Abstract
Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.
Highlights
Chk2 (Cds1) is a protein kinase that is involved in cellcycle checkpoint control by phosphorylating Cdc25 phosphatases, which subsequently results in their inhibition [1,2,3,4]
Seventy-four out of 139 (53%) sporadic breast tumors were detected with loss of heterozygosity (LOH) at chromosome 22q
To evaluate whether CHK2 sequence variants could have modifying effects on the phenotype of BRCA2 mutation carriers, these 74 samples and 45 breast tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene using single-strand conformation polymorphism (SSCP) and DNA sequencing
Summary
Chk (Cds1) is a protein kinase that is involved in cellcycle checkpoint control by phosphorylating Cdc phosphatases, which subsequently results in their inhibition (i.e. degradation or export from the nucleus) [1,2,3,4]. Chk is activated on DNA damage by phosphorylation signaling from the Atm kinase [8,9,10,11,12,13]. Chk is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. Methods: We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. Results: Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del mutation were screened for mutations in the CHK2 gene. Our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth
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