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.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Katherine S
KS
Elliott
Eleftheria
E
Zeggini
Mark I
MI
McCarthy
Julius
J
Gudmundsson
Patrick
P
Sulem
Simon N
SN
Stacey
Steinunn
S
Thorlacius
Laufey
L
Amundadottir
Henrik
H
Grönberg
Jianfeng
J
Xu
Valerie
V
Gaborieau
Rosalind A
RA
Eeles
David E
DE
Neal
Jenny L
JL
Donovan
Freddie C
FC
Hamdy
Kenneth
K
Muir
Shih-Jen
SJ
Hwang
Margaret R
MR
Spitz
Brent
B
Zanke
Luis
L
Carvajal-Carmona
Kevin M
KM
Brown
Nicholas K
NK
Hayward
Stuart
S
Macgregor
Ian P M
IP
Tomlinson
Mathieu
M
Lemire
Christopher I
CI
Amos
Joanne M
JM
Murabito
William B
WB
Isaacs
Douglas F
DF
Easton
Paul
P
Brennan
Rosa B
RB
Barkardottir
Daniel F
DF
Gudbjartsson
Thorunn
T
Rafnar
David J
DJ
Hunter
Stephen J
SJ
Chanock
Kari
K
Stefansson
John P A
JP
Ioannidis
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