Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.
OBJECTIVE
Biallelic mutations in the base excision DNA repair gene MUTYH lead to MUTYH-associated polyposis (MAP) and predisposition to colorectal cancer (CRC). Functional studies have demonstrated significant differences in base recognition and glycosylase activity between various MUTYH mutations, notably for the 2 mutations most frequently reported in MAP patients: Y179C and G396D (previously annotated as Y165C and G382D). Our goal was to establish correlations between genotypes and colorectal phenotype of patients with MAP.


METHODS
In this multicenter study, we analyzed genotype and phenotype data from 257 MAP patients. Data included age at presentation of MAP, polyp count, and the occurrence, location, and age at presentation of CRC.


RESULTS
Patients with a homozygous G396D mutation or compound heterozygous G396D/Y179C mutations presented later with MAP and had a significantly lower hazard of developing CRC than patients with a homozygous Y179C mutation (P < .001). The mean ages of CRC diagnosis in patients were 58 years (homozygous G396D) and 52 years (compound heterozygous G396D/Y179C) versus 46 years (homozygous Y179C; P = .001, linear regression).


CONCLUSIONS
Our study identified the phenotypic effects of Y179C as relatively severe and of G396D as relatively mild. These clinical data are in accord with findings from in vitro functional assays. Genotypic stratification may become useful in the development of guidelines for counseling, surveillance, and management of families with MAP.
Nielsen
Maartje
M
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. m.nielsen@lumc.nl
Joerink-van de Beld
Mirjam C
MC
Jones
Natalie
N
Vogt
Stefanie
S
Tops
Carli M
CM
Vasen
Hans F A
HF
Sampson
Julian R
JR
Aretz
Stefan
S
Hes
Frederik J
FJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D044483:Intestinal Polyposis / Q000235:genetics* / Q000473:pathology*; D016014:Linear Models; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012007:Rectum / Q000473:pathology*; D055815:Young Adult
D045647:DNA Glycosylases; C061738:mutY adenine glycosylase