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
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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
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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
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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
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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
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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
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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
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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
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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
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