|Written||2011-07||Anne Chauchereau, Safae Aarab-Terrisse|
|Prostate cancer group, INSERM U981, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94800 Villejuif, France, University Paris-Sud 11, France|
(Note : for Links provided by Atlas : click)
|ICD-Topo||C619 PROSTATE GLAND|
|Phylum||Male organs: Prostate::Prostate tumor|
|WHO/OMS Classification||Male organs|
| WHO histological classification of tumors of the prostate (2004):
Basal cell tumours:
Prostatic stromal tumours
TNM classification: The TNM system is the most widely used for the stratification of prostatic carcinoma and is the standard system only for prostate adenocarcinomas. The current revision of the TNM system is shown in the Table (ICD-O C61):
Classification of Prostatic Carcinoma: TNM classification:
N-Regional Lymph Nodes
3. Clinics and Pathology
|Etiology||The exact changes between a normal gland and a neoplasic one are not yet known. There is increasing evidence that predisposing genetic factors are implicated. Dietary and environmental factors may also play a role in this step of the neoplasic transformation.|
|Epidemiology|| Prostate cancer is the second most frequently diagnosed cancer of men (914000 new cases, 13.8% of the total) and the fifth most common cancer overall with large differences between countries. |
In the US, it is estimated that 217730 men will be diagnosed with and 32050 men will die of cancer of the prostate in 2010 (NCI). In Europe, the number of new cases was estimated at 338732 men in 2008 with 70821 deaths (21.1%). The age-adjusted incidence rate was 156.0 per 100000 men per year in the US, 110.5 per 100000 men per year in the Europe and 178.7 men per year in the France.
The worldwide mortality was estimated to 258000 deaths in 2008. Mortality rates are generally high in predominantly black populations, very low in Asia and intermediate in Europe and Oceania.
Prostate cancer rates increase with age. From 2004-2008, the median age at diagnosis for cancer of the prostate was 67 years of age in the US and the median age at death for cancer of the prostate was about 80 years.
Incidence can be influenced by several risk factors including genetic susceptibility, environmental exposure (cigarette smoking, alcohol consumption, infectious agents, dietary fat, endogenous hormones, ...) and difference in health care and cancer registration. Large clues on risk factors for prostate cancer are still not found.
|Clinics|| Patients with prostate cancer can present with a variety of symptoms but are most often asymptomatic. The presenting symptoms can be broadly divided into:|
- Bladder outflow obstruction symptoms: poor stream, hesitancy, sensation of incomplete emptying, frequency, urgency, urinary incontinence due to chronic urinary retention, recurrent urinary sepsis... The symptoms of bladder outlet obstruction are commonly related to concomitant nodular hyperplasia but may also result from the prostate cancer, especially if it is locally advanced.
- Symptoms related to local extension of the tumor: Pain, haematuria, rectal obstruction or bleeding, haemospermia, symptoms of renal failure...
- Symptoms of metastatic disease: include bone pain and tenderness. Involvement of the spinal column may lead to cord compression. Lymphatic involvement from prostate cancer may also cause a variety of symptoms including lymphoedema (particularly lower limb).
Digital rectal examination (DRE) should be performed and serum PSA measured in patients in whom there is clinical suspicion of prostate cancer or in those who wished to be screened.
|Pathology|| Definitive diagnosis requires biopsies of the prostate, using a needle under transrectal ultrasound-Guidance. The most prostate cancers are adenocarcinomas (95%) which develop from the secretory luminal cells of the prostatic gland, 70% arise in the peripheral zone, 15-20% arise in the central zone and 10-15 % arise in the transitional zone. The most prostate cancers are multifocal. |
The studies from J. Mc Neal on the zonale topography of the prostate and from D. Gleason on the tumoral differentiation constituted the basis of anatomopathological descriptions of prostate cancers. The most widely internationally accepted grading model is the Gleason score based on the progressive loss of the gland pattern and the increased peritumoural stroma invasion. Histopathological grading and Gleason scores range as follow:
Histopathological Grading and Gleason score
|Treatment|| Guidelines exist to help for treatment decisions. The choice of a specific treatment is based on the TNM staging and the evaluation of the low, intermediate or high-risk of prostate cancer.|
Therapeutic options for localized prostate cancer
Therapeutic options for locally advanced prostate cancer (T3-4N0M0)
Management of metastatic disease
Management of castration-refractory prostate cancer (CRPC)
|Evolution||The natural history of prostate cancer begins with a local tumour burden and a subsequent metastatic dissemination, preferentially to bones and the inescapable evolution to a castration refractory prostate cancer (CRPC).|
|Prognosis|| Predicting prognosis is essential for patient decision making. Prognostic factors are used to select the appropriate treatment option(s) and to predict biochemical recurrence (also called PSA failure) after radical local therapy.|
The most established independent prognostic factors are: the anatomical extend or stage of the disease (TNM stage) evaluated by digital rectal examination supplemented when necessary by ultrasound or MRI, the Gleason score, PSA level and post prostatectomy margin status.
Clinically localized prostate cancer should be classified as low, intermediate and high risk.
- Low risk is corresponding to T1-T2a, Gleason - Intermediate risk is T2b, Gleason=7, 10 - High risk is =T2c, Gleason >7, PSA>20.
Imaging investigations are not recommended for men with low risk disease, in contrast CT or MRI and bone scintigraphy should be considered in high risk disease. Other prognostic normograms can be used to predict disease progression and patient survival.
|Note||Several loci associated with an increased familial prostate cancer have been mapped to 1q24-25 (HPC1), 17p11 (HPC2), and Xq27-28 (HPCX). HPC1 corresponds to RNASEL which encodes an endoribonuclease for ssRNA implicated in the interferon response to viral infection.|
|Note|| Numerous single-nucleotide polymorphisms (SNPs) were reported that are associated with cancer risk. 8q24 is the most frequently gained chromosomal region in prostate tumors. Gain in 8q24 region has been associated with aggressive tumors, hormone independence, and poor prognosis. Although this region is frequently amplified in prostate tumors, it covered few known or predicted genes. The known genes that are closest to 8q24 are FAM84B and MYC. |
Other independent risk loci for prostate cancer risk are MSMB (10q11.23); HNF1B (17q12); NUDT10/NUDT11 (Xp11.22); 17q12; KLK2/3 (19q13.33); JAZF1 (7p15.1); 3p12.1; EHBP1 (2p15); CTBP2 (10q26.13); SLC22A3 (6q25.3); 22q13.
CGH (comparative genomic hybridization) was used to identify gains or losses of chromosomal regions. The most common alterations include chromosome 8 (23%) and chromosome 7 (20%). The most commonly reported are gains of 2p, 3q, 7q, 8q, 9q, 17q, 20q, and Xq, deletions of 2q, 5q, 6q, 8p, 10q, 12p, 13q, 16q, 17p, 17q, 18q, 21q, and 22q, hyperdiploidy, and aneusomy of chromosomes 7 and 17.
Outlier profile analysis was used to identify the TMPRSS2-ERG fusion as the single most prevalent gene fusion in prostate cancer (>60%) on 21q22. TMPRSS2 encodes for the androgen-activated transmembrane protease serine 2 and ERG encodes a member of the ETS transcription factor. Other gene fusions have been found with ETS genes (including ERG, ETV1, ETV4, and ETV5) involving different 5' partners (~10%): TMPRSS2 (t(7;21)(p21;q22)), SLC45A3 (t(1;7)(q32;p21.2)), ACSL3 (t(2;7)(q36.1;p21.2)), HERV-K (t(7;22)(p21.2;q11.23)), FLJ35294 (t(7;17)(p21.2;p13.1)), FOXP1 (t(3;7)(p13;p21)), EST14 (t(7;14)(p21;q21)), C15orf21 (t(7;15)(p21.3;q21)), and HNRPA2B1 (t(7;7)(p21.2;p15)) for ETV1; TMPRSS2 (t(17;21)(q21;q22)), KLK2 (t(17;19)(q21;q13)), CANT1 (inv(17;17)(q22;q25)) and DDX5 (t(17;17)(q24;q21)) for ETV4; TMPRSS2 (t(3;21)(q28;q22)) or SLC45A3 (t(1;3)(q32;q28)) for ETV5. TMPRSS2-ERG fusions may occur as an early event in the development of prostate cancer, but the gene fusion is not sufficient to cause cancer formation by itself. The prognostic significance of the TMPRSS2-ERG fusion and other ETS rearrangements in prostate cancer is still controversial. Integrative genomic profiling was used to identify a narrow deletion on 3p14 is highly associated with TMPRSS2-ERG fusion-positive tumors. PTEN loss is also associated with the presence of the fusion gene TMPRSS2-ERG.
For more details on the fusion gene TMPRSS2-ERG, see the section Deep insight: TMPRSS2:ETS gene fusions in prostate cancer.
|Translocations in Prostate tumors (Edtor June 2010).|
6. Genes involved and Proteins
|Note||Somatic point mutations in prostate cancer are rare relative to other tumor types such as glioblastoma, lung cancer and melanoma; alterations of gene copy number are more frequent.|
|Gene Name||AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease))|
|Protein||AR gene encodes for the nuclear receptor for the androgens, which belongs to the steroid/thyroid hormone receptor gene superfamily. This nuclear receptor mediates hormone action by binding to hormone in the cytoplasm and translocating to the nucleus where it dimerizes and binds DNA at androgen-responsive gene promoter to modify the transcription of target genes.|
|Somatic mutation|| Almost all prostate cancers express AR. AR expression is maintained during prostate carcinogenesis from primary prostate cancer to castration-refractory prostate cancer (CRPC). AR was found overexpressed in all CRPC and plays a predominant role in the transition from androgen-dependent to independent cancer. |
The AR plays a role of a dominant oncogene in castration-resistant prostate cancer. AR gene amplification has been recovered in ~30% of CRPC. AR is also activated by missense mutations (frequencies of 10-30%) that modify the scope of hormone specificity and/or enhance hormonal response. Activation of AR in androgen-independent disease may also be accomplished by activation of co-regulators that interact with AR to activate gene transcription. Another potential AR activation mechanism is a ligand-independent activation by growth-factors or cytokines. Several structurally different AR variants with divergent biologic activity recently identified could emerge as a primary cause of resistance to androgens. All of those variants required full-length AR through dimerisation to activate endogenous AR target genes and confer castration-resistant growth.
|Gene Name||BRCA2 (breast cancer 2, early onset)|
|Protein||BRCA2 encodes a large DNA repair protein. As for BRCA1, the primary roles of BRCA2 as a tumor suppressor gene is to maintain genomic stability through DNA repair system and is involved in transcriptional regulation process.|
|Germinal mutation||Mutations in BRCA2 and BRCA1 are responsible for the largest number of inherited breast cancers and a large proportion of ovarian cancers. While in BRCA1 mutation carriers, the risk increase did not reach significance, BRCA2 mutations were associated with a significantly increased risk of prostate cancer. Its mutation accounts for 30-35% of familial breast cancers. Prostate cancer screening by PSA assay and digital rectal examination annually are recommended at age 40-50 years for male carriers of BRCA mutations.|
|Somatic mutation||The BRCA2 mutation does not occur in sporadic prostate cancer.|
|Gene Name||CDKN1B (cyclin-dependent kinase inhibitor 1 B)|
|Protein||The gene CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 that inhibit cell proliferation.|
|Somatic mutation|| Loss or reduced expression of CDKN1B correlates with high grade prostate cancer and reduced disease-free survival. The CDKN1B gene is haploinsufficient, so hemizygous deletion reduces the expression of CDKN1B and affects its normal function through dosage reduction.|
In mouse, concomitant inactivation of PTEN and CDKN1B accelerates spontaneous neoplastic transformation and incidence of tumors.
|Gene Name||EZH2 (enhancer of zeste homolog 2 (Drosophila))|
|Protein||The Polycomb group gene EZH2 encodes a histone lysine methyltransferase which methylates histone H3 on lysine-9 and dimethyl lysine-27 leading to transcriptional repression of the affected target gene.|
|Somatic mutation||The gene EZH2 is frequently up-regulated in advanced prostate cancer, in some cases through gene amplification. Overexpression of EZH2 confers a poor prognosis in localized prostate cancers.|
|Gene Name||KLK3 (kallikrein related peptidase 3)|
|Protein|| The KLK3 gene encodes a kallikrein of the serine protease family. KLK3, like KLK2, is involved in semen liquefaction in the normal prostate by degrading seminogelin I/II, fibronectin and laminin. Nevertheless, KLK3 function can also stimulate prostate cancer cell growth and promote metastasis by activating and/or degrading a variety of substrates such as PTHRP, IGFBP3, IGFBP4 and TGFbeta. Independently of its serine protease activity, KLK3 is able to stimulate the production of reactive oxygen species in prostate cancer cells, probably by binding to a cell surface receptor.|
The KLK3 protein is commonly known as the Prostate-Specific Antigen (PSA) which is the most acceptable and broadly used cancer biomarker. Serum level of PSA in the clinical setting is useful in the diagnosis and monitoring of prostatic carcinoma.
|Gene Name||GSTP1 (glutathione S-transferase pi 1)|
|Protein||The GSTP1 gene encodes an enzyme that plays an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. The GSTP1 gene is involved in the DNA methylation of CpG island in prostate cancer and other cancers.|
|Somatic mutation||Silencing of GSTP1 expression by promoter hypermethylation is an early event in prostate cancer initiation, which is seen in up to 70% of PIN lesions and in 90-95% of prostate carcinomas. Decreased GSTP1 expression may predispose luminal cells to increased oxidative damage which in turn result in accumulation of genetic changes ultimately resulting in cell transformation and cancer.|
|Gene Name||MYC v-myc myelocytomatosis viral oncogene homolog (avian)|
|Protein||The proto-oncogene MYC encodes a transcription factor involved in activation of the cell-cycle progression and protein biosynthesis which is frequently amplified in variety of human malignancies.|
|Somatic mutation|| Amplification is observed in approximately 30-40% of primary prostate tumors and 90% of metastatic prostate cancers and is associated with poor patient outcome.|
The locus at 8q24 was identified as a major susceptibility locus in several large-scale genome-wide association studies of prostate cancer as well as other epithelial cancers. Experiments with mouse models of prostate cancer provided strong causal connection between the overexpression of MYC and the development of prostate cancer.
|Gene Name||NKX3-1 (NK3 homeobox 1)|
|Protein||The NKX3.1 gene encodes a prostate-specific homeobox transcription factor considered as a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner.|
|Germinal mutation||Human germ line mutations in Nkx3.1, which decreases its interaction with DNA, result in genetic predisposition to prostate cancer.|
|Somatic mutation|| Loss of NKX3.1 protein expression is a common finding in 12% prostatic intraepithelial neoplasia (PIN) and in 85% human prostate carcinomas.|
Nkx3.1 has been shown to be a critical regulator of prostate epithelial differentiation and stem cell function in mouse models. NKX3.1 represents a haploinsufficient tumor suppressor gene that acts as a gatekeeper gene for prostate cancer initiation.
|Gene Name||TP53 (Tumour protein p53 (Li-Fraumeni syndrome))|
|Protein||P53 encode the tumor suppressor most frequently lost in human cancer. P53 mutations in primary prostate cancer have been detected at a frequency of 10 to 32% and are correlated to recurrent prostate cancer. P53 immunostaining in prostatic needle biopsies predicts early recurrence after radiation therapy.|
|Gene Name||PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)|
|Protein||The tumor suppressor gene PTEN encodes a lipid phosphatase that negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells to activate PI3K/Akt signaling pathway.|
|Somatic mutation|| 17% of primary prostate tumors show a loss of PTEN protein and there is significant correlation between PTEN loss and Gleason Score and clinical stage.|
PTEN loss is associated with the presence of the fusion gene TMPRSS2-ERG.
|NCCN clinical practice practice guidelines in oncologie.|
|Prostate Cancer. Version 4. 2011.http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf|
|Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs.|
|Eble JN, Sauter JN, Epstein JI, Sesterhenn IA.|
|IARCPress International Agency for Research on Cancer (IARC) 69008 Lyon, France.|
|Estimates of cancer incidence and mortality in Europe in 2008.|
|Ferlay J, Parkin DM, Steliarova-Foucher E.|
|Eur J Cancer. 2010 Mar;46(4):765-81. Epub 2010 Jan 29.|
|Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.|
|Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.|
|Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516.|
|Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.|
|Horwich A, Parker C, Bangma C, Kataja V; ESMO Guidelines Working Group.|
|Ann Oncol. 2010 May;21 Suppl 5:v129-33.|
|SEER Cancer Statistics Review, 1975-2008.|
|Howlader N, et al.|
|National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.|
|Meta-analysis of genome-wide and replication association studies on prostate cancer.|
|Liu H, Wang B, Han C.|
|Prostate. 2011 Feb 1;71(2):209-24. doi: 10.1002/pros.21235. (REVIEW)|
|Counseling for male BRCA mutation carriers: a review.|
|Mohamad HB, Apffelstaedt JP.|
|Breast. 2008 Oct;17(5):441-50. Epub 2008 Jul 26. (REVIEW)|
|Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer.|
|Reid AH, Attard G, Ambroisine L, Fisher G, Kovacs G, Brewer D, Clark J, Flohr P, Edwards S, Berney DM, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter VE, Scardino PT, Cuzick J, de Bono JS, Cooper CS; Transatlantic Prostate Group.|
|Br J Cancer. 2010 Feb 16;102(4):678-84. Epub 2010 Jan 26.|
|Molecular genetics of prostate cancer: new prospects for old challenges.|
|Shen MM, Abate-Shen C.|
|Genes Dev. 2010 Sep 15;24(18):1967-2000. (REVIEW)|
|Prostate (ICD-O C61). In: TNM classification of malignant tumours.|
|Sobin L, Gospodarowicz M, Witteking C, Eds.|
|UICC International Union Against Cancer. Wiley-Blackwell, 7th edition. 2009; 243.|
|Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant.|
|Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR.|
|J Clin Invest. 2010 Aug 2;120(8):2715-30. doi: 10.1172/JCI41824. Epub 2010 Jul 19.|
|Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor.|
|Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers CL.|
|Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16759-65. Epub 2010 Sep 7.|
|Atlas of tumor pathology: Tumors of the prostate gland, seminal vesicles, male urethra, and penis.|
|Young RH, et al.|
|Armed Forces Institute of Pathology, Eds, Washington. 2000; 28. ISSN 0160-6344.|
|Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.|
|Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J, Gruschus J, Isaacs WB, Gelmann EP, Xu J.|
|Cancer Res. 2006 Jan 1;66(1):69-77.|
|This paper should be referenced as such :|
|Chauchereau, A ; Aarab-Terrisse, S|
|Prostate tumors: an overview|
|Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1067-1073.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Tumors/ProstateOverviewID5041.html|
9. Translocations implicated (Data extracted from papers in the Atlas)
|t(8;21) (24;q22) NDRG1/ERG|
10. External links
|REVIEW articles||automatic search in PubMed|
|Last year articles||automatic search in PubMed|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Wed Nov 28 16:26:19 CET 2018|
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