Newer Prognostic Markers
Currently, there are several markers that are being evaluated in prostate cancer staging. The list of these markers deserves close follow-up even though their clinical utility still has to be clearly established.
Botticelli and associates reported on the utility of silver stained nucleolar organizer regions (AgNORs) rates in 40 needle core biopsies. They noted a good correlation between PSA levels, Gleason scores, and AgNORs scores at biopsy. The quantitative method showed a higher average number of AgNORs dots per nucleus in moderately differentiated and undifferentiated cancers. Long-term results are awaited.[76,77,78]
Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is thought to play an important role in the induction of microvasculature. One study evaluating bFGF expression in prostatic carcinoma assessed by enzyme-linked immunosorbent assay (ELISA) concluded that increased bFGF release might be associated with a more aggressive tumor phenotype. The exact role of this marker is still not established.
OA-519 (fatty acid synthase) has been reported as an independent predictor of pathologic stage in adenocarcinoma of the prostate. In a study of 66 RP specimens of varying pathologic stages, it was found that both OA-519 and Gleason score were strong independent predictors of pathologic stage (P = .0004).[81,82,83]
Human metallopanstimulin (MPS-1) is a 9.4-kDa multifunctional, ribosomal S27/nuclear, "zinc finger" protein expressed in a wide variety of actively proliferating cells and tumor tissues. It has been shown that detection of MPS-N, immunoreactive material in sera, corresponding to the NH2 terminus of MPS-1, provides a method for detecting some abnormal proliferative conditions and/or active oncogenic processes in patients.
Fernandez-Pol and associates investigated MPS-N and MPS-N-like antigens present in the blood of patients with prostatic carcinoma and their relationship to clinical status. They observed that in individuals without prostate cancer, MPS-N levels were lower than 10 ng/mL. In untreated patients with prostate cancer at stage T1/T2, MPS-N levels were 10 ng/mL to 30 ng/mL; in stage T3/T4, MPS-N levels were 30 ng/mL to 50 ng/mL; and in stage Mlb (distant metastasis to the bones), MPS-N levels were extremely high (> 50 ng/mL). MPS-N levels remained very high (> 50 ng/mL) in Mlb patients who did not respond to therapy, but decreased in Mlb patients who went into remission after treatment. The authors concluded that (1) in untreated prostate cancer patients, the increase in serum MPS-N correlated with the stage of the disease; and (2) the MPS-N tumor marker predicted the degree of aggressiveness of tumor growth and response to therapy.
Giovannucci and associates have recently shown that the length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, is inversely related to transcriptional activity of the gene. They observed that an androgen receptor gene with fewer CAG repeats was associated with a higher risk of prostate cancer. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension or distant metastases (stage C or D) or high histologic grade. These results demonstrate that a shorter CAG repeat sequence in the androgen receptor gene predicted higher grade and advanced stage of prostate cancer at diagnosis, and metastasis and mortality from the disease.[85,86,87,88,89]
Trybus and associates examined 35 prostate tumors for allelic loss at 24 polymorphic loci spanning chromosome 10, using tissue microdissection and PCR techniques. Deletions in at least 1 chromosome 10 locus were found in 25 tumors (71%). The common region of deletion on 10p included loci D10S211-D10S89-D10S111. Fluorescence in situ hybridization of yeast artificial chromosome with probes encompassing these loci demonstrated that the 10p region of deletion maps to 10p11.2. Losses involving 10p loci alone were most common in localized (5/14, 36%) and least common in metastatic (0/8) tumors.
The common region of deletion on 10q included loci D10S219-D10S215, consistent with the major region of deletion recently defined for prostate tumors on 10q. Losses involving 10q loci alone were lowest in localized and locally invasive tumors and highest in tumors metastatic to regional lymph nodes. These results suggest that whereas 10p losses might define less invasive tumors, 10q losses may play a role in the progression to more advanced tumors with a greater potential to spread distantly.
Van Veldhuizen and associates evaluated the expression of the urokinase plasminogen activator in 36 human prostate cancer specimens by immunohistochemistry. A total of 71% of cancer specimens with extracapsular extension showed increased expression of urokinase plasminogen activator, vs 26.6% of those without capsular invasion. Increased expression was localized to the glandular cytoplasm, with tumor stroma yielding predominantly negative results. Authors concluded that the increased expression of this marker may signal the presence of aggressive tumors and have suggested further evaluation in a larger cohort of patients.
CYP3A4, a member of the cytochrome P450 super gene family, is involved in androgen metabolism resulting in the oxidation of testosterone to 2b-, 6b-, or 15b-hydroxytestosterone. A novel allelic variant CYP3A4-V containing an A to G mutation in the 5' regulatory element upstream of the CYP3A4 gene was shown to be associated with a higher clinical stage and grade in European American (EA) men with prostate cancer.[92,93] This novel variant was more pronounced in EA men diagnosed at an older age and may be associated with a relatively higher basal testosterone level in older men, resulting in prostate cancers of higher stage than those occurring in older men who do not carry this variant.
Over 60% of prostate tumors show loss of 10q23-25.[94,95,96,97] Recent studies have suggested that mutation of PTEN/MMAC1 is a late genetic event associated with advanced cancer, and prostate tumors of high grade and stage are more likely to harbor 10q loss and PTEN/MMAC1 mutations. The identification of PTEN/MMAC1 as a frequent target in sporadic prostate cancer highlights the gene as a candidate for novel diagnostic and therapeutic approaches.[94,95,96,97]
Loss of heterozygosity (LOH) frequently signifies the presence of a mutant copy of the remaining allele of a tumor suppressor gene. LOH at 16q22 has implicated E-cadherin as potential tumor suppressor gene.[98,99,100,101,102] E-cadherin is expressed on the cell surface of most, if not all, epithelial tissues. It functions as a mediator of cell-cell interactions, and it has been well characterized as a suppressor of invasiveness of epithelial tumor cells in vitro. E-cadherin maps to 16q22, a region that is subject to allelic deletion in carcinomas of the prostate, ovary, breast, and liver. LOH for 16q in the region of the E-cadherin gene was observed in 20% to 40% of breast carcinomas, and a significant inverse correlation was reported between E-cadherin expression and tumor grade, stage, and overall survival in prostate cancer patients. Microsatellite alterations on 16q22.1-23.1 have suggested a nonrandom event in prostate cancer, and implicate E-cadherin as a candidate tumor suppressor gene in this region of the long arm of chromosome 16.[98,99,100,101,102]KIP1
Negative cell cycle regulators that act as cyclin-dependent kinase (CDK) inhibitors (called CKIs) have been implicated as potential tumor suppressor genes. The p27KIP1 gene is located at 12p12-13.1.[103,104,105,106,107] Normal human prostate tissue has been shown to produce abundant amounts of p27 protein and high levels of p27KIP1 mRNA levels. In primary prostatic carcinomas, low levels of p27 were correlated with more aggressive tumors, based on their association with time to PSA detection after RP, while controlling for other variables.
There is accumulating evidence that dysregulation of apoptosis is one of the mechanisms involved in oncogenesis. Apoptosis, or programmed cell death, is under the genetic control of various genes, and Bcl-2, a proto-oncogene, is one such example. Bcl-2 has been shown to block apoptosis, and is thought to be involved in terminal cell differentiation. Bcl-2 protein expression in prostate cancer is associated with cell proliferation and may serve as a predictive factor for the prognosis of prostate cancer. Studies have evaluated Bcl-2 expression as a biomarker of ethnic difference in clinically localized prostate cancers of African American and EA men. They have shown that there was a significant association between Bcl-2 immunopositivity and higher S-phase fractions in African American men with prostate cancer.
The KAI1 gene, mapped to 11p11.2, was isolated originally as a prostate-specific tumor metastasis suppressor gene. KAI1-expressing cancer cells are suppressed in their metastatic ability, whereas their primary tumor growth is not affected.[109,110,111] KAI1 is identical to CD8, a surface glycoprotein of lymphocytes consisting of 267 amino acids. It plays a role in cell-cell and cell-extracellular matrix interactions, providing a line of defense against invasive cancer cells and metastasis. Immunohistochemical analyses of human tumor samples showed a decreased expression or down-regulation of this gene during tumor progression, which was correlated with poor patient survival. Recent evidence shows that KAI1 is directly activated by p53, and loss of p53 function leads to down-regulation of the KAI1 gene. Concomitant loss of expression of p53 and KAI1 resulted in poor survival outcomes.[109,110,111]
Several others markers, including proliferative index,[112,113] cell proliferation, apoptosis,[115,116] DNA ploidy,[117,118,119,120] insulin-like growth factor, c-erbB-2 oncoprotein, KI-67, [114,123,124,125] CD 34, 27 kip1, and cyclin D1, have also been investigated but their exact utility is not yet defined.
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Cite this: Evaluation of the Patient With Prostate Cancer - Medscape - Sep 14, 2000.