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Role of inherited defects of MYH in the development of sporadic colorectal cancer.
- Source :
-
Genes, chromosomes & cancer [Genes Chromosomes Cancer] 2004 May; Vol. 40 (1), pp. 1-9. - Publication Year :
- 2004
-
Abstract
- Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been associated with multiple colorectal adenomas that display somatic G:C-->T:A transversions in APC. However, the effect of single germ-line variants has not been widely studied. To examine the relationship between monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC), 92 cases of sporadic CRC, 19 cases of familial CRC not meeting the Bethesda guidelines, 17 cases with multiple adenomas, and 53 normal blood donors were screened for 8 potentially pathogenic germ-line MYH variants. Loss of heterozygosity (LOH) at 1p adjacent to the MYH locus, microsatellite instability (MSI) status, and somatic mutations in KRAS2 and APC were analyzed in sporadic cancers. Neither homozygote nor compound heterozygote MYH variants were observed in the germ-line of any subjects with sporadic CRC. There was no difference in the incidence of monoallelic variants between this group (20 of 92, 22%) and cancer-free controls (14 of 53, 26%). 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). Further, 4 of 5 tumors with 1p LOH contained monoallelic MYH variants compared with 15 of 53 without 1p LOH (P=0.04) and the normal population (P=0.03). The presence of G:C-->T:A transversions in KRAS2 or APC was significantly more common in single MYH variant tumors (9 of 12) than in MYH wild-type tumors (11 of 33; P=0.02). These results suggest that single germ-line variants of MYH may influence genetic pathways in CRC.<br /> (Copyright 2004 Wiley-Liss, Inc.)
- Subjects :
- Adenoma genetics
Adenomatous Polyposis Coli genetics
Age of Onset
Aged
Colorectal Neoplasms genetics
DNA Glycosylases genetics
Female
Genes, APC
Genetic Predisposition to Disease genetics
Germ-Line Mutation genetics
Humans
Loss of Heterozygosity genetics
Male
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins p21(ras)
Trinucleotide Repeat Expansion genetics
ras Proteins
Adenoma etiology
Adenomatous Polyposis Coli etiology
Colorectal Neoplasms etiology
Germ-Line Mutation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1045-2257
- Volume :
- 40
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Genes, chromosomes & cancer
- Publication Type :
- Academic Journal
- Accession number :
- 15034862
- Full Text :
- https://doi.org/10.1002/gcc.20011