Alpha methyl acyl CoA racemase deficiency: Diagnosis with isolated elevated liver enzymes.

Gündüz M, Ünal Ö, Küçükçongar-Yavas A, Kasapkara Ç. Alpha methyl acyl CoA racemase deficiency: Diagnosis with isolated elevated liver enzymes. Turk J Pediatr 2019; 61: 289-291. Alpha methy acyl CoA racemase (AMACR) deficiency is a rare autosomal recessive peroxisomal disorder characterized by cholestatic liver disease in the neonatal period, and variable neurologic symptoms affecting central and peripheral nervous systems in the following years. We report a Turkish patient who was diagnosed with AMACR deficiency with presentation of isolated elevated liver enzymes. The patient was referred for elevated liver enzymes when he was 10 months old. He had no cholestasis history in the neonatal period. Initially, an etiology could not be identified. Ultimately, the patient was diagnosed with AMACR deficiency with previously unreported p.Cys20Tyr (c.596G > A) homozygous pathogenic variant. At last visit, when he was 7.5 years old, his growth, development and neurologic examination were all normal. Biochemical analysis was normal except for mildly elevated AST levels. We suggest that checking VLCFA analysis may be useful in isolated elevated liver enzymes with unknown etiology.

Netrin 1 and Alpha-Methyl Acylcoenzim-A Racemase in diagnosis of prostate cancer.

OBJECTIVES: To investigate serum and urine levels of Alpha-methylacyl-CoA-racemase (AMACR) and Netrin 1 in patients with and without prostate cancer and to determine whether these markers could be used as alternatives in diagnosis of prostate cancer instead of serum prostate specific antigen (PSA) levels. METHODS: One hundred and seventy five patients between 45-75 years to whom transrectal ultrasound guided biopsies were performed for abnormal serum PSA levels or digital rectal examinations were included. The levels of AMACR and Netrin 1 levels of blood and urine samples of 5 mL those were taken prior to biopsies were measured. . RESULTS: The mean age of the patients was 62.7 ±6.4 years. Prostate cancer was detected in 40 patients (22.8%) while 135 of them (77.2%) were diagnosed as benign prostate hyperplasia (BPH). In BPH group, serum and urine levels of AMACR and Netrin 1 were 13.4 ±16.9 ng/mL; 7.1 ±3.4 ng/mL; 164.1±46 pg/mL and 19.5 ±5.0 pg/mL respectively. The levels of serum and urine levels of AMACR and Netrin 1 were 10.2 ±9.8 ng/mL; 6.8 ±2.5 ng/mL; 159.1 ±44.1 pg/mL and 20.1 ±5.3 pg/mL respectively in prostate cancer group. There was no statistically significant difference or correlation between these two groups serum and urine AMACR and Netrin 1 results. CONCLUSIONS: Serum and urine levels of AMACR and Netrin 1 were not found to be alternatives for serum PSA levels in the diagnosis of prostate cancer in this study.

OBJETIVOS: Investigar los niveles de alfa-metil acilcoenzima-A y Netrina 1 en pacientes con y sin cáncer de próstata y determinar si estos marcadores pueden ser usados como una alternativa en el diagnóstico de cáncer de próstata en lugar del antígeno prostático específico en suero (PSA). MÉTODOS: Fueron incluidos 175 pacientes entre 45-75 años, a quienes se les realizó una biopsia de próstata guiada por ultrasonido por presentar un nivel anormal de PSA en el suero o un tacto rectal. Se tomó una muestra de 5 mL de sangre y orina para medir los niveles de alfa-metil acilcoenzima-A y Netrina 1. Estos niveles se midieron antes del análisis de la biopsia. RESULTADOS: La edad media de los pacientes fue de 62.7±6.4 años. Se detectó cander en 40 pacientes (22.8%), mientras que a 135 de ellos (77.2%) se les diagnóstico una hiperplasia benigna de próstata (HBP). En el grupo HBP los niveles en suero y orina de alfa-metil acilcoenzima-A y Netrina 1 fueron 13.4 ±16.9 ng/mL; 7.1 ±3.4 ng/mL; 164.1 ±46 pg/mL y 19.5 ±5.0 pg/mL respectivamente. En el grupo con cáncer de próstata los niveles en suero y orina de alfa-metil acilcoenzima-A y Netrina 1 fueron 10.2 ±9.8 ng/mL; 6.8 ±2.5 ng/mL; 159.1 ±44.1 pg/mL y 20.1 ±5.3 pg/mL respectivamente. No hubo una diferencia significativa o una correlación entre los niveles de alfa-metil acilcoenzima-A y Netrina 1 en suero y orina al comparar estos dos grupos de pacientes. CONCLUSIONES: Los niveles de alfa-metil acilcoenzima-A y Netrina 1 en suero y orina no son una alternativa para reemplazar el PSA en suero para el diagnóstico de cáncer de próstata.

Netrin 1 and Alpha-Methyl Acylcoenzim-A Racemase in diagnosis of prostate cancer / Netrina 1 y Alfa Metil-Acil coenzima-A Racemasa para el diagnóstico de cáncer de próstata

Abstract Objectives: To investigate serum and urine levels of Alpha-methylacyl-CoA-racemase (AMACR) and Netrin 1 in patients with and without prostate cancer and to determine whether these markers could be used as alternatives in diagnosis of prostate cancer instead of serum prostate specific antigen (PSA) levels. Methods: One hundred and seventy five patients between 45-75 years to whom transrectal ultrasound guided biopsies were performed for abnormal serum PSA levels or digital rectal examinations were included. The levels of AMACR and Netrin 1 levels of blood and urine samples of 5 mL those were taken prior to biopsies were measured. . Results: The mean age of the patients was 62.7 ±6.4 years. Prostate cancer was detected in 40 patients (22.8%) while 135 of them (77.2%) were diagnosed as benign prostate hyperplasia (BPH). In BPH group, serum and urine levels of AMACR and Netrin 1 were 13.4 ±16.9 ng/mL; 7.1 ±3.4 ng/mL; 164.1±46 pg/mL and 19.5 ±5.0 pg/mL respectively. The levels of serum and urine levels of AMACR and Netrin 1 were 10.2 ±9.8 ng/mL; 6.8 ±2.5 ng/mL; 159.1 ±44.1 pg/mL and 20.1 ±5.3 pg/mL respectively in prostate cancer group. There was no statistically significant difference or correlation between these two groups serum and urine AMACR and Netrin 1 results Conclusions: Serum and urine levels of AMACR and Netrin 1 were not found to be alternatives for serum PSA levels in the diagnosis of prostate cancer in this study.

Resumen Objetivos: Investigar los niveles de alfa-metil acilcoenzima-A y Netrina 1 en pacientes con y sin cáncer de próstata y determinar si estos marcadores pueden ser usados como una alternativa en el diagnóstico de cáncer de próstata en lugar del antígeno prostático específico en suero (PSA). Métodos: Fueron incluidos 175 pacientes entre 45-75 años, a quienes se les realizó una biopsia de próstata guiada por ultrasonido por presentar un nivel anormal de PSA en el suero o un tacto rectal. Se tomó una muestra de 5 mL de sangre y orina para medir los niveles de alfa-metil acilcoenzima-A y Netrina 1. Estos niveles se midieron antes del análisis de la biopsia. Resultados: La edad media de los pacientes fue de 62.7±6.4 años. Se detectó cander en 40 pacientes (22.8%), mientras que a 135 de ellos (77.2%) se les diagnóstico una hiperplasia benigna de próstata (HBP). En el grupo HBP los niveles en suero y orina de alfa-metil acilcoenzima-A y Netrina 1 fueron 13.4 ±16.9 ng/mL; 7.1 ±3.4 ng/mL; 164.1 ±46 pg/mL y 19.5 ±5.0 pg/mL respectivamente. En el grupo con cáncer de próstata los niveles en suero y orina de alfa-metil acilcoenzima-A y Netrina 1 fueron 10.2 ±9.8 ng/mL; 6.8 ±2.5 ng/mL; 159.1 ±44.1 pg/mL y 20.1 ±5.3 pg/mL respectivamente. No hubo una diferencia significativa o una correlación entre los niveles de alfa-metil acilcoenzima-A y Netrina 1 en suero y orina al comparar estos dos grupos de pacientes. Conclusiones: Los niveles de alfa-metil acilcoenzima-A y Netrina 1 en suero y orina no son una alternativa para reemplazar el PSA en suero para el diagnóstico de cáncer de próstata.

Alpha-methylacyl-CoA racemase deletion has mutually counteracting effects on T-cell responses, associated with unchanged course of EAE.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Altering the metabolism of immune cells is an attractive strategy to modify their activity during autoimmunity in MS. We investigated the effect of modulating fatty acid metabolism in an animal model of MS, EAE. Alpha-methylacyl-CoA racemase (AMACR) converts R-configuration branched fatty acids into the S-configuration, thereby preparing them for ß-oxidation. We observed a significant, disease-dependent elevation of AMACR expression in monocytes and T cells from blood, draining lymph nodes and spleen of EAE mice during the preclinical phase. In vitro analysis revealed that the proliferation of T cells was inhibited in AMACR KO mice, but T-cell polarization was switched toward a pathogenic state involving the production of more IFN-γ and IL-17, but less IL-4. These opposing effects appeared to cancel out each other in vivo, because AMACR KO EAE mice showed a marginal increase in the severity of early clinical symptoms. AMACR was not regulated in the white blood cells of MS patients. Our data show that AMACR is regulated in immune cells during EAE, but it is not a suitable target for the treatment of MS due to its opposing effects.

[Related biomarkers in the diagnosis of prostate cancer].

Prostate cancer is one of the most common malignant tumors in the male urinary system as well as the second leading cause of cancer death in men. Prostate specific antigen (PSA) screening is the main method for the early diagnosis of prostate cancer, but has a low specificity for its detection. In recent years, a variety of tumor markers with high sensitivity and specificity have been found. This review focuses on some of the more promising tumor biomarkers such as prostate cancer antigen 3, early prostate cancer antigen, prostate-specific membrane antigen, alpha-methylacyl-CoA racemase, and vascular endothelial growth factor.

Effect of Cnidium Lactone on Serum Mutant P53 and BCL-2/BAX Expression in Human Prostate Cancer Cells PC-3 Tumor-Bearing BALB/C Nude Mouse Model.

BACKGROUND: Cnidium lactone is a natural coumarin compound that can inhibit a variety of cancer cell proliferation and induce cancer cell apoptosis. This experiment investigated the effect of cnidium lactone on molecular marker expression in prostate cancer nude mice to study its effect in inducing apoptosis. MATERIAL AND METHODS: We randomly and equally divided 30 male BALB/C nude mice inoculated with human prostate cancer cells PC-3 into a negative control group, a cyclophosphamide group (500 mg/Kg), and cnidium lactone groups at 3 doses (280 mg/Kg, 140 mg/Kg, and 70 mg/Kg). The mice were weighed at 2 weeks after administration. Tunnel assay was applied to test the nude mice tumor cell apoptosis. ELISA was performed to detect serum AMACR, CD147, mutant P53, BCL-2, AND BAX expression levels. Tumor tissue was separated and weighed. RESULTS: Mice weight did not change significantly in the groups receiving 3 different doses of cnidium lactone(p>0.05), while it decreased obviously in the cyclophosphamide group (p<0.05). Tumor weight, CD147, mutant P53, and BCL-2 levels were significantly lower in the groups receiving 3 different doses of cnidium lactone than in the negative control group (p<0.05). Among them, the abovementioned indexes decreased markedly in the 280 mg/Kg and 140 mg/Kg dose groups than in the cyclophosphamide group (p<0.05). AMACR and BAX levels showed no significant difference in the cnidium lactone group or the cyclophosphamide group (p>0.05). CONCLUSIONS: Cnidium lactone may induce prostate cancer cell apoptosis and inhibit its proliferation through regulating CD147, mutant P53, and BCL-2 expression in nude mice.

[Alternative tests to PSA for prostate cancer diagnosis]. / Nuovi test in competizione con il PSA per la diagnosidel carcinoma prostatico.

Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis.

[Emerging biomarkers for the diagnosis, staging and prognosis of prostate cancer]. / Les biomarqueurs émergents du diagnostic, du staging et du pronostic du cancer de la prostate.

The introduction and widespread adoption of prostate-specific antigen (PSA) has revolutionized the way prostate cancer is diagnosed and treated. However, the use of PSA has also led to overdiagnosis and overtreatment of prostate cancer resulting in controversy about its use for screening. PSA also has limited predictive accuracy for predicting outcomes after treatment and for making clinical decisions about adjuvant and salvage therapies. Hence, there is an urgent need for novel biomarkers to supplement PSA for detection and management of prostate cancer. A plethora of promising blood- and urine-based biomarkers have shown promise in early studies and are at various stages of development (Human kallikrein 2, Early Prostate Cancer Antigen, Transforming Growth Factor-Beta 1 and Interleukin-6, Endoglin, PCA3, AMACR and ETS Gene Fusions). In this article, we review those biomarkers and then discuss the challenges a biomarker has to undergo before it is approved in a clinical use.

Can molecular markers stratify the diagnostic value of high-grade prostatic intraepithelial neoplasia?

The diagnostic performance of isolated high-grade prostatic intraepithelial neoplasia in prostatic biopsies has recently been questioned, and molecular analysis of high-grade prostatic intraepithelial neoplasia has been proposed for improved prediction of prostate cancer. Here, we retrospectively studied the value of isolated high-grade prostatic intraepithelial neoplasia and the immunohistochemical markers α-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67 for better risk stratification of high-grade prostatic intraepithelial neoplasia in our local Swiss population. From an initial 165 diagnoses of isolated high-grade prostatic intraepithelial neoplasia, we refuted 61 (37%) after consensus expert review. We used 30 reviewed high-grade prostatic intraepithelial neoplasia cases with simultaneous biopsy prostate cancer as positive controls. Rebiopsies were performed in 66 patients with isolated high-grade prostatic intraepithelial neoplasia, and the median time interval between initial and repeat biopsy was 3 months. Twenty (30%) of the rebiopsies were positive for prostate cancer, and 10 (15%) showed persistent isolated high-grade prostatic intraepithelial neoplasia. Another 2 (3%) of the 66 patients were diagnosed with prostate cancer in a second rebiopsy. Mean prostate-specific antigen serum levels did not significantly differ between the 22 patients with prostate cancer and the 44 without prostate cancer in rebiopsies, and the 30 positive control patients, respectively (median values, 8.1, 7.7, and 8.8 ng/mL). None of the immunohistochemical markers, including α-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67, revealed a statistically significant association with the risk of prostate cancer in repeat biopsies. Taken together, the 33% risk of being diagnosed with prostate cancer after a diagnosis of high-grade prostatic intraepithelial neoplasia justifies rebiopsy, at least in our not systematically prostate-specific antigen-screened population. There is not enough evidence that immunohistochemical markers can reproducibly stratify the risk of prostate cancer after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia.

An adult onset case of alpha-methyl-acyl-CoA racemase deficiency.

α-Methyl-acyl-CoA-racemase (AMACR) deficiency (OMIM 604489) is a rare peroxisomal disorder with a variable age of onset from infancy to late adulthood. We describe a 45-year-old male with a history of seizures who presented with relapsing encephalopathy. Laboratory studies revealed an elevated serum pristanic acid concentration, an elevated pristanic/phytanic acid ratio, as well as the previously described homozygous mutation in the AMACR gene, c.154T>C, consistent with AMACR deficiency. This homozygous mutation is associated with a variable phenotype ranging from neonatal cholestasis to late-onset sensorimotor neuropathy. Dietary pristanic acid restriction was attempted to improve clinical status and the patient has remained in remission for more than 16 months.

Clinical applications of molecular biomarkers in prostate cancer detection.

Prostate cancer is a heterogeneous disease with regard to molecular alterations and clinical course. Early diagnosis of prostate cancer can increase the curative success rate for this disease. Because of the recent developments in the field of molecular biology, an increased interest occurred for molecular biomarkers, as tools for early prostate cancer detection, monitoring disease progression, predicting disease recurrence and therapeutic treatment efficacy. Many molecular biomarkers have been discovered in human serum, urine, seminal fluid and histological specimens.

P504S expressing circulating prostate cells as a marker for prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer deaths. The serum prostate specific antigen (PSA) is the only biomarker routinely used in screening. The aim of this study was to develop a system to test the presence of circulating prostate cells in men without a diagnosis of prostate cancer in relation with age, serum PSA levels and prostate biopsy by determining the co-expression of several markers such as CD82, HER-2 and matrix metalloproteinase 2 (MMP-2). For this purpose mononuclear cells were separated from blood using differential centrifugation and then prostate cells were identified by using standard immunocytochemical method. Results indicated that among 409 men screened for prostate cancer 16.6% were positive for circulating prostate cells. Cells were positive for MMP-2 and HER-2 in 100 and 14.3% of cases, respectively, without an association with age or PSA levels. However, CD82 protein expression was associated with older age and low grade tumors. It can be concluded that the study of circulating prostate cells with various markers could be a useful complementary screening test for prostate cancer in men with increased PSA level.

Use of a combination of biomarkers in serum and urine to improve detection of prostate cancer.

OBJECTIVE: To measure a combination of novel molecular biomarkers in urine/blood samples of consecutive patients referring lower urinary tract symptoms (LUTS) not previously diagnosed, to improve prostate cancer diagnosis. METHODS: Serum and urine samples from 113 men who went consecutively to the Department of Urology of our Institution. Biomarkers analyzed were AMACR and MMP-2 levels, and GSTP1/RASSF1A methylation status, in addition to PSA levels. Sensitivity, specificity, area under the ROC (AUROC) curves, and discriminant function analysis were assessed to determine the diagnostic potential of each variable alone or in combination. RESULTS: Of the patients, 30.08% had PCa and the remaining ones were tumor free. Areas under the ROC (AUROC) curves were as follows: 0.476 for PSA, 0.532 for AMACR, and 0.706 for MMP-2. Sensitivity and specificity for methylation status were 53.3 and 45.9%, respectively. The combination of these biomarkers resulted in an AUROC curve of 0.788, which significantly outperformed AUROC curves for PSA (P = 0.0033) and AMACR (P = 0.0375). Sensitivity, specificity, positive and negative predictive values for the combination of biomarkers were 57.1, 96.6, 88.9, and 82.4%, respectively. CONCLUSION: We conclude that analysis of this biomarker combination in body fluids improves very significantly the diagnosis of PCa compared to the PSA test.

Emerging biomarkers for the diagnosis and prognosis of prostate cancer.

BACKGROUND: Early detection of prostate cancer (CaP), the most prevalent cancer and the second-leading cause of death in men, has proved difficult, and current detection methods are inadequate. Prostate-specific antigen (PSA) testing is a significant advance for early diagnosis of patients with CaP. CONTENT: PSA is produced almost exclusively in the prostate, and abnormalities of this organ are frequently associated with increased serum concentrations. Because of PSA's lack of specificity for CaP, however, many patients undergo unnecessary biopsies or treatments for benign or latent tumors, respectively. Thus, a more specific method of CaP detection is required to augment or replace screening with PSA. The focus recently has been on creating cost-effective assays for circulating protein biomarkers in the blood, but because of the heterogeneity of CaP, it has become clear that this effort will be a formidable challenge. Each marker will require proper validation to ensure clinical utility. Although much work has been done on variations of the PSA test (i.e., velocity, density, free vs bound, proisoforms) with limited usefulness, there are many emerging markers at various stages of development that show some promise for CaP diagnosis. These markers include kallikrein-related peptidase 2 (KLK2), early prostate cancer antigen (EPCA), PCA3, hepsin, prostate stem cell antigen, and alpha-methylacyl-CoA racemase (AMACR). We review biomarkers under investigation for the early diagnosis and management of prostate cancer. SUMMARY: It is hoped that the use of panels of markers can improve CaP diagnosis and prognosis and help predict the therapeutic response in CaP patients.

Nonhuman primates as models for studies of prostate specific antigen and prostatic diseases.

BACKGROUND: Because prostate specific antigen (PSA) is released at increased levels into the blood early in the development of prostate cancer, benign prostatic hyperplasia (BPH) and prostatitis, it is widely used as a marker for these diseases. However, PSA has clinical limitations as a screen for prostatic diseases due to its low sensitivity and specificity. There is a strong need to better understand the biology of PSA and factors affecting its serum levels. METHODS: We evaluated cynomolgus macaques, rhesus macaques, baboons, and marmosets for their suitability as models for the study of PSA biology and prostatic diseases. RESULTS: Prostates of several nonhuman primates are anatomically similar to the human counterpart. Anti-human PSA antibody detected PSA antigens in all the Old World monkeys (cynomolgus macaques, rhesus macaques, and baboons) but not in marmosets. Of the Old World monkeys, cynomolgus macaques have the highest serum PSA levels; baboons have the lowest. Serum PSA levels from macaques includes a number of outlier samples with unusually high values. We also report two cases of abnormal pathologies in macaques accompanied by high serum PSA levels. One case consisted of prostatic hyperplasia involving both glandular and basal cells in a cynomolgus macaque and another of glandular hyperplasia and atrophy in a rhesus macaque. The finding that pathological changes in the prostate of macaques may lead to increases in serum PSA is worthy of further exploration. CONCLUSION: Cynomolgus macaques and rhesus macaques are promising animal models for PSA biology studies.

Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk: a replication study in an ethnically homogeneous population.

BACKGROUND: Examination of variants of the alpha-methylacyl-CoA racemase (AMACR) gene, as genetic contributors to prostate cancer risk, has been of considerable interest given the gene's recently established role as a diagnostic biomarker for prostate cancer. METHODS: The AMACR gene variants, M9V and D175G, were genotyped in a familial dataset comprising 127 cases and in a second sporadic prostate cancer dataset comprising 414 cases and 319 controls. Genotype-disease associations were examined employing the M(QLS) test and unconditional logistic regression. Differences in allele frequencies were examined using the Fisher's exact test. Association between the AMACR haplotypes and prostate cancer risk was also investigated using haplo.score. RESULTS: Significant evidence for association with prostate cancer risk for both the M9V and D175G variants was observed in the Tasmanian prostate cancer dataset. Whilst this association remained significant, it was diminished when relatedness amongst the familial prostate cancer cases was considered. CONCLUSION: This study, performed in a relatively genetically homogenous Tasmanian population, provides further evidence for a significant association between variants within the AMACR gene and prostate cancer risk. Risk was found to be more significantly associated with AMACR gene variants in sporadic compared to familial prostate cancer cases. These findings again highlight that genetic heterogeneity in the study population should be considered when examining genetic risk factors in prostate cancer.

Sequence variation in alpha-methylacyl-CoA racemase and risk of early-onset and familial prostate cancer.

BACKGROUND: Expression of the alpha-methylacyl-CoA racemase (AMACR) gene has been established as a sensitive and specific biomarker for the diagnosis of prostate cancer. An initial study has also suggested that the risk of familial (but not sporadic) prostate cancer may be associated with germline variation in the AMACR gene. METHODS: In a study of brothers discordant for the diagnosis of prostate cancer (including 449 affected and 394 unaffected men) from 332 familial and early-onset prostate cancer families, we used conditional logistic regression and family-based association tests to investigate the association between prostate cancer and five single nucleotide polymorphisms (SNPs) tagging common haplotype variation within the coding and regulatory regions of AMACR. RESULTS: The strongest evidence for prostate cancer association was for SNP rs3195676, with an estimated odds ratio of 0.58 (95% confidence interval = 0.38-0.90; P = 0.01 for a recessive model). This non-synonymous SNP (nsSNP) results in a methionine-to-valine substitution at codon 9 (M9V) in exon 2 of the AMACR gene. Three additional nsSNPs showed suggestive evidence for prostate cancer association (P < or = 0.10). CONCLUSIONS: Our results confirm an initial report of association between the AMACR gene and the risk of familial prostate cancer. These findings emphasize the value of studying early-onset and familial prostate cancer when attempting to identify genetic variation associated with prostate cancer.

Incorporating monotonicity into the evaluation of a biomarker.

In the assessment of clinical utility of biomarkers, case-control studies are often undertaken based on existing serum samples. A common assumption made in these studies is that higher levels of the biomarker are associated with increased disease risk. In this article, we consider methods of analysis in which monotonicity is incorporated in associating the biomarker and the clinical outcome. We consider the roles of discrimination versus association and assess methods for both goals. In addition, we propose a semiparametric isotonic regression model for binary data and describe a simple estimation procedure as well as attendant inferential procedures. We apply the various methodologies to data from a prostate cancer study involving a serum biomarker.

Detection of alpha-methylacyl-coenzyme-A racemase transcripts in blood and urine samples of prostate cancer patients.

BACKGROUND: Alpha-methylacyl-coenzyme-A racemase (AMACR) has been shown to be a highly specific marker for prostate cancer cells, even in the earliest stages of malignant progression. It is expressed at much higher levels than prostate-specific antigen (PSA) in malignant tissues, and is not expressed at appreciable levels in normal prostatic epithelium. In this study, we demonstrate the quantitative detection of AMACR transcripts in peripheral blood of prostate cancer patients using real-time RT-PCR. In addition, we have undertaken a pilot study to demonstrate the potential application of this technique for the detection of prostate tumor cells in urine samples from patients with prostate cancer. METHODS: A real-time RT-PCR assay was developed for detection of the expression of AMACR in prostate cancer patients. Blood samples from 163 patients were tested at various stages of disease progression, with or without therapy. Blood specimens from patients with benign prostate disorders and other types of cancer were also evaluated. RESULTS: In 28 of 58 samples from patients with known metastatic disease who were undergoing treatment, an AMACR expression signal above the cut-off value was detected, consistent with the presence of circulating tumor cells. In 39 of 88 patients with presumptive organ-confined disease, there was evidence of low levels of circulating tumor cells. Comparison of AMACR RT-PCR with known serum PSA values indicated that a combination of these parameters significantly increased the sensitivity for detection of progressive disease. In a pilot study analyzing urine samples from seven prostate cancer patients, elevated AMACR expression levels were detected in the urine sediments of four of six stage-T1 prostate cancer patients and in the one patient with stage-T2 prostate cancer. CONCLUSION: The data presented in this study indicates that AMACR real-time RT-PCR may aid in the detection and staging of prostate cancer.

Can p503s, p504s and p510s gene expression in peripheral-blood be useful as a marker of prostatic cancer?

BACKGROUND: The aim of the study was to investigate whether p503S, p504S and p510S gene expression in peripheral-blood be useful as a diagnostic or prognostic marker of prostatic cancer. METHODS: Circulating cells were identified by reverse transcription-polymerase chain reaction (RT-PCR) to detect p503S, p504S and p510S mRNA in peripheral blood (PB) from 11 patients with treated prostatic carcinoma (CaP), 11 with newly-diagnosed untreated CaP and 20 with benign prostatic hyperplasia (BPH) (controls). RESULTS: RT-PCR amplified P503S in 7 of 11 untreated and 2 of 11 treated patients with CaP and 5 of 20 with BPH; p504S in 7 of 11 untreated and in 9 of 11 treated patients with CaP and 11 of 20 with BPH; whereas it amplified p510S in all subjects with CaP and in 15 of 20 with BPH. CONCLUSION: These findings suggest that the investigated genes are poorly specific and probably of little use as diagnostic or prognostic prostatic markers in peripheral blood for monitoring disease progression and recurrence.