ORPHA: 1331;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq12 | {Prostate cancer, susceptibility to} | 301120 | X-linked | 3 | AR | 313700 |
A number sign (#) is used with this entry because of evidence that susceptibility to X-linked hereditary prostate cancer-3 (HPCX3) can be conferred by germline or somatic mutation in the androgen receptor gene (AR; 313700) on chromosome Xq12.
Genetic predisposition to prostate cancer has been well established. The androgen receptor gene became a compelling candidate for the study of prostate cancer because of the essential role that androgens play in prostate development, growth, and maintenance (Chang et al., 2002).
For a general discussion of hereditary prostate cancer, see 176807.
Goddard et al. (2001) detected linkage near 3 locations for prostate cancer: 1q24-q25, 1q42.2-q43, and Xq12-q13.
Cui et al. (2001) conducted single- and 2-locus segregation analyses of data from 1,476 men with prostate cancer diagnosed under the age of 70 years and ascertained through population registers in Australia, together with brothers, fathers, and both maternal and paternal lineal uncles. All 2-locus models gave better fits than did single-locus models, even if lineal uncles were excluded. The best-fitting genetic models included a dominantly inherited increased risk that was greater, in multiplicative terms, at younger ages, as well as a recessively inherited or X-linked increased risk that was greater, in multiplicative terms, at older ages. Penetrance to age 80 years was approximately 70% for the dominant effect and virtually 100% for the recessive and X-linked effects.
In a prostate cancer patient from northern Finland, Elo et al. (1995) identified an arg726-to-leu mutation in the AR gene (R726L; 313700.0047). Koivisto et al. (1999) found the same mutation in another Finnish prostate cancer patient when screening for AR mutations by single-strand conformation polymorphism in 6 patients whose cancers appeared during finasteride treatment for benign prostatic hyperplasia. The R726L mutation affected the hormone-binding region in exon E and led to activation of the androgen receptor not only by dihydrotestosterone and testosterone but also by estradiol.
Mononen et al. (2000) analyzed the frequency of the AR R726L mutation in over 1,400 specimens from blood donors, 418 consecutive prostate cancer patients with no family history of prostate cancer, and 106 patients with a positive family history of prostate cancer. Its frequency in blood donors was 3 in 900 (0.33%). In contrast, 8 (1.91%) mutations were found in the prostate cancer group without family history, and 2 mutations (1.89%) were found in the hereditary group. Mononen et al. (2000) suggested that the R726L substitution may confer up to 6-fold increased risk of prostate cancer and may contribute to cancer development in up to 2% of Finnish prostate cancer patients.
Somatic Mutations
In 1 of 26 specimens of untreated organ-confined stage B prostate cancer, Newmark et al. (1992) identified a somatic mutation in the AR gene (313700.0013) in a highly conserved region within the hormone-binding domain. An abundance of the mutated fragment indicated its presence in cells with a growth advantage. The authors postulated that somatic mutation in the AR gene leading to persistent expression could give rise to androgen-independent prostate cancer.
Associations Pending Confirmation
The length of a polymorphic CAG repeat sequence occurring in the androgen receptor gene is inversely correlated with transcriptional activity by the androgen receptor. Prostate carcinogenesis is dependent on androgens. Because shorter CAG repeat lengths are associated with high transcriptional activity of AR, Irvine et al. (1995) proposed that men with shorter repeat lengths will be at higher risk for prostate cancer. Some indirect evidence is consistent with this hypothesis. African Americans, who have generally shorter CAG repeat lengths in the AR gene, have a higher incidence and mortality rate from prostate cancer (Coetzee and Ross, 1994). Moreover, because of X linkage, a history of disease in a brother carries greater risk than paternal history. Against this background, Giovannucci et al. (1997) conducted within the Physician's Health Study a nested case-controlled study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer. They found an association between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension, distant metastases, or high histologic grade. Variability in the CAG repeat length was not associated with low-grade or low-stage disease.
To test for an association between clinical parameters of human prostate cancer and CAG repeat length, Hardy et al. (1996) analyzed normal lymphocyte DNA from 109 patients. The median age of patients was 63 years (range, 42 to 83), with 104 Caucasian, 2 African American, 1 Asian, and 2 of other racial origin. The median repeat length was 25, 22, 22, and 23 for patients presenting with stage A, B, C, and D disease, respectively. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age.
Chang et al. (2002) found significantly increased frequencies of AR alleles carrying 16 or less GGC repeats in 159 independent hereditary prostate cancer cases (71%) and 245 sporadic prostate cancer cases (68%) compared with 211 controls (59%). No evidence for association between CAG repeats and prostate cancer risk was observed. Similar results were found with a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test.
Chang, B., Zheng, S. L., Hawkins, G. A., Isaacs, S. D., Wiley, K. E., Turner, A., Carpten, J. D., Bleecker, E. R., Walsh, P. C., Trent, J. M., Meyers, D. A., Isaacs, W. B., Xu, J. Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Hum. Genet. 110: 122-129, 2002. [PubMed: 11935317] [Full Text: https://doi.org/10.1007/s00439-001-0662-6]
Coetzee, G. A., Ross, R. K. Re: Prostate cancer and the androgen receptor. (Letter) J. Nat. Cancer Inst. 86: 872-873, 1994. [PubMed: 8182772] [Full Text: https://doi.org/10.1093/jnci/86.11.872]
Cui, J., Staples, M. P., Hopper, J. L., English, D. R., McCredie, M. R. E., Giles, G. G. Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am. J. Hum. Genet. 68: 1207-1218, 2001. [PubMed: 11309686] [Full Text: https://doi.org/10.1086/320114]
Elo, J. P., Kvist, L., Leinonen, K., Isomaa, V., Hentuu, P., Lukkarinen, O., Vihko, P. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol. J. Clin. Endocr. Metab. 80: 3494-3500, 1995. [PubMed: 8530589] [Full Text: https://doi.org/10.1210/jcem.80.12.8530589]
Giovannucci, E., Stampfer, M. J., Krithivas, K., Brown, M., Dahl, D., Brufsky, A., Talcott, J., Hennekens, C. H., Kantoff, P. W. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Nat. Acad. Sci. 94: 3320-3323, 1997. Note: Erratum: Proc. Nat. Acad. Sci. 94: 8272 only, 1997. [PubMed: 9096391] [Full Text: https://doi.org/10.1073/pnas.94.7.3320]
Goddard, K. A. B., Witte, J. S., Suarez, B. K., Catalona, W. J., Olson, J. M. Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am. J. Hum. Genet. 68: 1197-1206, 2001. [PubMed: 11309685] [Full Text: https://doi.org/10.1086/320103]
Hardy, D. O., Scher, H. I., Bogenreider, T., Sabbatini, P., Zhang, Z.-F., Nanus, D. M., Catterall, J. F. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J. Clin. Endocr. Metab. 81: 4400-4405, 1996. [PubMed: 8954049] [Full Text: https://doi.org/10.1210/jcem.81.12.8954049]
Irvine, R. A., Yu, M. C., Ross, R. K., Coetzee, G. A. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. 55: 1937-1940, 1995. [PubMed: 7728763]
Koivisto, P. A., Schleutker, J., Helin, H., Ehren-van Eekelen, C., Kallioniemi, O.-P., Trapman, J. Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia. Clin. Cancer Res. 5: 3578-3582, 1999. [PubMed: 10589774]
Mononen, N., Syrjakoski, K., Matikainen, M., Tammela, T. L. J., Schleutker, J., Kallioniemi, O.-P., Trapman, J., Koivisto, P. A. Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene. Cancer Res. 60: 6479-6481, 2000. [PubMed: 11103816]
Newmark, J. R., Hardy, D. O., Tonb, D. C., Carter, B. S., Epstein, J. I., Isaacs, W. B., Brown, T. R., Barrack, E. R. Androgen receptor gene mutations in human prostate cancer. Proc. Nat. Acad. Sci. 89: 6319-6323, 1992. [PubMed: 1631125] [Full Text: https://doi.org/10.1073/pnas.89.14.6319]