Humpath.com - Human pathology

Home > E. Pathology by systems > Reproductive system > Male genital system > Prostate > prostate cancer genetics

prostate cancer genetics

Tuesday 7 February 2012

genetics of prostate acinar adenocarcinoma

In developed countries, prostate cancer is the most commonly diagnosed nonskin malignancy in males. It is estimated that 1 in 9 males will be diagnosed with prostate cancer during their lifetime.

Multiple factors contribute to the high incidence and prevalence of prostate cancer. Risk factors include age, family history, and race.

Environmental exposures

Environmental exposures are clearly involved as well.

Although the exact exposures that increase prostate cancer risk are
unclear, diet (especially those high in animal fat such as red meat, as well as, those with low levels of antioxidants such as selenium and vitamin E) job/industrial chemicals, sexually transmitted infections, and chronic prostatitis have been implicated to varying degrees.

The marked increase in incidence in prostate cancer that occurred in the mid 1980s, which subsequently leveled off in the mid to late 1990s, indicates that wide spread awareness and serum prostate specific antigen screening can produce a transient marked increase in prostate cancer incidence.

Hereditary prostate cancer

- hereditary prostate cancer (familial prostate cancer)

Susceptibility to prostate cancer

- germline MSR1 variants gene coding for macrophage scavenger receptor 1 (12471593)
- germline RNASEL (HPC1) gene variants (12145743)
- germline BRCA2 mutations (2%)
- Locus at 22q12.3 (17047086)
- 8q24 (Nature Genetics: 38, 652-658, 2006)

Molecular alterations in sporadic prostate cancer

While mutations in any of the classic oncogenes and tumour suppressor genes are not found in high frequency in primary prostate cancers, a large number of studies have identified non-random somatic genome alterations.

Using comparative genomic hybridization (CGH) to screen the DNA of prostate cancer, the most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q and gains at 1q, 2p, 7, 8q, 18q, and Xq.

Numerous genes have now been implicated in prostate cancer progression. Several genes have been implicated in the earliest development of prostate cancer.

The pi-class of Glutathione S-transferase (GST), which plays a caretaker role by normally preventing stress related damage, demonstrates hypermethylation in high percentage of prostate cancers, thus preventing expression of this protective gene.

NKX3.1, a homeobox gene located at 8p21 has also been implicated
in prostate cancer. Although no mutations have been identified in this gene, recent work suggests that decreased expression is associated with prostate caner progression.

PTEN encodes a phosphatase, active against both proteins
and lipids, is also commonly altered in prostate cancer progression. PTEN is believed to regulate the phosphatidylinositol 3’-kinase/protein kinase B (PI3/Akt) signaling pathway and therefore mutations or alterations lead to tumour progression.

Mutations are less common than initially thought in prostate cancer, however, tumour suppressor activity may occur from the loss of one allele, leading to decreased expression of PTEN (i.e. haploinsufficiency).

A number of other genes have also been associated with prostate cancer including p27 and E-cadherin.

p53 mutations are late events in prostate cancer and tend to occur in advanced and metastatic prostate tumours.

Another very common somatic genomic alteration in prostate and other cancers is telomere shortening. This molecular alteration is gaining heightened awareness as it has become clear that critically short telomere may lead to genetic instability and increased epithelial cancers in p53+/- mice.

Recent advances in genomic and proteomic technologies suggest that molecular signatures of disease can be used for diagnosis, to predict survival, and to define novel molecular subtypes of disease.

Several studies have used cDNA microarrays to characterize the gene expression profiles of prostate cancer in comparison with benign prostate disease and normal prostate tissue.

Several interesting candidates include AMACR, hepsin, KLF6 and
EZH2.

Alpha-methylacyl-CoA racemase (AMACR), an enzyme that plays an important role in bile acid biosynthesis and β- oxidation of branched-chain fatty acids was determined to be upregulated in prostate cancer. AMACR protein expression was also determined to be upregulated in prostate cancer.

Hepsin is overexpressed in localized and metastatic prostate cancer when compared to benign prostate or benign prostatic hyperplasia.

By immunohistochemistry, hepsin was found to be highly expressed in prostatic intraepithelial neoplasia (PIN), suggesting that dysregulation of hepsin is an early event in the development of prostate cancer.

Kruppel-like factor 6 (KLF6) is a zinc finger is mutated in a
subset of human prostate cancer.

EZH2, a member of the polycomb gene family, is a transcriptional repressor known to be active early in embryogenesis, showing decreased expression as cells differentiate. It has been demonstrated
that EZH2 is highly over expressed in metastatic hormone refractory prostate cancer as determined by cDNA and TMA analysis. EZH2 was also seen to be overexpressed in localized prostate cancers that have a higher risk of developing biochemical recurrence following radical prostatectomy.

The androgen receptor (AR) plays critical role in prostate development. It has been know for many years that withdrawal of androgens leads to a rapid decline in prostate cancer growth with significant clinical response. This response is short-lived and tumour cells reemerge, which are independent of androgen stimulation (androgen independent). Numerous mutations have been identified in the androgen receptor gene. It has been hypothesized that through mutation, prostate cancers can grow with significantly lower circulating levels of androgens. In addition to common mutations, the amino-terminal domain encoded by exon one demonstrates a high percentage of polymorphic CAG repeats. Shorter CAG repeat lengths have been associated with a greater risk of developing prostate cancer and prostate cancer progression. Shorter CAG repeat lengths have been identified in African American men.

LOH

- 6q15-16.3 LOH (48%) (12967473)
- 7q31 LOH
- 8p22-p23 LOH (51%-57%) (16470536)
- 8q LOH
- 10q23 LOH (PTEN)
- 11p15 LOH
- 11p12 LOH
- 11q22 LOH
- 11q23-24 LOH
- 12p12-13 LOH (10379873)
- 13q13-13q14 LOH (41%-86%) (12886522, 11724291)
- 13q21-22 LOH
- 13q33 LOH
- 16q LOH (31%) (10411092)
- 18q21 LOH

- 8p22-p23 LOH (16470536)

  • No 8p22-p23 LOH in high-grade prostatic intraepithelial neoplasia (HGPIN) (16470536)
  • The frequency of 8p22 deletion was significantly higher in clinical prostate cancers (CPC) and latent prostate cancers (LPC) than in incidental prostate cancers (IPC) or lesions. (16470536)
  • The frequency of LOH at 8p22 and 8p23.1 loci in high-grade tumors was significantly higher than in low-grade tumors in both the LPCs/IPCs and CPCs. (16470536)
  • Allelic loss at 8p22 was significantly more frequent in CPC than in IPC and in pT4 CPC than in earlier-stage CPC. (16470536)
  • Deletion of 8p is an important event in both the initiation and metastasis of prostate cancer.
  • The extremely high frequency of LOH at 8p22-23.1 in high-grade tumors suggests the existence of a novel putative tumor-suppressor gene associated with the progression of prostate cancer.

Somatic mutations

- genic inactivations

Gene copy increase

- 8q

  • gene targets: PDP at 8q22.1, PABPC1 at 8q22.3 (102 Mb), KIAA0196 at 8q24.13 (16130124)

Aggressiveness

- ch. 7
- 19q
- 8q gene copy increase

ETSs family gene overexpression

- gene fusions of the 5’-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members in prostate cancer (prostatic adenocarcinoma) :

- Wnt/beta-catenin pathway deregulation (17691963)

Prostate cancer genes

- GST-pi Glutathione S-transferase pi 11q13 Caretaker gene Hypermethlyation
- NKX3.1 NK3 transcription factor homolog A 8p21 Homeobox gene No mutations
- PTEN Phosphatase and tensin homolog 10q23.3 Mutations and haplotype (mutated in multiple advanced insufficiency
cancers 1) Tumour supressor gene insufficiency
- AMACR Alpha-methylacyl-CoA racemase 5p13.2-q11.1 B-oxidation of branched- Overexpressed in chain fatty acids PIN/Pca
- Hepsin Hepsin 19q11-q13.2 Transmembrane protease, Overexpressed in serine 1 PIN/Pca
- KLF-6 Kruppel-like factor 6/COPEB Zinc finger transcription Mutations and haplotype 10p15 factor insufficiency
- EZH2 Enhancer of zeste homolog 2 7q35 Transcriptional memory Overexpressed in aggressive Pca
- p27 Cyclin-dependent kinase inhibitor 1B 12p13 Cyclin dependent kinases Down regulated with Pca (p27, Kip1) 2 and 4 inhibitor progression
- E-cadherin E-cadherin 16q22.1 Cell adhesion molecule Down regulated with Pca progression

See also

- urokinase plasminogen activator (uPA) (PLAU) (MIM.191840)
- prostate cancer genomics

References

- Prostate cancer genomics: towards a new understanding. Witte JS. Nat Rev Genet. 2009 Feb;10(2):77-82. PMID: 19104501

- Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, Kalyana-Sundaram S, Wei JT, Rubin MA, Pienta KJ, Shah RB, Chinnaiyan AM. Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007 Jan;39(1):41-51. PMID: 17173048

- Liu W, Chang B, Sauvageot J, Dimitrov L, Gielzak M, Li T, Yan G, Sun J, Sun J, Adams TS, Turner AR, Kim JW, Meyers DA, Zheng SL, Isaacs WB, Xu J. Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array. Genes Chromosomes Cancer. 2006 Nov;45(11):1018-32. PMID: 16897747

- Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, Tchinda J, Tomlins SA, Hofer MD, Pienta KG, Kuefer R, Vessella R, Sun XW, Meyerson M, Lee C, Sellers WR, Chinnaiyan AM, Rubin MA. TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer. Cancer Res. 2006 Sep 1;66(17):8337-41. PMID: 16951139

- Murillo H, Schmidt LJ, Karter M, Hafner KA, Kondo Y, Ballman KV, Vasmatzis G, Jenkins RB, Tindall DJ. Prostate cancer cells use genetic and epigenetic mechanisms for progression to androgen independence. Genes Chromosomes Cancer. 2006 Jul;45(7):702-16. PMID: 16615098

- Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005 Oct 28;310(5748):644-8. PMID: 16254181

Reviews

- Ellem SJ, Risbridger GP. Treating prostate cancer: a rationale for targeting local oestrogens. Nat Rev Cancer. 2007 Aug;7(8):621-7. PMID: 17611544

- Tycko B, Li CM, Buttyan R. The Wnt/beta-catenin pathway in Wilms tumors and prostate cancers. Curr Mol Med. 2007 Aug;7(5):479-89. Review. PMID: 17691963

- Hunter DJ, Riboli E, Haiman CA, Albanes D, et al.; National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A candidate gene approach to searching for low-penetrance breast and prostate cancer genes. Nat Rev Cancer. 2005 Dec;5(12):977-85. PMID: 16341085

- Stecca B, Mas C, Altaba AR. Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol Med. 2005 May;11(5):199-203. PMID: 15882606

- Sanchez P, Clement V, i Altaba AR. Therapeutic targeting of the Hedgehog-GLI pathway in prostate cancer. Cancer Res. 2005 Apr 15;65(8):2990-2. PMID: 15833820

- Schaid DJ. The complex genetic epidemiology of prostate cancer. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R103-21. Epub 2004 Jan 28. PMID: 14749351

- Gonzalgo ML, Isaacs WB. Molecular pathways to prostate cancer. J Urol. 2003 Dec;170(6 Pt 1):2444-52. PMID: 14634448

- Nelson WG, De Marzo AM, Isaacs WB. N Engl J Med. 2003 Jul 24;349(4):366-81. PMID: 12878745

- Nwosu V, Carpten J, Trent JM, Sheridan R. Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum Mol Genet. 2001 Oct 1;10(20):2313-8. PMID: 11673416

- Rubin MA. Use of laser capture microdissection, cDNA microarrays, and tissue microarrays in advancing our understanding of prostate cancer. J Pathol. 2001 Sep;195(1):80-6. PMID: 11568894