EDITOR—Prostate cancer is the second most common cause of male cancer mortality in the UK. 1 Current indications are that like many common cancers, prostate cancer has an inherited component. 2 Segregation analysis has led to the proposed model of at least one highly penetrant, dominant gene (with an estimated 88% penetrance for prostate cancer by the age of 85 in the highly susceptible population). Such a gene or genes would account for an estimated 43% of cases diagnosed at less than 55 years. 2 One prostate cancer susceptibility locus (HPC1) has been reported on 1q24-253 and confirmed by Cooney et al4 and Gronberg et al. 5 Latest estimates suggest that this locus would only account for 4% of families overall in the UK (upper 95% confidence interval (CI) limit of 31%). 6 Another locus has been reported on 1q42. 2-43 after a genome wide search of 47 French and German families. 7 This locus is estimated to explain 50% of these families and appears to be distinct from the HPC1 locus as the two are estimated to be 60 cM apart. Confirmatory studies of this second locus have not yet been reported. A third locus has been reported. This locus, situated on the X chromosome, is estimated to explain approximately 16% of the families studied (including the families which were first typed to map the 1q24 locus). 8 The heterogeneity lod score for linkage to this locus is 3.85 with the strongest evidence being a locus in proximity to the markers DXS297 and DXS1200. While linkage studies have not identified chromosome 10 as the site of a predisposing gene, the long arm of chromosome 10 is the fourth commonest region showing loss of heterozygosity (LOH) in sporadic prostate cancers after 7q, 8p, and 16q. 9 Deletion mapping studies have identified 10q23 to be the minimal region of loss. 10–12 One candidate gene which maps adjacent to this region, MXI1, has been assessed for a role in familial prostate cancer susceptibility but no germline mutations were identified. 13 PTEN/MMAC1 (Phosphatase and Tensin homologue deleted on chromosome Ten/Mutated in Multiple Advanced Cancers 1), a tumour suppressor gene, has recently been identified at 10q23 through mapping of homozygous deletions in tumour cell lines. 14–16 Li et al14 15 and Steck et al16 found PTEN mutations in four out of four and one out of three prostate cancer cell lines respectively, suggesting a role in prostate carcinogenesis. 15 16 Cairns et al17 found LOH at 10q in 23 of 80 prostate tumours. Sequencing identified a mutation in PTEN in 10 of these 23 tumours (43%). 17 More recently, Wang et al18 found that of 60 prostate adenocarcinomas, 10-15% of primary stage B prostate carcinomas had PTEN inactivation by homozygous deletion. A number of studies have examined the frequency of somatic mutations in this gene. For instance, somatic mutations have been found in glioblastomas, melanomas, and breast and prostate carcinomas. 15 16 Germline mutations in PTEN have been shown to be the cause of Cowden disease, 19 20 while PTEN deficient mice (PTEN+/-) show hyperplastic and dysplastic changes in the prostate and indeed develop prostate cancer. 21 22 We hypothesised that germline PTEN mutations could be important in familial prostate cancer for the following three reasons: somatic mutations have been found in PTEN in prostate tumours; germline mutations in Cowden disease produce a phenotype (although with no evidence of an associated susceptibility to prostate cancer); and PTEN deficient mice exhibit prostate abnormalities. We have therefore screened the Cancer Research Campaign/British Prostate Group (CRC/BPG) UK Familial …