ATM polymorphisms as risk factors for prostate cancer development

Prostate cancer is the second most common malignancy and the second commonest cause of cancer deaths in men in the European Union, with 143 000 new cases and 60 000 deaths year−1 (GLOBCAN 2000, www-dep.iarc.fr). The aetiology of prostate cancer is poorly understood. Prostate cancer is known to aggregate in families, indicating that genetic susceptibility may be important, but the genes involved are largely unknown. Linkage studies in multiple case families have suggested susceptibility loci on chromosomes 1q24, 1q42, 1p36, 8p22–23, 17p, 20q13 and Xq (see recent reviews by DeMarzo et al, 2003; Gronberg, 2003) but none have been definitively replicated. As a consequence of these linkage studies, variants in prostate cancer families have been identified in several genes including Macrophage Scavenger Receptor 1(MSR1), 2′-5′-oligoadenylate-dependent ribonuclease L (RNASEL) and ELAC2 (chromosome 17p11/HPC2 region) (reviewed in Simard et al, 2003), but again none have been reliably associated with risk. Several independent studies have demonstrated that individuals with germline mutations in BRCA2 are at increased risk of prostate cancer (The Breast Cancer Linkage Consortium, 1999; Edwards et al, 2003; Giusti et al, 2003). There is also some evidence for an increased risk in carriers of BRCA1 mutations (Thompson et al, 2002). More recently, Seppala et al (2003) have found that the CHEK2 variant 1100delC, known to be associated with an increased risk of breast cancer, is also associated with an increased risk of prostate cancer, and Dong et al (2003) found that this and other missense variants in CHEK2 occurred at increased frequency in prostate cancer cases. The proteins encoded by the BRCA1 and BRCA2 genes participate in the maintenance of genomic stability through their involvement in the homologous recombination pathway for the repair of DNA double-strand breaks and transcription coupled repair and the CHEK2 protein is also involved in DNA damage signalling pathways. BRCA1 and CHEK2 are both phosphorylated in response to DNA damage in an ATM-dependent fashion (Matsuoka et al, 2000). Thus, we hypothesised that the ATM gene, whose protein functions upstream of these known susceptibility genes, could also be a mutation target in prostate cancer. In a preliminary study by Hall et al (1998), germline mutations in ATM were identified in three out of 17 (17.6%) prostate cancer patients who showed a severe late response to radiation therapy and in whom most or all of the ATM gene was examined, while no such mutations were found in the control group. In this same study, the 5557G>A ATM sequence variant was found in 35% of cases compared with the reported population frequency of 15%. This variant has been found to modulate the penetrance of hereditary nonpolyposis colorectal cancer in carriers of germline MLH1 and MLH2 mutations (Maillet et al, 2000). Loss of heterozygosity of chromosome 11q, the location of the ATM gene, has also been reported in metastatic prostate carcinoma (Ruijter et al, 1999). In order to assess whether ATM variants play a pathogenic role in prostate cancer development, we compared the frequencies of five ATM single-nucleotide polymorphisms (SNPs) 5557G>A, 5558A>T, 3161C>G, ivs38-8t>c, ivs38-15g>c in 618 British prostate cancer cases and 445 controls. In addition, the cellular phenotype of a lymphoblastoid cell line carrying the 3161G variant allele in a homozygote state was evaluated.