A novel germline CHEK2 deletion truncating the kinase domain identified in a French family with high-risk of breast/ovarian cancer

Abstract

To the Editor, Five to ten percent of breast and ovarian cancers are mainly due to hereditary mutations in the two susceptibility genes, BRCA1 and BRCA2. In addition to these highpenetrance genes, other genes have been reported to confer moderate risks to develop breast/ovarian cancer [1–4]. Among these lowor moderate-susceptibility alleles, the checkpoint kinase 2 (CHEK2) gene has been involved in inherited cancer susceptibility, first in Li-Fraumeni families [5], and then in families with breast and ovarian aggregation [1]. CHEK2 encodes for a cell-cycle checkpoint kinase involved in the cellular response to DNA, through cell cycle and cell death regulation. Several variants of this gene have been successively identified as SNP [6–8]; small [5] or large genomic deletions [9]. Despite its low frequency, the c.1100delC CHEK2 mutation has been the most extensively studied in populations. This mutation results in an approximatively two fold increase of breast cancer in women [1, 10] but there was some evidence of a higher prevalence of CHEK2 c.1100delC among cases with a first-degree relative affected with breast cancer [10] or in families with a case of male breast cancer [1, 11]. More recently, a meta-analysis of 16 different studies demonstrated that CHEK2 c.1100DelC heterozygosity increases the risk of breast cancer three to five-fold with a 37% risk of developing breast cancer before the age 70 years if positive [12]. Considering these results, to complete the screening of predisposition genes for our high risk breast/ ovarian cancer patients, we investigated the presence of c.1100DelC mutation in our population of BRCA1/BRCA2 negative high breast/ovarian cancer risk patients. Breast/ovarian cancer families were ascertained after genetic counselling at the Institute Claudius Regaud in Toulouse in the south of France. All the 392 affected index patients entering this study have been tested for BRCA1 and BRCA2 germline mutations and present neither mutation in the coding exons of the genes including flanking intron–exon boundaries nor large rearrangements. DNA from peripheral blood was isolated as described earlier [13]. Primers (50-TTAATTTAAGCAAATTAAAT GTC -30 for forward primer and 50-GAATAACTCCTAAACTCCAGC-30 for reverse primer) were used to amplify the CHEK2 exon 10 coding region carrying the c.1100 DelC mutation (Genbank accession number AF086904.1). Sequencing was performed using the Big DyeTerminator v3.1 Cycle Sequencing Kit (Applied Biosystems) in an automated Sequencer ABI Prism 3100 (Applied Biosystems). We investigated the presence of the c.1100DelC mutation on CHEK2 exon10 in 392 patients from high breast/ P. Escudie S. Monteil-Onteniente G. Favre C. Toulas Laboratoire d’Oncogenetique, Institut Claudius Regaud, Toulouse 31000, France