673 REVIEW J Clin Pathol: first published as 10.1136/jcp.2002.003954 on 23 June 2005. Downloaded from Molecular pathology of prostate cancer C Hughes, A Murphy, C Martin, O Sheils, J O’Leary ............................................................................................................................... J Clin Pathol 2005;58:673–684. doi: 10.1136/jcp.2002.003954 The molecular pathology of prostate cancer is complex; not largely reflects an increasing number of men being diagnosed with very early stage prostate only are multiple genes involved in its pathogenesis, but cancer as a result of the widespread use of additional environmental factors such as diet and prostate specific antigen (PSA) testing. PSA is a inflammation are also involved. The exhaustive research protein produced by both normal and cancerous prostate cells and a high PSA value can be a sign into prostate cancer to date has demonstrated a complex of cancer. Most men diagnosed at a very early interaction of multiple genes and environmental factors, stage will die with prostate cancer but not from some of which may be more important in individual it; therefore, the survival rate has increased. The American Cancer Society recommends in its prostate cancer cases. This is an exciting era, with the prostate cancer screening guidelines that men emergence of new investigative tools such as DNA should be informed of what is known and what microarray technology and the application of the field of is uncertain about the benefits and limitations of proteomics to the study of human cancers. Knowledge of early detection of prostate cancer, so that they can make an informed decision about testing. genetic changes underlying the initiation, development, Therefore, the early diagnosis of prostate cancer and progression of prostate cancer is accumulating through screening creates difficulties in predict- rapidly. With increasing knowledge, it may be possible to ing the outcome of individual patients. The difficulty is in distinguishing between clinically distinguish indolent from aggressive prostate tumours by indolent prostate cancers, which will be asymp- molecular fingerprinting. This review discusses the most tomatic, and aggressive prostate cancers with the consistently reported molecular pathological findings in potential to kill the patient. Gleason grading on histopathological examination is the best prog- hereditary and sporadic prostate cancer, together with nostic indicator to date in prostate cancer; new concepts and technologies. however, interobserver variation can occur, ........................................................................... grading on biopsies may not correlate with the prostatectomy specimen because of sampling problems, and cases of morphologically identical rostate cancer is the second leading cause of prostate cancer can behave differently. http://jcp.bmj.com/ cancer deaths in men. It is not invariably This is an exciting era with the emergence of Plethal, however, and is a heterogeneous new investigative tools such as DNA microarray disease ranging from asymptomatic to a rapidly technology and the application of the field of fatal systemic malignancy. The prevalence of proteomics to the study of human cancers. prostate cancer is so high that it could be Knowledge of genetic changes underlying the considered a normal age related phenomenon: initiation, development, and progression of in a Spanish study examining white prostate cancer is accumulating rapidly. With on September 25, 2021 by guest. Protected copyright. Mediterranean men, 33% of men in their 8th increasing knowledge it may be possible to decade had evidence of prostate cancer at distinguish indolent from aggressive prostate necropsy and died with the disease, but not tumours by molecular fingerprinting. A clinical from it. Data from American postmortem studies application of this knowledge would be that show an even higher prostate cancer prevalence radical treatment and its associated morbidity rate.1 In recent years, there have been large could be avoided in prostate cancers that are increases in the five year survival rates for unlikely to progress. Resources and radical prostate cancer, with a five year relative age treatment could be focused on prostate cancers standardised survival rate of 65% in England and with poor prognostic indicators. In this review, Wales for the years 1996–9. This was the third we shall discuss the most consistently reported highest survival rate of all cancers over this time molecular pathological findings in prostate can- See end of article for period, with only testicular cancer and mela- cer, together with new concepts and technolo- authors’ affiliations noma having better survival rates, and was gies. ....................... around 11% higher than that for patients 2 Correspondence to: diagnosed during 1991–5. Professor J O’Leary, Abbreviations: AMACR, a-methylacyl coenzyme A Pathology Department, racemase; AR, androgen receptor; GSTP1, glutathione S- Coombe Women’s ‘‘The prevalence of prostate cancer is so high transferase; IFN, interferon; IL-6, interleukin 6; KLF, Hospital, Dublin 8, Ireland; that it could be considered a normal age Kruppel-like factor; MAPK, mitogen activated protein [email protected] related phenomenon’’ kinase; P13K–Akt, phosphatidylinositol 39-kinase–protein kinase B; PIN, prostate intraepithelial neoplasia; PSA, Accepted for publication prostate specific antigen; PTEN, phosphatase and tensin 16 February 2005 Unfortunately, this improvement does not homologue; Rb, retinoblastoma; STAT, signal transducer ....................... reflect better treatment for prostate cancer. It and activator of transcription; VDR, vitamin D receptor www.jclinpath.com 674 Hughes, Murphy, Martin, et al HEREDITARY PROSTATE CANCER in the RNASEL gene have been identified in familial and Prostate cancer can be divided epidemiologically into sporadic prostate cancer in many studies,8–12 although other J Clin Pathol: first published as 10.1136/jcp.2002.003954 on 23 June 2005. Downloaded from hereditary and sporadic forms,3 but it is not possible to studies have not supported these findings.13 14 distinguish these two groups at a molecular level. Highly Overall, there is strong support for the notion that RNASEL penetrant inherited genes conferring the prostate cancer is the most important hereditary prostate cancer gene phenotype have not been identified. identified to date. Linkage studies using genetic markers to search for chromosomal regions that show excessive sharing of inher- MSR1 ited alleles in cancer affected families have been helpful in MSR1 encodes a macrophage scavenger receptor responsible identifying important cancer susceptibility genes in other for cellular uptake of molecules, including bacterial cell wall cancers. However, similar studies using families prone to products. The importance of MSR1 as a prostate cancer prostate cancer have not yielded the same success. susceptibility gene in hereditary prostate cancer is contro- versial. Germline MSR1 mutations have been linked to prostate cancer in some families with prostate cancer and ‘‘The failure to identify highly penetrant genes in in sporadic prostate cancer.15 16 However, a recent report, hereditary prostate cancer may result from the fact that which investigated 163 families with familial prostate cancer, multiple genes with a small to moderate effect are involved did not provide confirmatory evidence of the role of MSR1 in in hereditary prostate carcinogenesis’’ familial prostate cancer.17 Mutations of these host response to infection genes may Although possible inherited prostate cancer susceptibility increase the risk of prostate cancer by predisposing to chronic genes have been identified such as the ELAC2, RNASEL, inflammation as a result of failure of viral RNA and bacterial MSR1, NSB1, and CHEK2 genes in some families (table 1), degradation. There is accumulating knowledge supporting the proportion of cases of hereditary prostate cancer the role of inflammation in prostate cancer, which we will attributable to germline mutations in these loci is small. refer to again later in the article. Many studies have not supported the role of these genes in hereditary prostate cancer. Mutations of these candidate Cell cycle checkpoint genes genes have also been identified in sporadic prostate cancer. NBS1 Because prostate cancer is a common cancer, it may be The rare human genetic disorder, Nijmegen breakage difficult to distinguish clustering of sporadic prostate cancer syndrome, is characterised by radiosensitivity, immunodefi- within families from true hereditary prostate cancer. This ciency, chromosomal instability, and an increased risk for difficulty may have hindered research into hereditary cancer of the lymphatic system. The NBS1 gene, which is prostate cancer to date. Alternatively, the failure to identify involved in this human genetic disorder, encodes a protein, highly penetrant genes in hereditary prostate cancer may nibrin, involved in the processing/repair of DNA double result from the fact that multiple genes with a small to strand breaks and in cell cycle checkpoints.18 Mutations in moderate effect are involved in hereditary prostate carcino- the gene for the Nijmegen breakage syndrome (NBS1) have genesis. The risk of disease in the presence of a susceptibility been identified in both sporadic and familial cases of prostate gene might be substantially increased only in the appropriate cancer and are associated with a small increased risk