Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.
The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
Authors' Affiliations: The University of Texas School of Public Health, Houston, Texas.
Bridget
B
Charbonneau
Kirsten B
KB
Moysich
Kimberly R
KR
Kalli
Ann L
AL
Oberg
Robert A
RA
Vierkant
Zachary C
ZC
Fogarty
Matthew S
MS
Block
Matthew J
MJ
Maurer
Krista M
KM
Goergen
Brooke L
BL
Fridley
Julie M
JM
Cunningham
David N
DN
Rider
Claudia
C
Preston
Lynn C
LC
Hartmann
Kate
K
Lawrenson
Chen
C
Wang
Jonathan
J
Tyrer
Honglin
H
Song
Anna
A
deFazio
Sharon E
SE
Johnatty
Jennifer A
JA
Doherty
Catherine M
CM
Phelan
Thomas A
TA
Sellers
Starr M
SM
Ramirez
Allison F
AF
Vitonis
Kathryn L
KL
Terry
David
D
Van Den Berg
Malcolm C
MC
Pike
Anna H
AH
Wu
Andrew
A
Berchuck
Aleksandra
A
Gentry-Maharaj
Susan J
SJ
Ramus
Brenda
B
Diergaarde
Howard
H
Shen
Allan
A
Jensen
Janusz
J
Menkiszak
Cezary
C
Cybulski
Jan
J
Lubiłski
Argyrios
A
Ziogas
Joseph H
JH
Rothstein
Valerie
V
McGuire
Weiva
W
Sieh
Jenny
J
Lester
Christine
C
Walsh
Ignace
I
Vergote
Sandrina
S
Lambrechts
Evelyn
E
Despierre
Montserrat
M
Garcia-Closas
Hannah
H
Yang
Louise A
LA
Brinton
Beata
B
Spiewankiewicz
Iwona K
IK
Rzepecka
Agnieszka
A
Dansonka-Mieszkowska
Petra
P
Seibold
Anja
A
Rudolph
Lisa E
LE
Paddock
Irene
I
Orlow
Lene
L
Lundvall
Sara H
SH
Olson
Claus K
CK
Hogdall
Ira
I
Schwaab
Andreas
A
du Bois
Philipp
P
Harter
James M
JM
Flanagan
Robert
R
Brown
James
J
Paul
Arif B
AB
Ekici
Matthias W
MW
Beckmann
Alexander
A
Hein
Diana
D
Eccles
Galina
G
Lurie
Laura E
LE
Hays
Yukie T
YT
Bean
Tanja
T
Pejovic
Marc T
MT
Goodman
Ian
I
Campbell
Peter A
PA
Fasching
Gottfried
G
Konecny
Stanley B
SB
Kaye
Florian
F
Heitz
Estrid
E
Hogdall
Elisa V
EV
Bandera
Jenny
J
Chang-Claude
Jolanta
J
Kupryjanczyk
Nicolas
N
Wentzensen
Diether
D
Lambrechts
Beth Y
BY
Karlan
Alice S
AS
Whittemore
Hoda Anton
HA
Culver
Jacek
J
Gronwald
Douglas A
DA
Levine
Susanne K
SK
Kjaer
Usha
U
Menon
Joellen M
JM
Schildkraut
Celeste Leigh
CL
Pearce
Daniel W
DW
Cramer
Mary Anne
MA
Rossing
Georgia
G
Chenevix-Trench
Paul D P
PD
Pharoah
Simon A
SA
Gayther
Roberta B
RB
Ness
Kunle
K
Odunsi
Lara E
LE
Sucheston
Keith L
KL
Knutson
Ellen L
EL
Goode
D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D053645:Interleukin-2 Receptor alpha Subunit