FaCD Online Syndrome Fact Sheet

Last updated: 06 Mar 2013

Name: Hereditary Prostate Cancer

Synonym: HPC

Mode of Inheritance: AD / XL

OMIM number: 176807  

Genes

BRCA2, mapped to 13q12.3
CAPB/PCBC/EPHB2, mapped to 1p36
EHBP1/HPC12, mapped to 2p15
ELAC2/HPC2, mapped to 17p11
HNF1B/HPC11, mapped to 17q12
HOXB13, mapped to 17q21.2
HPC1/HPT1/PRCA1/RNASEL, mapped to 1q25
HPC10, mapped to 8q24
HPC14, mapped to 11q13
HPC15, mapped to 19q13.4
HPC3, mapped to 20q13
HPC4, mapped to 7p11-q21
HPC5, mapped to 3p26
HPC6, mapped to 22q12.3
HPC7, mapped to 15q12
HPC9, mapped to 17q21-q22
HPCX1, mapped to Xq27-q28
HPCX2, mapped to Xp11.22
MSMB/HPC13, mapped to 10q11.2
PCA3/DD3, mapped to 9q21-q22
PCAP/HPC8, mapped to 1q42.2-q43

Tumor features

prostate cancer

Tumor features (possible)

brain tumor
breast cancer
gastric cancer
renal cell cancer

Comment

Based on the study of families with a striking clustering of prostate cancer, it has been proposed that a subset of families exists with a strong hereditary predisposition to develop his tumor[1-4]. The name Hereditary Prostate Cancer (HPC) has been coined to refer to this condition[1]. The HPC gene is postulated to confer a cumulative risk of developing prostate cancer of approximately 90 % at age 85[1;5] (although an estimate of 63 % has also been suggested[3]), and should be responsible for 43 % of all prostate cancer cases diagnosed before the age of 65 and 9 % of cases before the age of 86[1]. In general, 5-10 % of prostate cancer cases are thought to be hereditary.

Clinical HPC Criteria used for research purposes (would need to be adjusted given the evidence for X-linked loci):

  • 1) three or more affected individuals within one nuclear family, or
  • 2) affected individuals occurring in three successive generations, or
  • 3) a cluster of two or more relatives, each affected before the age of 55 years.


In HPC families, tumors other than prostate cancer are not found at increased frequency, possibly except for brain tumors, breast cancer and renal cancer[6-9]. There is no significant difference in clinical and pathological parameters compared to sporadic prostate cancer cases, with the possible exception of relatively early age of onset and lower Gleason scores in HPC[6;10-14]. Kupelian et al.[15] showed that familial prostate cancer, defined as a patient plus a first-degree affected relative, may have a more aggressive course than nonfamilial prostate cancer. However, no survival differences between sporadic, familial and hereditary prostate cancer were found by Grönberg et al.[16]. Also, Bova et al.[17] found no difference in biochemical relapses following radical prostatectomy between familial prostate cancer patients, including HPC cases, and prostate cancer patients without a family history of prostate cancer. However, these conclusions may not hold true for subsets of patients linked with a specific locus. For example, in families specifically linking to the HPC1 locus, younger age at diagnosis, higher-grade tumors and more advanced-stage disease have been observed[18]and familial prostate cancer linked to markers on 8q24 is associated with early onset or clinically aggressive disease[26].

Genetically, HPC is very heterogeneous[e.g. see 24,25] and a wide range of moderate genetic risk factors have been identified (not listed separately in this syndrome file). Identifying a highly penetrant prostate cancer sucseptibility gene has proven to be difficult in general and in the subset of families with aggressive clinical disease[23]. It has been suggested that BRCA2 mutations may account for about 5% of familial prostate cancer[19] and 2% of British cases diagnosed before the age of 56 years[20] and less than 1% in similar American Caucasian cases[21]. Another study could not confirm a role for BRCA2 in high risk prostate cancer families[22]. More recently the HOXB13 G84E germline mutation has been shown to be associated with cumulative prostate cancer risks of up to 60% at age 80 years, depending on birth cohort[27]. In men of European descent, the carrier rate was 1.5% in single cases of prostate cancer, 1.9% among all familial cases and 2.7% among probands of pedigrees with 3 or more affected individuals[28].

References

[1] Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992; 89:3367-3371.
[2] Walsh PC, Partin AW. Family history facilitates the early diagnosis of prostate carcinoma. Cancer 80[9], 1871-1874. 1997.
[3] Gronberg H, Damber L, Damber JE, Iselius L. Segregation analysis of prostate cancer in Sweden: Support for dominant inheritance. Am J Epidemiol 146[7], 552-557. 1997.
[4] Bishop DT, Kiemeney LA. Family studies and the evidence for genetic susceptibility to prostate cancer. Sem Cancer Biol 1997; 8:45-51.
[5] Schaid DJ, McDonnell SK, Blute ML, Thibodeau SN. Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62[6], 1425-1438. 1998.
[6] Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs WB, Walsh PC. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150:797-802.
[7] Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, Beaty TH, Walsh PC. Risk of cancer in relatives of prostate cancer probands. J Natl Cancer Inst 1995; 87(13):991-996.
[8] Damber L, Gronberg H, Damber JE. Familial prostate cancer and possible associated malignancies: Nation- wide register cohort study in Sweden. Int J Cancer 78[3], 293-297. 1998.
[9] Gronberg H, Bergh A, Damber JE, Emanuelsson M. Cancer risk in families with hereditary prostate carcinoma. Cancer 2000; 89(6):1315-1321.
[10] Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein JI. Pathological features of hereditary prostate cancer. J Urol 1995; 153:987-992.
[11] Aprikian AG, Bazinet M, Plante M, Meshref A, Trudel C, Aronson S, Nachabe M, Peloquin F, Dessureault J, Narod S, Begin L, Elhilali MM. Family history and the risk of prostatic carcinoma in a high risk group of urological patients. J Urol 1995; 154:404-406.
[12] Keetch DW, Humphrey PA, Smith DS, Stahl D, Catalona WJ. Clinical and pathological features of hereditary prostate cancer. J Urol 155[6], 1841-1843. 1996.
[13] Gronberg H, Xu JF, Smith JR, Carpten JD, Isaacs SD, Freije D, Bova GS, Walsh PC, Collins FS, Trent JM, Meyers DA, Isaacs WB. Early age at diagnosis in families providing evidence of linkage to the hereditary prostate cancer locus (HPC1) on chromosome 1. Cancer Res 57[21], 4707-4709. 1997.
[14] Valeri A, Azzouzi R, Drelon E, Delannoy A, Mangin P, Fournier G, Berthon P, Cussenot O. Early-onset hereditary prostate cancer is not associated with specific clinical and biological features. Prostate 2000; 45(1):66-71.
[15] Kupelian PA, Kupelian VA, Witte JS, Macklis R, Klein EA. Family history of prostate cancer in patients with localized prostate cancer: An independent predictor of treatment outcome. J Clin Oncol 15[4], 1478-1480. 1997.
[16] Gronberg H, Damber L, Tavelin B, Damber JE. No difference in survival between sporadic, familial and hereditary prostate cancer. Br J Urol 82, 564-567. 1998.
[17] Bova GS, Partin AW, Isaacs SD, Carter BS, Beaty TL, Isaacs WB, Walsh PC. Biological aggressiveness of hereditary prostate cancer: long-term evaluation following radical prostatectomy. J Urol 1998; 160:660-663.
[18] Gronberg H, Isaacs SD, Smith JR, Carpten JD, Bova GS, Freije D, Xu JF, Meyers DA, Collins FS, Trent JM, Walsh PC, Isaacs WB. Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA 278[15], 1251-1255. 1997.
[19] Gayther SA, de Foy KAF, Harrington P, Pharoah P, Dunsmuir WD, Edwards SM, Gillett C, Ardern-Jones A, Dearnaley DP, Easton DF, Ford D, Shearer RJ, Kirby RS, Dowe AL, Kelly J, Stratton MR, Ponder BAJ, Barnes D, Eeles RA. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 2000; 60(16):4513-4518.
[20] Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, Jackson R, Southgate C, Singh R, Falconer A, Dearnaley DP, Ardern-Jones A, Murkin A, Dowe A, Kelly J, Williams S, Oram R, Stevens M, Teare DM, Ponder BA, Gayther SA, Easton DF, Eeles RA. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. American journal of human genetics 2003; 72(1):1-12.
[21] Agalliu I, Karlins E, Kwon EM, Iwasaki LM, Diamond A, Ostrander EA, Stanford JL. Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. British journal of cancer 2007; 97(6):826-31.
[22] Agalliu I, Kwon EM, Zadory D, McIntosh L, Thompson J, Stanford JL, Ostrander EA. Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clinical cancer research 2007; 13(3):839-43.
[23] Schaid DJ, McDonnell SK, Zarfas KE, Cunningham JM, Hebbring S, Thibodeau SN, Eeles RA, Easton DF, Foulkes WD, Simard J, Giles GG, Hopper JL, Mahle L, Moller P, Badzioch M, Bishop DT, Evans C, Edwards S, Meitz J, Bullock S, Hope Q, Guy M, Hsieh CL, Halpern J, Balise RR, Oakley-Girvan I, Whittemore AS, Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Friedrichsen DM, Deutsch K, Kolb S, Janer M, Hood L, Ostrander EA, Stanford JL, Ewing CM, Gielzak M, Isaacs SD, Walsh PC, Wiley KE, Isaacs WB, Lange EM, Ho LA, Beebe-Dimmer JL, Wood DP, Cooney KA, Seminara D, Ikonen T, Baffoe-Bonnie A, Fredriksson H, Matikainen MP, Tammela TL, Bailey-Wilson J, Schleutker J, Maier C, Herkommer K, Hoegel JJ, Vogel W, Paiss T, Wiklund F, Emanuelsson M, Stenman E, Jonsson BA, Grönberg H, Camp NJ, Farnham J, Cannon-Albright LA, Catalona WJ, Suarez BK, Roehl KA, . Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics. Human genetics 2006; 120(4):471-85.
[24] Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Eeles RA, Easton DF, Foulkes WD, Simard J, Giles GG, Hopper JL, Mahle L, Moller P, Bishop T, Evans C, Edwards S, Meitz J, Bullock S, Hope Q, Hsieh CL, Halpern J, Balise RN, Oakley-Girvan I, Whittemore AS, Ewing CM, Gielzak M, Isaacs SD, Walsh PC, Wiley KE, Isaacs WB, Thibodeau SN, McDonnell SK, Cunningham JM, Zarfas KE, Hebbring S, Schaid DJ, Friedrichsen DM, Deutsch K, Kolb S, Badzioch M, Jarvik GP, Janer M, Hood L, Ostrander EA, Stanford JL, Lange EM, Beebe-Dimmer JL, Mohai CE, Cooney KA, Ikonen T, Baffoe-Bonnie A, Fredriksson H, Matikainen MP, Tammela TLj, Bailey-Wilson J, Schleutker J, Maier C, Herkommer K, Hoegel JJ, Vogel W, Paiss T, Wiklund F, Emanuelsson M, Stenman E, Jonsson BA, Gronberg H, Camp NJ, Farnham J, Cannon-Albright LA, Seminara D, . A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. American journal of human genetics 2005; 77(2):219-29.
[25] Baffoe-Bonnie AB, Kittles RA, Gillanders E, Ou L, George A, Robbins C, Ahaghotu C, Bennett J, Boykin W, Hoke G, Mason T, Pettaway C, Vijayakumar S, Weinrich S, Jones MP, Gildea D, Riedesel E, Albertus J, Moses T, Lockwood E, Klaric M, Faruque M, Royal C, Trent JM, Berg K, Collins FS, Furbert-Harris PM, Bailey-Wilson JE, Dunston GM, Powell I, Carpten JD. Genome-wide linkage of 77 families from the African American Hereditary Prostate Cancer study (AAHPC). The Prostate 2007; 67(1):22-31.
[26] Beebe-Dimmer JL, Levin AM, Ray AM, Zuhlke KA, Machiela MJ, Halstead-Nussloch BA, Johnson GR, Cooney KA, Douglas JA. Chromosome 8q24 markers: risk of early-onset and familial prostate cancer. International journal of cancer 2008; 122(12):2876-9.
[27] Macinnis RJ, Severi G, Baglietto L, Dowty JG, Jenkins MA, Southey MC, Hopper JL, Giles GG. Population-Based Estimate of Prostate Cancer Risk for Carriers of the HOXB13 Missense Mutation G84E. PLoS One. 2013;8(2):e54727.
[28] Breyer JP, Avritt TG, McReynolds KM, Dupont WD, Smith JR. Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer. Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1348-53