Prostate Cancer, Hereditary, 2

A number sign (#) is used with this entry because of evidence that susceptibility to hereditary pancreatic cancer-2 (HPC2) is associated with variation in the ELAC2 gene (605367) on chromosome 17p12.

For a general discussion of hereditary prostate cancer, see 176807.

By linkage analysis of a genomewide scan of large Utah pedigrees at high risk for early-onset prostate cancer, Tavtigian et al. (2000, 2001) found evidence of linkage to a 1.5-Mb region on chromosome 17p.

In Utah families at high risk for prostate cancer, Tavtigian et al. (2000, 2001) identified 4 mutations in the ELAC2 gene. In 1 family with 8 prostate cancer cases in 3 generations, an insertion/frameshift mutation (1641insG; 605367.0003) segregated with the disease. In another family, a missense mutation (R781H; 605367.0004) was identified in the proband, who was diagnosed at the age of 50. The mutation was traced back through 4 generations to a man who had affected descendants from 5 wives. Within the generations with phenotype information, there were only 2 unaffected males over age 45 who carried the mutation. In other Utah families at high risk for prostate cancer, Tavtigian et al. (2000, 2001) identified 2 common missense variants in the ELAC2 gene that were associated with a diagnosis of prostate cancer: a ser-to-leu change at amino acid 217 (S217L; 605367.0001), and an ala-to-thr change at amino acid 541 (A541T; 605367.0002).

To investigate the relationship between HPC2 and prostate cancer risk, Xu et al. (2001) performed the following analyses: (1) a linkage study of 6 markers in and around the HPC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer; (2) a mutation screening analysis of all coding exons of the gene in 93 probands with hereditary prostate cancer; and (3) a family-based and population-based association study of common HPC2 missense variants in 159 probands with hereditary prostate cancer, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample or in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the 2 previously reported missense changes, S217L and A541T, were identified by mutation analysis of all HPC2 exons in 93 probands with HPC. Xu et al. (2001) concluded that, considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies, the results could not rule out the possibility of a highly penetrant prostate cancer gene at this locus that segregates in only a small number of pedigrees. Nor could they rule out a prostate cancer modifier gene that confers a lower than reported risk.

In a sample of cases unselected for family history, Rebbeck et al. (2000) studied the relationship of the 2 missense variants identified by Tavtigian et al. (2000) with the probability of having prostate cancer. They studied 359 subjects with prostate cancer and 266 male control subjects matched for age and race. Among control subjects, the thr541 frequency was 2.9%, and the leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was observed only in men who also carried leu217. The probability of having prostate cancer was increased in men who carried the leu217/thr541 variant (odds ratio = 2.37; 95% confidence interval 1.06-5.29). This risk also did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of prostate cancer in the general population studied.

Camp and Tavtigian (2002) performed a metaanalysis indicating that carriage of the thr541 allele, either alone or in combination with carriage of the leu217 allele (605367.0001), is significantly associated with prostate cancer. The summary analysis of leu217 data did not support the original finding of Tavtigian et al. (2001) that homozygotes for leu217 are at increased risk of prostate cancer. A very modest dominant effect may indicate that the best model for leu217 is codominant. The analyses further suggested that the original maximum odds ratio (OR) risk estimates of 3.1 and 2.37 for carriage of thr541 for ELAC2 variants on prostate cancer risk were inflated. An OR of 1.3, which translates to a population-attributable risk of 2%, was considered more realistic. The summary analyses provided convincing evidence for the role of ELAC2 in prostate cancer, suggested moderate familial risk, and estimated that risk genotypes in ELAC2 may cause 2% of prostate cancer in the general population.

Vesprini et al. (2001) investigated whether the S217L and A541T variants could be informative in the prediction of the presence of prostate cancer in men undergoing biopsy for the evaluation of an elevated serum prostate-specific antigen (PSA; 176820) level (4.0 ng/ml or more). They genotyped a control population of unselected women from the same population. The prevalence of the HPC2 A541T allele was similar in men with prostate cancer (6.3%), men with other prostate conditions (6.8%), and healthy women (6.3%). The authors concluded that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.

In a study at the Mayo Clinic, Wang et al. (2001) likewise concluded that alterations in the ELAC2 gene play a limited role in genetic susceptibility to HPC. The frequency of the leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the thr541 variant. Furthermore, they found no association of the joint effects of leu217 and thr541. In a study of Afro-Caribbean males from Tobago, Shea et al. (2002) noted the absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls. They concluded that ELAC2 does not significantly contribute to the elevated prevalence of prostate cancer in this population.