Genomic signatures associated with the development, progression, and outcome of prostate cancer

Prostate cancer remains a common cause of cancer death in men. Applications of new genomic technologies to the recent development of high-quality prostate cancer models in multiple contexts have added great molecular insight into the development of and progression to metastasis. Genomic analysis of DNA, RNA, and protein alterations allows for the global assessment of this disease and provides the molecular framework to improve risk classification, outcome prediction, and development of targeted therapies. The creation of expression profiles and signatures will allow the evaluation of cancer phenotypes and give insight into determining those with increased risk of cancer, identification of critical pathways involved in the development of cancer, prediction of disease outcome, and assessment of the response of cancer to established and novel therapies.This review focuses on highlighting recent work in genomics and on its role in evaluating potential genetic modifiers of prostate cancer and novel biomarkers that may help with prostate cancer diagnosis, its potential to provide a better understanding of prostate cancer behavior and transition to metastatic disease, and its role in current and new therapies in prostate cancer. This framework has the exciting potential to be predictive and provide personalized and individual treatment to the large number of men diagnosed with prostate cancer each year.     

Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the “stemness” marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease.     

Nuclear matrix proteins as biomarkers in prostate cancer

The nuclear matrix (NM) is the structural framework of the nucleus that consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. The NM contains proteins that contribute to the preservation of nuclear shape and its organization. These protein components better known as the NM proteins have been demonstrated to be tissue specific, and are altered in many cancers, including prostate cancer. Alterations in nuclear morphology are hallmarks of cancer and are believed to be associated with changes in NM protein composition. Prostate cancer is the most frequently diagnosed cancer in American men and many investigators have identified unique NM proteins that appear to be specific for this disease. These NM protein changes are associated with the development of prostate cancer, as well as in some cases being indicative of cancer stage. Identification of these NM proteins specific for prostate cancer provides an insight to understanding the molecular changes associated with this disease. This article reviews the role of NM proteins as tumor biomarkers in prostate cancer and the potential application of these proteins as therapeutic targets in the treatment of this disease.     

Prostate cancer association studies: pitfalls and solutions to cancer misclassification in the PSA era

Widespread screening of American men for elevated PSA has changed the characteristics of prostate cancer cases in the U.S. The influence of the changed nature of prostate cancer cases in the PSA era and the need for careful consideration of who is a "case" and who is a "control" on the ability to detect associations of risk factors with prostate cancer in etiologic epidemiologic studies merits discussion. Issue 1: prostate cancer cases diagnosed in the PSA era are enriched with a pool of early lesions, which may differ in etiology, and are deficient in advanced lesions, which are the most likely to be the product of promotion and progression events. By admixing the two types of cases (i.e., imperfect specificity), the associations previously detected using epidemiologic designs when the majority of cases were clinically detected may no longer be apparent in the PSA era when the majority of cases are now detected in the pre-clinical phase. Researchers must now tailor hypotheses such that they are testable using early stage cases or specifically augment the number of advanced cases when testing hypotheses related to extraprostatic growth and progression. Issue 2: even when controls are screened for elevated PSA to rule out the presence of prostate cancer, some proportion of those controls currently will have one or more foci of prostate cancer. The imperfect sensitivity of the PSA test coupled with diagnostic work-up may in part result from (a) lack of PSA elevation in some men with prostate cancer or (b) failure of biopsy to sample the tumor focus in men with elevated PSA. Misclassification of men with undetected prostate cancer as controls usually produces a bias that tends to deflate associations. Given this type of disease misclassification, whether an association still can be statistically detected depends on the extent of misclassification, the magnitude of the true association, the prevalence of the exposure in the true controls, and the sample size, although in general moderate nondifferential misclassification does not lead to profound attenuation. However, under the same scenario attenuation does not occur in cohort or case-cohort studies in which the rate or risk ratio (RR) is calculated. That prostate cancer cases diagnosed in the PSA era are enriched with early stage, minimally invasive disease in our opinion is likely to pose a far more serious obstacle to epidemiologic research on the etiology of clinically important prostate cancer than the issue of inclusion as controls some men who have undiagnosed prostate cancer because of imperfect sensitivity of PSA screening and biopsy sampling error.     

区域效应－一个前列腺癌早期诊断的新思路

目前临床上有许多怀疑前列腺癌但穿刺阴性的病例,为了避免漏诊,多数患者必须接受重复穿刺。尽管部分患者经重复穿刺确诊为前列腺癌,而更多患者经过长期随访以及反复穿刺最终确诊为良性病变。近期研究证实,癌灶附近的组织学表现正常的组织中也可发生与癌灶相似的分子改变。因此,我们认为在前列腺癌的发生过程中存在区域效应。在这一理论指导下,选择适当的可反映前列腺癌区域效应的标记物,在穿刺阴性的标本中检出与癌灶相似的分子改变,就可以帮助临床医生在常规病理诊断之前,提前预测前列腺癌的发生。如果能够找到这样的标记物,并在大规模的诊断试验中证实其可行性,那么就可以极大地改善前列腺癌诊断的现状。     

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study

IntroductionOver 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score.ConclusionsA novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.     

Proteomics in prostate cancer biomarker discovery

Despite advances in molecular medicine, genomics, proteomics and translational research, prostate cancer remains the second most common cause of cancer-related mortality for men in the Western world. Clearly, early detection, targeted treatment and post-treatment monitoring are vital tools to combat this disease. Tumor markers can be useful for diagnosis and early detection of cancer, assessment of prognosis, prediction of therapeutic effect and treatment monitoring. Such tumor markers include prostate-specific antigen (prostate), cancer antigen (CA)15.3 (breast), CA125 (ovarian), CA19.9 (gastrointestinal) and serum α-fetoprotein (testicular cancer). However, all of these biomarkers lack sensitivity and specificity and, therefore, there is a large drive towards proteomic biomarker discovery. Current research efforts are directed towards discovering biosignatures from biological samples using novel proteomic technologies that provide high-throughput, in-depth analysis and quantification of the proteome. Several of these studies have revealed promising biomarkers for use in diagnosis, assessment of prognosis, and targeting treatment of prostate cancer. This review focuses on prostate cancer proteomic biomarker discovery and its future potential.     

Racial disparity in colorectal cancer:Gut microbiome and cancer stem cells

Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.     

Newer potential biomarkers in prostate cancer

Prostate-specific antigen (PSA) screening has led to a significant rise in the number of men diagnosed with prostate cancer and an associated increase in biopsies performed. Despite its limitations, including a positive predictive value of only 25%-40%, PSA remains the only generally accepted biomarker for prostate cancer. There is a need for better tools to not only identify men with prostate cancer, but also to recognize those with potentially lethal disease who will benefit from intervention. A great deal of work has been done worldwide to improve our knowledge of the genetics behind prostate cancer and the specificity of PSA by developing assays for different PSA isoforms. Common genetic alterations in prostate cancer patients have been identified, including CpG hypermethylation of GSPT1 and TMPRSS2:ERG gene fusion. Serum and urine detection of RNA biomarkers (eg, PCA3) and prostate cancer tissue protein antibodies (eg, EPCA) are being evaluated for detection and prognostic tools. This article reviews some of the promising developments in biomarkers.     

Antiandrogen gold nanoparticles dual-target and overcome treatment resistance in hormone-insensitive prostate cancer cells

Prostate cancer is the most commonly diagnosed cancer among men in the developed countries. (1) One in six males in the U.S. (2) and one in nine males in the U.K. (3) will develop the disease at some point during their lifetime. Despite advances in prostate cancer screening, more than a quarter of a million men die from the disease every year (1) due primarily to treatment-resistance and metastasis. Colloidal nanotechnologies can provide tremendous enhancements to existing targeting/treatment strategies for prostate cancer to which malignant cells are less sensitive. Here, we show that antiandrogen gold nanoparticles-multivalent analogues of antiandrogens currently used in clinical therapy for prostate cancer-selectively engage two distinct receptors, androgen receptor (AR), a target for the treatment of prostate cancer, as well as a novel G-protein coupled receptor, GPRC6A, that is also upregulated in prostate cancer. These nanoparticles selectively accumulated in hormone-insensitive and chemotherapy-resistant prostate cancer cells, bound androgen receptor with multivalent affinity, and exhibited greatly enhanced drug potency versus monovalent antiandrogens currently in clinical use. Further, antiandrogen gold nanoparticles selectively stimulated GPRC6A with multivalent affinity, demonstrating that the delivery of nanoscale antiandrogens can also be facilitated by the transmembrane receptor in order to realize increasingly selective, increasingly potent therapy for treatment-resistant prostate cancers.     

Therapeutic strategies for localized prostate cancer

Prostate-specific antigen determinations for prostate cancer screening have led to a dramatic increase in the number of men who are diagnosed with organ-confined and therefore potentially curable prostate cancer. Advances in predicting outcomes with artificial neural networks may help to recommend one therapy over another. Less invasive forms of treatment, such as high-intensity focused ultrasound, may ultimately give patients additional options for treatment. Furthermore, attempts to better define the role of both neoadjuvant hormonal therapy and chemotherapy may give higher-risk patients better outcomes than with current treatments. These advances as well as continued research will likely lead to a day when more and more men with organ-confined disease will be cured.     

Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention. Here, we review the subject of inflammation and prostate cancer as part of a "chronic epithelial injury" hypothesis of prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment.     

Identifying skeletal-related events for prostate cancer patients in routinely collected hospital data

BackgroundNon-osteoporotic skeletal-related events (SREs) are clinically important markers of disease progression in prostate cancer. We developed and validated an approach to identify SREs in men with prostate cancer using routinely-collected data.MethodsPatients diagnosed with prostate cancer between January 2010 and December 2013 were identified in the National Prostate Cancer Audit, based on English cancer registry data. A coding framework was developed based on diagnostic and procedure codes in linked national administrative hospital and routinely-collected radiotherapy data to identify SREs occurring before December 2015. Two coding definitions of SREs were assessed based on whether the SRE codes were paired with a bone metastasis code (‘specific definition’) or used in isolation (‘sensitive definition’). We explored the validity of both definitions by comparing the cumulative incidence of SREs from time of diagnosis according to prostate cancer stage at diagnosis with death as a competing risk.ResultsWe identified 40,063, 25,234 and 13,968 patients diagnosed with localised, locally advanced and metastatic disease, respectively. Using the specific definition, we found that the 5-year cumulative incidence of SREs was 1.0 % in patients with localised disease, 6.0 % in patients with locally advanced disease, and 42.3 % in patients with metastatic disease. Using the sensitive definition, the corresponding cumulative incidence figures were 9.0 %, 14.9 %, and 44.4 %, respectively.ConclusionThe comparison of the cumulative incidence of SREs identified in routinely collected hospital data, based on a specific coding definition in patients diagnosed with different prostate cancer stage, supports their validity as a clinically important marker of cancer progression.     

Breast cancer clinical and translational research: analogies and implications for prostate cancer

Breast and prostate cancer, respectively, are the most common cancers in women and in men in the United States. The management of locally advanced prostate cancer involves a multidisciplinary approach, bearing similarity to the therapeutic approach to breast cancer. Better understanding of the molecular biology of these cancers and the identification of the role played by the cancer stem cells and the tumor microenvironment may translate into better clinical decision making regarding risk classification and treatment allocation. A systematic assessment is presented of the many parallel evolutions in defining and treating high-risk breast cancer as they pertain to prostate cancer.     

The Antioxidant,MnTE-2-PyP,Prevents Side-Effects Incurred by Prostate Cancer Irradiation

Prostate cancer is the most commonly diagnosed cancer, with an estimated 240,000 new cases reported annually in the United States. Due to early detection and advances in therapies, more than 90% of patients will survive 10 years post diagnosis and treatment. Radiation is a treatment option often used to treat localized disease; however, while radiation is very effective at killing tumor cells, normal tissues are damaged as well. Potential side-effects due to prostate cancer-related radiation therapy include bowel inflammation, erectile dysfunction, urethral stricture, rectal bleeding and incontinence. Currently, radiation therapy for prostate cancer does not include the administration of therapeutic agents to reduce these side effects and protect normal tissues from radiation-induced damage. In the current study, we show that the small molecular weight antioxidant, MnTE-2-PyP, protects normal tissues from radiation-induced damage in the lower abdomen in rats. Specifically, MnTE-2-PyP protected skin, prostate, and testes from radiation-induced damage. MnTE-2-PyP also protected from erectile dysfunction, a persistent problem regardless of the type of radiation techniques used because the penile neurovascular bundles lay in the peripheral zones of the prostate, where most prostate cancers reside. Based on previous studies showing that MnTE-2-PyP, in combination with radiation, further reduces subcutaneous tumor growth, we believe that MnTE-2-PyP represents an excellent radioprotectant in combination radiotherapy for cancer in general and specifically for prostate cancer.     

Tissue biomarkers for prostate cancer radiation therapy

Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.     

Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer

Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.Key words: Prostate cancer, localized; Minimally invasive ablative treatment for prostate cancer; Photodynamic therapy; WST-09; WST-11; Vascular targeted photodynamic therapy; Padoporfin; Palladium bacteriopheophorbideProstate cancer represents the second most common cause of cancer-related deaths in American men; it is estimated that 27,000 men in the United States died from the disease in 2007.¹ Survival for men with prostate cancer directly depends on the stage and grade of the disease at the time of diagnosis.² These sobering mortality statistics and the more favorable prognosis associated with early detection provide the primary justification for prostate cancer screening, which is performed by measuring the level of serum prostate-specific antigen (PSA) and conducting a digital rectal examination (DRE). It is estimated that 50% of men over the age of 50 years are screened annually for prostate cancer.³Despite widespread acceptance, prostate cancer screening is debated,^4,5 and recommendations for prostate cancer screening are inconsistent. Screening protagonists emphasize that radical prostatectomy increases prostate cancer survival in men with localized disease,⁶ and that the recently observed progressive and significant decline in prostate cancer mortality rates is the direct result of PSA screening and aggressive intervention.⁷ Screening antagonists emphasize the indolent natural history of most prostate cancers detected by screening,⁸ and that the vast majority of men who are treated for prostate cancer do not recognize any survival advantage from early detection and are simply left suffering the ravages of treatment.⁹Both sides of the screening debate have valid arguments. In the absence of widespread screening, many men are denied an opportunity to cure their disease. These men will experience the otherwise preventable consequences of disease progression, which include the development of androgen-insensitive disease¹⁰ and death. However, widespread screening exposes many men to unnecessary complications associated with treatment for localized disease. The challenges are to identify and treat only those cancers that have the biological potential to cause serious and preventable consequences, or to develop treatment options that are associated with fewer complications.     

Prostate cancer in elderly men

Due to increasing life expectancy and the introduction of prostate-specific antigen (PSA) screening, a rising number of elderly men are diagnosed with prostate cancer. Besides PSA serum levels and Gleason score, age is considered to be a key prognostic factor in terms of treatment decisions. In men older than 70 years, treatment without curative intent may deprive the frail patient of years of life. Modern radical prostatectomy techniques are associated with low perioperative morbidity, excellent clinical outcome, and documented long-term disease control. Thus, radical prostatectomy should be considered because local treatment of organ-confined prostate cancer potentially cures disease. The huge extent of PSA screening programs may lead to overdiagnosis of prostate cancer. Not every man who is diagnosed with prostate cancer will develop clinically significant disease. This has led to the concept of expectant management for screen-detected, small-volume, low-grade disease, with the intention of providing therapy for those men with disease progression.     

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1–14.3 (LOD = 2.4), and 20p11.21–q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13–22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives. The names of all authors and their affiliations are listed in the Acknowledgements. The fact that Dr Schaid’s name is given here for purposes of correspondence should not be taken to imply that he played the sole leading part in writing this article. An erratum to this article can be found at