HPC2 variants and screen-detected prostate cancer.
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ABSTRACT:
SUBMITTER: Vesprini D
PROVIDER: S-EPMC1275645 | biostudies-literature | 2001 Apr
REPOSITORIES: biostudies-literature
Publications
HPC2 variants and screen-detected prostate cancer.
Vesprini D D Nam R K RK Trachtenberg J J Jewett M A MA Tavtigian S V SV Emami M M Ho M M Toi A A Narod S A SA
American journal of human genetics 20010314 4
Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our in ...[more]
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Project description:HPC2/ELAC2 has been identified as a prostate cancer (CaP) susceptibility gene. Two common missense variants in HPC2/ELAC2 have been identified: a Ser-->Leu change at amino acid 217, and an Ala-->Thr change at amino acid 541. Tavtigian et al. reported that these variants were associated with CaP in a sample of men drawn from families with hereditary CaP. To confirm this report in a sample unselected for family history, we studied 359 incident CaP case subjects and 266 male control subjects that were frequency matched for age and race and were identified from a large health-system population. 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 only observed in men who also carried Leu217. The probability of having CaP was increased in men who carried the Leu217/Thr541 variants (odds ratio = 2.37; 95% CI 1.06-5.29). This risk did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of CaP in the general population of inference. These results suggest that common variants at HPC2/ELAC2 are associated with CaP risk in a sample unselected for family history or other factors associated with CaP risk.
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Project description:PURPOSE:Shared patient-physician decision making regarding the treatment of prostate cancer detected by prostate specific antigen screening involves a complex calculus weighing cancer risk and patient life expectancy. We sought to quantify these competing risks using the probability that the cancer was over diagnosed, ie would not have been clinically diagnosed (diagnosed without screening) during the remaining lifetime of the patient. MATERIALS AND METHODS:Using an established model of prostate cancer screening and clinical diagnosis we simulated screen detected cases and determined whether a modeled clinical diagnosis would occur before noncancer death. Time of noncancer death was based on comorbidity adjusted population lifetables. Logistic regression models were fitted to the simulated data and used to estimate over diagnosis probabilities given patient age, prostate specific antigen level, Gleason sum and comorbidity category. An online calculator was developed to communicate over diagnosis estimates. Face validity and ease of use were assessed by surveying 32 clinical experts. RESULTS:Estimated probabilities of over diagnosis ranged from 4% to 78% across clinicopathological variables and comorbidity status. When ignoring comorbidity, the estimated probability of over diagnosis in a 70-year-old man with prostate specific antigen 9.4 ng/ml and Gleason 6 was 34%. With severe comorbidities the estimate increased to 51%. Such a personalization may help inform the choice between active surveillance and definitive treatment. Based on responses from 20 of 32 experts we modified the explanation of over diagnosis for the online calculator and the input method for comorbid conditions. CONCLUSIONS:The probability of over diagnosis is strongly influenced by comorbidity status in addition to age. Personalized estimates incorporating comorbidity may contribute to shared decision making between patients and providers regarding personalized treatment selection.
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Project description:To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor 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 two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.
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Project description:BACKGROUND: The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation. METHODS: We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro. RESULTS: We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (?Thr656Ile) and gamma (?Pro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3' end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p?=?0.009, OR?=?1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p?=?0.042, OR?=?1.23). The obesity risk-alleles at Thr484Ala and ?Thr656Ile/?Pro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants ? and ?. CONCLUSION: The rare coding mutation ?Thr656Ile/?Pro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.
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