[-2]proPSA is an early marker for prostate cancer aggressiveness

 

News  30.October.2013

I Heidegger, H Klocker, E Steiner, V Skradski, M Ladurner, R Pichler, G Schäfer, W Horninger and J Bektic

Prostate Cancer and Prostatic Diseases , (29 October 2013) | doi:10.1038/pcan.2013.50

Background: The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ-confined (NOC) disease in patients undergoing radical prostatectomy (RP).

Methods: Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP.

Results: [-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [-2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with GS8 and lowest in those with GS6.

The difference in [-2]proPSA values between GS 8 and GS 7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.

The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP.

Conclusions: Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa.

Downregulation of Glutathione S-transferase mu 3/natural history of Renal cell carcinoma

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehranclinic  Hospital Tehran Iran

[e-mail]

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

29,October, 2013

Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta.

This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic.

 These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Mutations of this class mu gene have been linked with a slight increase in a number of cancers, likely due to exposure with environmental toxins. Alternative splicing results in multiple transcript variants.

Glutathione S-transferase mu 3 (GSTM3) has been proven to be downregulated in renal cell carcinoma (RCC). We aimed to characterise the role of GSTM3 and its genetic predisposition on the occurrence and postoperative prognosis of RCC.

Glutathione S-transferase mu 3 expression in renal tissues was examined by immunohistochemistry. The associations of rs1332018 (A-63C) and rs7483 (V224I) polymorphisms with RCC risk were examined using 400 RCC patients and 802 healthy controls. The factors contributing to postoperative disease-specific survival of RCC patients were evaluated using the Cox proportional hazard model.

Glutathione S-transferase mu 3 silencing increased the invasion and anchorage-independent growth of RCC cell lines. rs1332018 (AC+CC vs AA), which correlated with low expression of GSTM3 in kidney, was associated with RCC risk (odds ratio, 1.446; 95% confidence interval (CI), 1.111–1.882). rs1332018 variants and low GSTM3 expression significantly predicted unfavourable postoperative survivals of RCC patients (P<0.05).

Glutathione S-transferase mu 3 may function as a tumour suppressor in RCC. rs1332018 genetic variants predispose the host to downregulating GSTM3 expression in kidney, facilitate carcinogenesis, and predict an unfavourable postoperative prognosis of RCC.

References:

1- Genetic variation in the GSTM3 promoter confer risk and prognosis of renal cell carcinoma by reducing gene expression

X Tan, Y Wang, Y Han, W Chang, T Su, J Hou, D Xu, Y Yu, W Ma, T C Thompson and G Cao/ British Journal of Cancer , (24 October 2013) | doi:10.1038/bjc.2013.669

2- Glutathione S-transferase mu 3     PubMed  21 Aug 2013

The latest Prostate / Prostate Cancer News articles published daily.

29.October.2013

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TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate

News  29.October.2013 

Michael D. Nyquist^a,^b, Yingming Li^a, Tae Hyun Hwang^c,¹, Luke S. Manlove^a,^b, Robert L. Vessella^d,^e,

Kevin A. T. Silverstein^a,^c,^f, Daniel F. Voytas^g,^h,², and Scott M. Dehm^a,ⁱ,² 

^aMasonic Cancer Center, ^bGraduate Program in Molecular, Cellular, and Developmental Biology and Genetics, and ^cBiostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; ^dDepartment of Urology, University of Washington Medical Center, Seattle, WA 98195; ^ePuget Sound VA Health Care System, Seattle, WA 98108; and ^fSupercomputing Institute for Advanced Computational Research, ^gDepartment of Genetics, Cell Biology, and Development, ^hCenter for Genome Engineering, and ⁱDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

 

The androgen receptor (AR) is a master regulator in cells of prostatic origin, including prostate cancer. How AR activity can persist in tumors that are resistant to second-generation AR-targeted therapies remains unknown. This study describes the discovery of AR gene rearrangements in clinical prostate cancer tissues, and the use of genome engineering in prostate cancer cells with transcription activator-like effector nucleases to functionally classify these gene rearrangements as drivers of resistance. This knowledge is expected to lead to better patient management and enable the development of more effective therapies for advanced prostate cancer.

Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa.

AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism.

We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens.

These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC. 

Prostate cancer:Prevention & Causes 29.October.2013

 

Hutchinson Center experts are identifying key factors that affect a person's prostate cancer risk:

Genetic mutation – A team of researchers led by Janet Stanford, Ph.D., of Fred Hutchinson Cancer Research Center has discovered that mutations in the gene BTNL2, which encodes a protein involved in regulating T-cell proliferation and cytokine production – both of which impact immune function – increase the risk of developing prostate cancer.

Circumcision – Dr. Jonathan Wright and colleagues have determined that circumcision before a male’s first sexual intercourse is associated with a reduced risk of prostate cancer, which may be related to the procedures ability to hinder infection and inflammation that may lead to prostate cancer.  The study, which included Drs. Daniel Lin and Janet Stanford, included 3,399 men and determined that circumcised men were 15 percent less likely to develop prostate cancer than uncircumcised men. The reduced relative risk applied for both less and more aggressive forms of the cancer.

Deep-fried foods increase risk – Regular consumption of deep-fried foods such as French fries, fried chicken, fried fish and doughnuts is associated with an increased risk of prostate cancer, and the effect appears to be slightly stronger with regard to more aggressive forms of the disease. The findings were published in 2013 by Drs. Stanford, Marian Neuhouser and collaborators.

Diet – Separate studies led by Drs. Alan Kristal and Ulrike Peters have found a connection between greater consumption of dark green and cruciferous vegetables, especially broccoli and cauliflower, and decreased risk of aggressive prostate cancer. That research also shows that eating more tomatoes and fruit does not help prevent prostate cancer. Drs. Lin, Neuhouser and Kristal are also examining how a biologically active compound in broccoli called sulforaphane affects mechanisms in prostate tissue that are related to cancer development.

Estrogen pathway genes – Variations in estrogen-related genes may contribute to prostate cancer risk, according to a population-based case-control study conducted by Hutchinson Center investigators and colleagues. Study authors include Drs. Stanford, Ziding Feng and collaborators. Additional research may assess genetic variants in genes that are part of this pathway in specific subsets of patients with particular environmental exposures or genetic backgrounds.

Family history – The Prostate Cancer Genetic Research Study (PROGRESS) is a nationwide research project exploring why some families have several men, often in multiple generations, who develop prostate cancer. Discovering the inherited genetic mutations for prostate cancer in families and how they work will hopefully provide new clues to help diagnose, treat, cure and even prevent prostate cancer in future generations.  A whole-exome sequencing project in multiple members of selected hereditary prostate cancer (HPC) families recently revealed two genetic mutations that may contribute to risk of HPC.  Current research efforts focus on validation of these findings.  In addition, Center investigators are collaborating with multiple groups in the discovery and validation of genetic markers called SNPs that are associated with risk of developing prostate cancer in both HPC families and among men without a strong family history.  For example, Dr. Stanford contributes to the African American Genome-wide Association Study and the international PRACTICAL Study that recently validated 23 SNPs that are associated with risk of developing prostate cancer.

HOXB13 genetic mutation – An association of a rare HOXB13 gene mutation with prostate cancer risk in the general population suggests that the mutation may be associated with features of more aggressive disease, according to a study co-authored by Drs. Stanford, Elaine Ostrander, Marni Stott-Miller and collaborators.

Medication – The Center’s Program in Prostate Cancer Research studies several types of commonly used medications to determine if they affect prostate cancer risk or outcomes. These medications include:

 Aspirin and NSAIDs – A population-based, case-control study led by Drs. Stanford, Ziding Feng, Peter Nelson and Ulrike Peters that was published in 2010 observed a 21 percent reduction in prostate cancer risk among regular aspirin users. Inflammation may play in the development of prostate cancer, so the use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) is a growing focus for scientists and requires additional research.

Statins and increased risk – An initial study published in 2008 and led by Dr. Stanford showed that obese men who take statins to control their cholesterol, particularly for extended durations, have an increased risk of prostate cancer. The study found non-obese men do not have the same risk. The study’s findings warrant further investigation, particularly since some studies have suggested that statins may be associated with reducing cancer risk.

Statin and decreased mortality risk – Statins taken to lower blood cholesterol levels – taken before and at the time of prostate cancer diagnosis are associated with a decrease in risk of prostate cancer-specific mortality, according to a Hutchinson Center study conducted by Drs. Stanford, Feng and collaborators. The study also observed that statins taken before or at the time of prostate cancer diagnosis were unrelated to prostate cancer recurrence or progression.

Finasteride – Dr. Mary Redmand and colleagues associated with the Prostate Cancer Prevention Trial determined that finasteride (Proscar), a common therapy for the treatment of an enlarged prostate or BPH, helped reduce the incidence of prostate cancer by about 25 percent. Additionally, researchers found that participants who took finasteride and did develop high-grade cancer had their tumors detected earlier and at a less extensive stage.

Metformin – Men taking the diabetes drug metformin had significantly lower risk of a prostate cancer diagnosis, according to a population-based case-control study by Drs. Stanford and Jonathan Wright. Dr. Wright is now studying metformin as a cancer therapy as well as the drug’s effect at the tissue level.

Obesity – Obese men who are diagnosed with prostate cancer have more than two-and-a-half times the risk of dying from the disease as compared to men of normal weight. An earlier study found that obese men have an 80 percent higher risk of developing aggressive prostate cancer.

Smoking – Middle-aged men who are long-term, heavy smokers face twice the risk of developing aggressive forms of prostate cancer than men who have never smoked, according to a study by Drs. Stanford, Thomas Vaughan and colleagues.

Smokers, dairy and fatty foods – Research led by Dr. Neuhouser has found that current or former heavy smokers who ate more dairy foods had a 41 percent reduced risk of aggressive prostate cancer, compared to men in that category with lower dairy intake. On the other hand, smokers who followed diets rich in omega-6 fatty acids — found in large quantities in safflower, soybean and corn oils — faced a more than doubled risk of prostate cancer, but only if they had a family history of prostate cancer.

Coffee – Stanford and colleagues found that men who drank four or more cups of coffee per day experienced a 59 percent reduced risk of prostate cancer recurrence and/or progression as compared to those who drank only one or fewer cups per week.

Tea and risk reduction – Consuming 2 or more cups of  tea daily reduces the risk of developing prostate cancer, which is the most common form of cancer among men, according to findings from a study conducted by Drs. Stanford, Neuhouser and colleagues. The study, published in 2013, joins a growing body of research linking tea consumption to reduced prostate cancer risk.

Red wine – Men who drank four or more 4-ounce glasses of red wine per week experienced about a 60 percent lower incidence of the more aggressive types of prostate cancer.

Synchronous primary neoplasms of the bladder, skin and breast in a male patient

Case report   29.October.2013

Antonio Luigi Pastore^1*, Giovanni Palleschi¹, Domenico Autieri¹, Antonino Leto¹, Andrea Ripoli¹, Cristina Maggioni¹, Davide Moschese¹, Yazan Al Salhi¹, Natale Porta², Claudio Di Cristofano², Andrea Fuschi¹, Luigi Silvestri¹, Carlo Della Rocca², Silverio Tomao³, Vincenzo Petrozza², Antonio Carbone¹ and Sapienza University of Rome, Faculty of Pharmacy and Medicine

¹ Department of Medical and Surgical Sciences and Biotechnologies, Unit of Urology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, (LT), Italy ² Department of Medical-Surgical Sciences and Biotechnologies, Histopathology Unit-I.C.O.T, Latina, Italy ³ Department of Medical-Surgical Sciences and Biotechnologies, Oncology Unit-I.C.O.T, Latina, Italy

World Journal of Surgical Oncology 2013, 11:282 doi:10.1186/1477-7819-11-282

The incidence of multiple primary malignant neoplasms increases with age, reflecting an increase in overall cancer risk in older patients. Cases of two or more concurrent primary cancers are still rare, although its incidence is increasing Multiple primary cancers (MPC) in a single patient was first documented by Billroth et al. in 1889 .Since then, many cases of double, triple or even quintuple primary malignant neoplasms have been documented involving single or multiple organs .MPCs are first classified as either synchronous or metachronous depending on their timing of diagnosis. Synchronous lesions are relatively uncommon, with most cases involving metachronous lesions .

However, there remains some confusion over the terms used to describe MPC, such as synchronous, simultaneous, and metachronous or successive neoplasms. All these definitions are based on the time that the neoplasms are discovered rather than the onset of disease. Thus, the term 'synchronous’ refers to neoplasms discovered simultaneously, while 'metachronous’ indicates a distinct neoplasm discovered when the same patient is already known to have a neoplasm (successive neoplasm) .

The generally accepted definition of MPC was introduced by Worren and Gates, who stated that each neoplasm must represent a distinct malignancy, and that a metastatic origin must be excluded .Ray et al. reported that 13.5% patients with MPC had genitourinary neoplasms .

In this report, we describe the case of a patient who developed synchronous primary transitional cell carcinoma (TCC) of the urinary bladder, squamous cell carcinoma (SCC) of the skin on the forehead, and infiltrating ductal breast carcinoma. This combination, to the best of our knowledge, has never previously been reported in the literature.

Case presentation

A 57-year-old man, a farmer and heavy smoker (90 to 100 cigarettes a day from the age of 15 years), was referred to our institute for gross haematuria with cloths retention that required an acute catheterisation with bladder irrigation. An ultrasound examination showed papillary neoplasms arising from the posterior-lateral left wall of the bladder.

The patient had suffered lower urinary tract symptoms over the preceding 1 year and seemed cachectic, but had not previously reported weight loss or any other specific complaints. He did have a family history of malignancy though, as his father had developed rectal cancer and his sister had a kidney neoplasm.

He had no signs or symptoms until his physician noticed a hard lump with skin retraction on his left nipple. The patient also had an erythematous nodular skin lesion developing on his forehead. For these lesions, the patient underwent left modified radical mastectomy (based on the Madden technique) with axillary lymph node dissection.

Histopathological examination revealed an infiltrating ductal carcinoma (grade III, score 8 according to Nottingham) with metastasis to one of the 11 axillary lymph nodes examined. Approximately 90% of the neoplastic cells stained positive with antibody to the oestrogen receptor, and 20% stained positive with antibody to the progesterone receptor. The proliferative index using a Ki-67 monoclonal antibody was 10%. HER-2/neu was not over-expressed .

The nodular skin lesion was completely resected, and histopathological examination revealed it to be a SCC (grade II), infiltrating the hypodermis .

Immediately after these surgical procedures, the patient was hospitalised in our institution where a cystoscopy was performed confirming ultrasound findings of multiple bladder papillary lesions arising from the posterior-lateral left wall, with a large base plant and active bleeding. A trans-urethral resection of the bladder lesion (TURB) was performed at the same time in which the neoplasm was completely excised. Subsequent histopathological examination showed a grade 3 papillary TCC that was in the process of infiltrating the muscular bladder wall (T2). The neoplastic cells were positive for cytokeratin 7 and negative for both cytokeratin 20 and Gross Cystic Disease Fluid Protein 15 (GCDFP-15) .

Although a bone scan failed to find any skeletal metastasis, a whole body computed tomography (CT) scan revealed a diffuse thickening of the left bladder wall approximately 12.2 mm in diameter. This was found to be hypervascularised and in contact with the left vesicoureteral junction with minimal local infiltration of the perivesical area. There was also adenopathy in four retroperitoneal lymph nodes and concomitant left moderate hydroureteronephrosis.

Therefore, the patient underwent total cystoprostatectomy with pelvic lymphadenectomy and a continent ileal urinary diversion. In consideration of the patient’s age and overall physical condition, an orthotopic bladder replacement (neobladder reconstruction) using the Paduan technique was chosen.

 

News  28.October.2013

MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells

A Formosa, E K Markert, A M Lena, D Italiano, E Finazzi-Agro', A J Levine, S Bernardini, A V Garabadgiu, G Melino and E Candi

Oncogene , (28 October 2013) | doi:10.1038/onc.2013.451

miRNAs act as oncogenes or tumor suppressors in a wide variety of human cancers, including prostate cancer (PCa). We found a severe and consistent downregulation of miRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 region in metastatic cell lines as compared with normal prostatic epithelial cells (PrEC).

 In specimens of human prostate (28 normals, 99 primary tumors and 13 metastases), lower miRNA levels correlated significantly with a higher incidence of metastatic events and higher prostate specific antigen (PSA) levels, with similar trends observed for lymph node invasion and the Gleason score.

We transiently transfected 10 members of the 14q32.31 cluster in normal prostatic epithelial cell lines and characterized their affect on malignant cell behaviors, including proliferation, apoptosis, migration and invasion.

Finally, we identified FZD4, a gene important for epithelial-to-mesenchymal transition in (PCa), as a target of miR-377. 

Multiple, Distinct Y Chromosomes Associated With Significant Excess Risk of Prostate Ca.

News  28.October.2013

Lisa Cannon-Albright, Ph.D., Professor and Chief of the Division of Genetic Epidemiology at the University of Utah School of Medicine. 

The study identified multiple, distinct Y chromosomes associated with a significant excess risk of prostate cancer. 

Because most of the Y chromosome does not recombine during cell division, it is passed virtually unchanged from father to son. "As a result, each male resident of Utah shares the Y chromosome of his father and his father's father and so on," she said. "This provided the ability to estimate the risk for prostate cancer in independent Y chromosomes represented in Utah."

The study relied upon the Utah Population Data Base (UPDB), which identifies over 6.5 million individuals, including many of the Utah pioneers in the 1800s. The pioneer genealogies in the UPDB are typically large, spanning 15 generations. The Utah population represented in the UPDB is genetically representative of Northern Europe. The database was created in the 1970s to define familial clustering and identify evidence for heritable contribution to cancer.

The Y-chromosomes associated with prostate cancer risk were detected through an analysis of male lineage in the computerized genealogical UPDB. Because UPDB is linked to the Utah Cancer Registry, an NCI Surveillance, Epidemiology and End Results (SEER) registry, the researchers were able to identify the men who developed prostate cancer.

The researchers began the study with 1.25 million living and deceased males who had at least 2 parents, 4 grandparents and 6 or 8 great grandparents in the database. All males whose fathers were not identified in the database were labeled as founders. Each founder was then assigned a unique, sequential Y chromosome identification (YID). The founder's sons, his son's sons and so on also were assigned this same YID.

The YID groups with at least two males sharing the same Y chromosome totaled 257,252. "We effectively identified each independent Y chromosome in the UPDB," Dr. Cannon-Albright said. Each group of males with the same YID was theorized to share the same Y chromosome since they descended from the same male founder.

The researchers used the Utah cancer registry to estimate specific rates of prostate cancer in the UPDB, birth year and birth state. To estimate the number of prostate cancer cases expected to occur in each YID group, the researchers applied the results to all males in each group. The researchers compared the observed number of prostate cancers to the expected number of cases.

Dr. Cannon-Albright and her team focused on the 1,000 YID groups that included the most men. These groups ranged from 167 to 2,264 men. In 73 Y chromosome groups, the prostate cancer incidence was significantly higher (p<0.05) than expected, she said. 

In one YID group of 9,750 men, the researchers had predicted that 45.6 prostate cancers cases would have occurred. According to the state's cancer registry, 65 males in the group had been diagnosed with prostate cancer. In another group of 498 men, 26 had prostate cancer. However, 9.5 cases had been predicted for this group, said Dr. Cannon-Albright.

Among the male descendants who did not share the Y chromosome of this founder, 39 men had prostate cancer. The scientists had predicted 36.1, which was not statistically different from the actual rate. These results indicate that grouping males by their Y chromosomes reveals a Y chromosome-linked prostate cancer risk, while no such association was observed among males that do not share a common Y chromosome.

The research of Dr. Cannon-Albright and her colleagues may lead to the identification of specific Y-chromosome variants associated with prostate cancer. These and other variants associated with prostate cancer perhaps will provide the basis of a genetic test that will help to determine a man's genetic predisposition to the disease. Understanding the genes that increase a male's genetic risk for prostate cancer also may fuel research to improve the treatment of the cancer.

American Society of Human Genetics.