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Genetics of Prostate Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Genes With Potential Clinical Relevance in Prostate Cancer Risk

Table 6. Case-Control Studies ofBRCA1andBRCA2and Survival Outcomes continued...

HOXB13

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[26] Fine-mapping of this region provided strong evidence of linkage (LOD score = 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[33] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins).[34]Probands from four families were discovered to have a recurrent mutation (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the mutation. The mutation status was determined in 5,083 additional case subjects and 2,662 control subjects. Carrier frequencies and odds ratios for prostate cancer risk were as follows:

  • Men with a positive family history of prostate cancer: 2.2% versus negative: 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
  • Men with an age at diagnosis younger than 55 years: 2.2% versus older than 55 years: 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
  • Men with a positive family history of prostate cancer and age at diagnosis younger than 55 years: 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years: 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
  • Men with a positive family history of prostate cancer and age at diagnosis older than 55 years: 1.2%.
  • Control subjects: 0.1% to 0.2%.[34]

Additional rare variants in HOXB13 were also observed. Penetrance estimates of the G84E variant in HOXB13 are under study. HOXB13 plays a role in prostate development and binds to the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene proven to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer, but the clinical utility of testing for this mutation has not yet been defined.

References:

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  19. Agalliu I, Kwon EM, Zadory D, et al.: Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clin Cancer Res 13 (3): 839-43, 2007.
  20. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007.
  21. Kote-Jarai Z, Leongamornlert D, Saunders E, et al.: BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer 105 (8): 1230-4, 2011.
  22. Leongamornlert D, Mahmud N, Tymrakiewicz M, et al.: Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 106 (10): 1697-701, 2012.
  23. Edwards SM, Evans DG, Hope Q, et al.: Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 103 (6): 918-24, 2010.
  24. Thorne H, Willems AJ, Niedermayr E, et al.: Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res (Phila) 4 (7): 1002-10, 2011.
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  28. Douglas JA, Levin AM, Zuhlke KA, et al.: Common variation in the BRCA1 gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (7): 1510-6, 2007.
  29. Soravia C, van der Klift H, Bründler MA, et al.: Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum. Am J Med Genet 121A (2): 159-62, 2003.
  30. Grindedal EM, Møller P, Eeles R, et al.: Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (9): 2460-7, 2009.
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  32. Bauer CM, Ray AM, Halstead-Nussloch BA, et al.: Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer 10 (1): 37-42, 2011.
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  34. Ewing CM, Ray AM, Lange EM, et al.: Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366 (2): 141-9, 2012.
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Last Updated: February 25, 2014
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