Here, we report the identification of seven further unrelated patients with >100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH: four were homozygous for truncating mutations, two were homozygous for Y165C and one was a Y165C/G382D compound heterozygote.
However, it was recently discovered that biallelic mutations in the BER DNA glycosylase MYH lead to an autosomal recessive syndrome of adenomatous colorectal polyposis and very high colorectal cancer risk.
These results confirm that biallelic MYH mutations confer susceptibility to colorectal cancer but are unlikely to account for more than 3% of early-onset colorectal cancer.
However, the presence of monoallelic germ-line MYH variants was negatively associated with an MSI-high (MSI-H) tumor phenotype, with an incidence of only 1 of 23 (4%) MSI-H CRCs as contrasted with 19 of 69 (28%) non-MSI-H (P=0.02).
The aim of this study was to analyse the incidence of germ-line MYH mutations in selected Portuguese families recorded in a hereditary tumour registry and to evaluate the risk of colorectal cancer in this syndrome.
The Y165C and 1103delC mutations significantly reduce MUTYH protein stability and thus repair activity, whereas the G382D mutation produces dysfunctional protein only suggesting different functional molecular mechanisms by which the MAP phenotype may contribute to the development of CRC.
We show that biallelic MUTYH defects impart a 93-fold (95% CI 42-213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort.
AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect.
In summary, biallelic germline mutations of MYH are unlikely to cause colorectal cancer in patients sharing clinical features with hereditary nonpolyposis colorectal cancer families without mismatch repair defect and therefore cannot fill the molecular diagnostic gap in this subgroup of Bethesda-positive patients.
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.
In addition, three bi-allelic MYH mutation carriers, who eventually developed MYH-associated polyposis, were also identified in families with pedigree structures consistent with dominant inheritance of CRC susceptibility.
Biallelic germline mutations of MUTYH-a gene encoding a base excision repair protein-are associated with an increased susceptibility of colorectal cancer.
The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility.
Multiplex tetra-primer amplification refractory mutation system PCR to detect 6 common germline mutations of the MUTYH gene associated with polyposis and colorectal cancer.
CRC was identified at a mean age of 54 years (range 24-83 years) in families with APC and at 50 years (range 39-70 years) in families with MUTYH (p = 0.29).
The value of MUTYH testing in patients with early onset microsatellite stable colorectal cancer referred for hereditary nonpolyposis colon cancer syndrome testing.
In 2007 it is well established that mutations in DNA repair genes (MLH1, MSH2, MSH6, MYH) and Wnt pathway signal transduction inhibitors (APC) underlie a significant percentage of hereditary CRC susceptibility.