A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.
BACKGROUND
defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk.


METHODS
MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study.


RESULTS
all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77).


CONCLUSIONS
overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.
Colon Cancer Genetics Group and Academic Coloproctology, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
E
E
Theodoratou
H
H
Campbell
A
A
Tenesa
R
R
Houlston
E
E
Webb
S
S
Lubbe
P
P
Broderick
S
S
Gallinger
E M
EM
Croitoru
M A
MA
Jenkins
A K
AK
Win
S P
SP
Cleary
T
T
Koessler
P D
PD
Pharoah
S
S
Küry
S
S
Bézieau
B
B
Buecher
N A
NA
Ellis
P
P
Peterlongo
K
K
Offit
L A
LA
Aaltonen
S
S
Enholm
A
A
Lindblom
X-L
XL
Zhou
I P
IP
Tomlinson
V
V
Moreno
I
I
Blanco
G
G
Capellà
R
R
Barnetson
M E
ME
Porteous
M G
MG
Dunlop
S M
SM
Farrington
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors
D045647:DNA Glycosylases; C061738:mutY adenine glycosylase