Locked Nucleic Acid-Enhanced Detection of 1100delC*CHEK2 Germ-Line Mutation in Spanish Patients with Hematologic Malignancies

Abstract

The prediction that there might be common DNA sequence variants that confer a small but appreciably enhanced risk of cancer has been validated with the discovery of the germ-line mutation 1100delC in the cell cycle checkpoint kinase gene ( CHEK2 ; OMIM 604373) (1)(2). CHEK2 is located on chromosome 22q and encodes the human ortholog of yeast Cds1 and Rad53, which are G2-checkpoint kinases (3). CHEK2 is a protein kinase activated in response to DNA damage involved in cell-cycle arrest. It serves as a link in the ATM-CHEK2-CDC25A-CDK2 pathway that checks genomic integrity in response to DNA damage (4). The 1100delC mutation in exon 10 abolishes the kinase function of CHEK2 (5) and has been reported in patients with Li–Fraumeni syndrome in the United States and in Finnish families with a cancer phenotype suggestive of Li–Fraumeni syndrome, including breast cancer (5). There have been recent reports of a higher incidence of the 1100delC mutated allele in patients with a family history of breast cancer who are not carriers of BRCA1 (OMIM 113705) or BRCA2 (OMIM 600185) mutations, compared with healthy controls (4.2% and 5.5% in breast cancer cases vs 1.4% and 1.1% in controls, respectively) (1)(6). The presence of the mutated allele approximately doubles the breast cancer risk in women and increases it 10-fold in men (1). It has also been reported that 4.8% of individuals with familial prostate cancer are carriers of distinct CHEK2 germ-line mutations (7). These mutations may contribute to prostate cancer risk, highlighting the importance of the integrity of DNA damage-signaling pathways in the development of prostate cancer. The few reports for patients with hematologic malignancies have been concerned mainly with CHEK2 somatic mutations (8)(9)(10). Thus, in a series of 109 patients with leukemia and myelodysplastic …