Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3.
BACKGROUND
MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.


OBJECTIVE
To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.


METHODS
Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in approximately 300 population controls.


RESULTS
Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases.


CONCLUSIONS
Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.
Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
A R
AR
Dallosso
S
S
Dolwani
N
N
Jones
S
S
Jones
J
J
Colley
J
J
Maynard
S
S
Idziaszczyk
V
V
Humphreys
J
J
Arnold
A
A
Donaldson
D
D
Eccles
A
A
Ellis
D G
DG
Evans
I M
IM
Frayling
F J
FJ
Hes
R S
RS
Houlston
E R
ER
Maher
M
M
Nielsen
S
S
Parry
E
E
Tyler
V
V
Moskvina
J P
JP
Cheadle
J R
JR
Sampson
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D045647:DNA Glycosylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000235:genetics; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D012042:Registries
D009363:Neoplasm Proteins; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes