Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization.
OBJECTIVE
Biallelic mutations in the base-excision repair gene MYH have recently been associated with recessive inheritance of multiple colorectal adenomas. An investigation and characterization of MYH mutations in Swedish patients were therefore carried out.


METHODS
A set of 15 unrelated adenomatous polyposis coli (APC)-mutation negative patients from the Swedish Polyposis Registry was screened for germline mutations in the MYH gene. The patients were clinically characterized and compared with 43 APC-mutation positive probands diagnosed during the same period.


RESULTS
Disease-causing biallelic MYH mutations were identified in 6 patients (40%). The mean age at diagnosis was 47.8 years versus 34.1 years in APC-mutation positive patients (P = .015). Colorectal cancer at diagnosis of polyposis was present in 67% (4/6) of the patients, and all were right-sided, compared with only 19% versus 12.5% right-sided cancer in APC-mutation positive patients. Upper gastrointestinal manifestations were diagnosed in 1 of 5 compared with 23 of 27 in APC-mutation positive patients (odds ratio, 23; 95% confidence interval, 2-263; P = .0086). One family exhibited apparent dominant inheritance of colorectal adenomatous polyposis. Two new pathogenic mutations, MYH p.G175E and p.P391L, were identified. The mutations are argued to introduce profound changes in substrate-recognizing domains of the protein.


CONCLUSIONS
Biallelic MYH mutations, including 2 novel mutations, were found in a substantial number of the patients with multiple colorectal adenomas who were negative for APC-mutation. The examined MYH-mutation positive patients were found to have higher risks of colorectal cancer at diagnosis, right-sided location of cancers, and a significantly lower incidence of upper gastrointestinal manifestations, compared with APC-mutation positive patients.
Kanter-Smoler
Gunilla
G
Department of Clinical Genetics, Göteborg University, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden.
Björk
Jan
J
Fritzell
Kaisa
K
Engwall
Yvonne
Y
Hallberg
Birgitta
B
Karlsson
Göran
G
Grönberg
Henrik
H
Karlsson
Per
P
Wallgren
Arne
A
Wahlström
Jan
J
Hultcrantz
Rolf
R
Nordling
Margareta
M
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000367:Age Factors; D000368:Aged; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011379:Prognosis; D013548:Sweden
D045647:DNA Glycosylases; C061738:mutY adenine glycosylase