depa men o Clinical Biochemis y, He le Hospi al, Copenhagen Uni e si y Hospi al, Uni e si y o Copenhagen, Copenhagen, Denma k 127 Cance Epidemiology Uni , Nu field Depa men o Popula ion Heal h, Uni e si y o Ox o d, Ox o d, UK 128 Su gical Oncology (U o-Oncology: S4), Uni e si y o Camb idge, Box 279, Addenb ooke’s Hospi al, Hills Road, Camb idge, UK and Cance Resea ch UK Camb idge Resea ch Ins i u e, Li Ka Shing Cen e, Camb idge, UK 129 P o esso o Social Medicine, Uni e si y o B is ol, Canynge Hall, 39 Wha ley Road, B is ol BS8 2PS 130 Nu field Depa men o Su gical Sciences, Old Road Campus Resea ch Building (o Roose el D i e), Uni e si y o Ox o d, Heading on, Ox o d, OX3 7DQ 131 Camb idge Ins i u e o Public Heal h, Uni e si y o Camb idge, Fo ie Si e, Robinson Way, Camb idge CB2 0SR 132 Di ision o Public Heal h Sciences, F ed Hu chinson Cance Resea ch Cen e , Sea le, Washing on, USA 133 Depa men o Epidemiology, School o Public Heal h, Uni e si y o Washing on, Sea le, Washing on, USA 134 In e na ional Epidemiology Ins i u e, 1455 Resea ch Bl d., Sui e 550, Rock ille, MD 20850 135 Depa men o Obs e ics, Gynecology and Rep oduc i e Sciences, Uni e si y o Pi sbu gh School o Medicine, Pi sbu gh, PA, USA 136 Depa men o U ology, Uni e si y Hospi al Ulm, Ge many 137 Ins i u e o Human Gene ics Uni e si y Hospi al Ulm, Ge many 138 B igham and Women’s Hospi al/Dana-Fa be Cance Ins i u e, 45 F ancis S ee - ASB II-3, Bos on, MA 02115 139 Washing on Uni e si y, S Louis, Missou i 140 In e na ional He edi a y Cance Cen e , Depa men o Gene ics and Pa hology, Pome anian Medical Uni e si y, Szczecin, Poland 141 Di ision o Gene ic Epidemiology, Depa men o Medicine, Uni e si y o U ah School o Medicine 142 Di ision o Cance P e en ion and Con ol, H. Lee Mo fi Cance Cen e , 12902 Magnolia D ., Tampa, Flo ida, USA 143 Molecula Medicine Cen e and Depa men o Medical Chemis y and Biochemis y, Medical Uni e si y –Sofia, 2 Zd a e S , 1431, Sofia, Bulga ia 144 Aus alian P os a e Cance Resea ch Cen e-Qld, Ins i u e o Heal h and Biomedical Inno a ion and Schools o Li e Science and Public Heal h, Queensland Uni e si y o Technology, B isbane, Aus alia 145 Depa men o Gene ics, Po uguese Oncology Ins i u e, Po o, Po ugal and Biomedical Sciences Ins i u e (ICBAS), Po o Uni e si y, Po o, Po ugal 146 Uni e si y Hospi al E langen, Depa men o Gynecology and Obs e ics, F ied ich- Alexande -Uni e si y E langen-Nu embe g, Comp ehensi e Cance Cen e E langen- EMN, Uni e si ae ss asse 21-23, 91054 E langen, Ge many 147 Uni e si y Hospi al E langen, Ins i u e o Pa hology, F ied ich-Alexande -Uni e si y E langen-Nu embe g, Comp ehensi e Cance Cen e E langen-EMN, Uni e si ae ss asse 21-23, 91054 E langen, Ge man 148 Vesalius Resea ch Cen e , VIB, Leu en, Belgium 149 Labo a o y o T ansla ional Gene ics, Depa men o Oncology, Uni e si y o Leu en, Belgium 150 Depa men o Epidemiology, The Geisel School o Medicine a Da mou h, Lebanon, NH, USA 151 Depa men o Epidemiology, The Geisel School o Medicine a Da mou h, Hanno e , NH, USA 152 P og am in Epidemiology, Di ision o Public Heal h Sciences, F ed Hu chinson Cance Resea ch Cen e , Sea le, WA, USA 153 Depa men o Epidemiology, Uni e si y o Washing on, Sea le, WA, USA 154 Ge man Cance Resea ch Cen e , Di ision o Cance Epidemiology, Heidelbe g, Ge many 155 Depa men o Obs e ics and Gynecology, Uni e si y o Ulm, Ulm, Ge many 156 Depa men o Gynecological Oncology, Roswell Pa k Cance Ins i u e, Bu alo, NY 157 Cance Epidemiology P og am, Uni e si y o Hawaii Cance Cen e , Hawaii, USA 158 Depa men o Pa hology, Kapiolani Medical Cen e o Women and Child en, John A. Bu ns School o Medicine, Uni e si y o Hawaii, Honolulu, Hawaii 96826, USA 159 Cance P e en ion and Con ol, Samuel Oschin Comp ehensi e Cance Ins i u e, Ceda s-Sinai Medical Cen e , Los Angeles, Cali o nia, USA 160 Communi y and Popula ion Heal h Resea ch Ins i u e, Depa men o Biomedical Sciences, Ceda s-Sinai Medical Cen e , Los Angeles, Cali o nia, USA 161 Depa men o Gynecology and Obs e ics, F ied ich Schille Uni e si y, Jena Uni e si y Hospi al, Jena, Ge many 162 Clinics o Obs e ics and Gynaecology, Hanno e Medical School, Hanno e , Ge many 163 Depa men o Pa hology, Helsinki Uni e si y Cen al Hospi al, Helsinki, 00029 HUS, Finland 164 Uni e si y o Pi sbu gh Depa men o Obs e ics, Gynecology and Rep oduc i e Sciences and O a ian Cance Cen e o Excellence Pi sbu gh PA USA 165 Uni e si y o Pi sbu gh Depa men o Epidemiology, Uni e si y o Pi sbu gh G adua e School o Public Heal h and Womens Cance Resea ch P og am, Magee- Womens Resea ch Ins i u e and Uni e si y o Pi sbu gh Cance Ins i u e Pi sbu gh PA USA 166 The Uni e si y o Texas School o Public Heal h, Hous on, TX, USA 167 Depa men o Cance P e en ion and Con ol, Roswell Pa k Cance Ins i u e, Bu alo, NY 168 Depa men o Gynecology and Gynecologic Oncology, Kliniken Essen-Mi e/ E ang. Huyssens-S i ung/ Knappscha GmbH, Essen, Ge many 169 Depa men o Gynecology and Gynecologic Oncology, D . Ho s Schmid Kliniken Wiesbaden, Wiesbaden, Ge many 170 Tuebingen Uni e si y Hospi al, Depa men o Women’sHeal h,Tuebingen, Ge many 171 Women’s Cance P og am a he Samuel Oschin Comp ehensi e Cance Ins i u e, Ceda s-Sinai Medical Cen e , Los Angeles, Cali o nia 172 Depa men o Vi us, Li es yle and Genes, Danish Cance Socie y Resea ch Cen e , Copenhagen, Denma k 173 Depa men o Obs e ics and Gynecology, Rigshospi ale , Copenhagen, Denma k 174 Molecula Uni , Depa men o Pa hology, He le Hospi al, Uni e si y o Copenhagen, Copenhagen, Denma k 175 Uni o Medical Gene ics, Depa men o P e en i e and P edic i e Medicine, Fondazione IRCCS Is i u o Nazionale dei Tumo i (INT), Milan, I aly 176 Di ision o Cance P e en ion and Gene ics, Is i u o Eu opeo di Oncologia (IEO), Milan, I aly 177 Depa men o Expe imen al Oncology, Is i u o Eu opeo di Oncologia (IEO), Milan, I aly and Cogen ech Cance Gene ic Tes Labo a o y, Milan, I aly 178 Uni e si y o Kansas Medical Cen e , Kansas Ci y, KS, USA 179 Depa men o Medical Oncology, Mayo Clinic, Roches e , Minneso a, USA 180 College o Pha macy and Heal h Sciences, Texas Sou he n Uni e si y, Hous on, Texas, USA 181 Depa men o Gynecologic Oncology, The Uni e si y o Texas MD Ande son Cance Cen e , Hous on, Texas, USA 182 Depa men o Epidemiology, The Uni e si y o Texas MD Ande son Cance Cen e , Hous on, Texas, USA 183 Gynecology Se ice, Depa men o Su ge y, Memo ial Sloan-Ke e ing Cance Cen e , New Yo k, NY, USA 184 Depa men o Obs e ics and Gynecology, Duke Uni e si y Medical Cen e , Du ham, No h Ca olina, USA 185 Depa men o S a is ical Science, Duke Uni e si y, Du ham, No h Ca olina, USA 186 Depa men o Su ge y, Duke Uni e si y Medical Cen e , Du ham, No h Ca olina, USA 187 Cance P e en ion, De ec ion & Con ol Resea ch P og am, Duke Cance Ins i u e, Du ham, No h Ca olina, USA 188 Obs e ics and Gynecology Epidemiology Cen e , B igham and Women’sHospi al, Bos on, Massachuse s, USA 189 Channing Di ision o Ne wo k Medicine, B igham and Women’sHospi aland Ha a d Medical School 190 Depa men o Epidemiology, Ha a d TH Chan School o Public Heal h, Bos on, Massachuse s, USA 191 Cance P e en ion and Con ol P og am, Ru ge s Cance Ins i u e o New Je sey, The S a e Uni e si y o New Je sey, New B unswick, NJ, USA 192 Depa men o Epidemiology and Bios a is ics, Memo ial Sloan Ke e ing Cance Cen e , New Yo k, NY, USA 193 Depa men o Gynecology and Obs e ics, Haukeland Uni e si y Ho pi al, Be gen, No way 194 Cen e o Cance Bioma ke s, Depa men o Clinical Sciences, Uni e si y o Be gen, Be gen, No way 808 Sou hey MC, e al.J Med Gene 2016;53:800–811. doi:10.1136/jmedgene -2016-103839 Cance gene ics g oup.bmj.com on No embe 29, 2016 - Published by h p://jmg.bmj.com/Downloaded om