Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies.
BACKGROUND
Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.


RESULTS
In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association.


CONCLUSIONS
The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.
Elliott
Katherine S
KS
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Zeggini
Eleftheria
E
McCarthy
Mark I
MI
Gudmundsson
Julius
J
Sulem
Patrick
P
Stacey
Simon N
SN
Thorlacius
Steinunn
S
Amundadottir
Laufey
L
Grönberg
Henrik
H
Xu
Jianfeng
J
Gaborieau
Valerie
V
Eeles
Rosalind A
RA
Neal
David E
DE
Donovan
Jenny L
JL
Hamdy
Freddie C
FC
Muir
Kenneth
K
Hwang
Shih-Jen
SJ
Spitz
Margaret R
MR
Zanke
Brent
B
Carvajal-Carmona
Luis
L
Brown
Kevin M
KM
Hayward
Nicholas K
NK
Macgregor
Stuart
S
Tomlinson
Ian P M
IP
Lemire
Mathieu
M
Amos
Christopher I
CI
Murabito
Joanne M
JM
Isaacs
William B
WB
Easton
Douglas F
DF
Brennan
Paul
P
Barkardottir
Rosa B
RB
Gudbjartsson
Daniel F
DF
Rafnar
Thorunn
T
Hunter
David J
DJ
Chanock
Stephen J
SJ
Stefansson
Kari
K
Ioannidis
John P A
JP
D003299:Cooperative Behavior; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta