Radiological evaluation of postchemotherapy residual masses of metastatic seminoma is characterized by poor diagnostic accuracy. Serum levels of microRNA-371a-3p (M371) involve high specificity and ...sensitivity for the primary diagnosis of seminoma. We evaluated if M371 levels can indicate the presence of vital disease in postchemotherapy residual masses in patients with metastatic seminoma.
Twenty-three seminoma patients (median age 52 years) with residual masses had posttreatment measurements of serum M371 levels (group A), fourteen of whom had measurements also beforehand. The posttreatment results were compared with the clinical outcome during follow-up. Eleven patients with complete remission after treatment of metastatic seminoma (group B) and 33 men with non-malignant testicular diseases (group C) served as controls. M371 serum levels were measured by quantitative real-time PCR using miR-30b-5p as endogenous control. An evaluation was performed with descriptive statistical methods.
Twenty-two patients of Group A had uneventful follow-up so far, twenty-one of whom had M371 level <5, and one other had a mildly elevated level below relative quantity (RQ) = 10. One patient with a level of RQ = 26.2 rapidly progressed. The median posttreatment M371 level of the non-progressing patients of group A is not significantly different from the median level of the control group with complete remission (B). Before treatment, the median M371 levels in groups A and B were 507.6 and 143.9, respectively. In both groups, significant drops in M371 levels resulted from treatment.
Normal M371 serum levels at the time of completion of treatment of metastatic seminoma indicate the absence of vital seminoma in residual masses, while elevated levels >RQ = 10 predict the presence of disease. The optimal timing of M371 measurement after chemotherapy and the appropriate cutoff level still need to be determined. Based on the present results, measuring serum M371 levels involves the potential of a novel tool for assessing postchemotherapy residual masses of metastatic seminoma.
In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor ...PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
In testicular neoplasms, the interrelationship of elevations of the novel serum tumor marker microRNA-371a-3p (M371) and traditional markers with other clinical features is still incompletely ...understood. The present study evaluated marker expression rates in relation to various other clinical parameters.
Methods
The following data were retrospectively registered from 641 consecutive patients with testicular neoplasms: histology, such as seminoma (
n
= 365), nonseminoma (
n =
179), benign tumor (
n =
79), other malignant tumor (
n =
18); patients age (years); clinical stage (CS1, CS2a/b, CS2c, CS3); and preoperative elevation of beta HCG, AFP, LDH, M371 (yes/no). Descriptive statistical methods were employed with comparisons of various subgroups to disclose associations of marker expression rates with age, histology and CS, and of age with histology.
Results
The histologic subgroups revealed significantly different expression rates of tumor markers. M371 performed best with expression rates of 82.69% and 93.58% in seminoma and in nonseminoma, respectively. In germ cell tumors, all markers had significantly higher expression rates in metastasized stages than in localized disease. All markers except LDH have significantly higher expression rates in younger than in older patients. Nonseminoma is most prevalent in the youngest age category, seminoma predominates in patients > 40 years, other malignancies were restricted to patients > 50 years.
Conclusion
The study documented significant associations of serum marker expression rates with histology, age and clinical staging, with highest rates in nonseminomas, young age and advanced clinical stages. M371 showed significantly higher expression rates than other markers suggesting its superior clinical usefulness.
Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum ...levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse.
In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis.
Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse.
The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.
RAGE is a member of the immunoglobulin superfamily of cell surface molecules playing key roles in pathophysiological processes, e.g. immune/inflammatory disorders, Alzheimer's disease, diabetic ...arteriosclerosis and tumourigenesis. In humans 19 naturally occurring
RAGE splicing variants resulting in either N-terminally or C-terminally truncated proteins were identified and are lately discussed as mechanisms for receptor regulation. Accordingly, deregulation of sRAGE levels has been associated with several diseases e.g. Alzheimer's disease, Type 1 diabetes, and rheumatoid arthritis. Administration of recombinant sRAGE to animal models of cancer blocked tumour growth successfully. In spite of its obvious relationship to cancer and metastasis data focusing sRAGE deregulation and tumours is rare. In this study we screened a set of tumours, healthy tissues and various cancer cell lines for
RAGE splicing variants and analysed their structure. Additionally, we analysed the ratio of the mainly found transcript variants using quantitative Real-Time PCR. In total we characterised 24 previously not described canine and 4 human RAGE splicing variants, analysed their structure, classified their characteristics, and derived their respective protein forms. Interestingly, the healthy and the neoplastic tissue samples showed in majority RAGE transcripts coding for the complete receptor and transcripts showing insertions of intron 1.
High-mobility group AT-hook 2 (HMGA2) protein acts as an oncofoetal transcriptional regulator. In mesenchymal tissues, its expression can be induced by a variety of growth factors such as fibroblast ...growth factor-1 (FGF1) and platelet-derived growth factor-BB (PDGF-BB) as well as by foetal bovine serum (FBS), thus enhancing proliferation.
To examine these effects in epithelial malignancies, we used the PC-3 prostate cancer cell line for assaying proliferation and HMGA2 expression in response to incubation with growth factors and FBS. The HMGA2 locus was investigated by fluorescence in situ hybridisation (FISH) for loss, amplification or re-arrangement.
PC-3 is a cell line that moderately overexpresses HMGA2. None of the growth factors nor FBS caused significantly increased expression of HMGA2. In contrast, a significantly augmented proliferation rate was observed when applying FGF1 or PDGF-BB for 12 h.
HMGA2 is expressed independently of external stimuli, whereas proliferation stimulated by growth factors is independent of further elevated HMGA2 expression.
The chromosomal translocation t(2;3)(q13;p25) characterizes a subgroup of tumors originating from the thyroid follicular epithelium and was initially discovered in a few cases of adenomas. Later, a ...fusion of the genes PAX8 and PPARG resulting from this translocation was frequently observed in follicular carcinomas and considered as a marker of follicular thyroid cancer. According to subsequent studies, however, this rearrangement is not confined to carcinomas but also occurs in adenomas, with considerably varying frequencies. Only five cases of thyroid adenomas with this translocation detected by conventional cytogenetics have been documented. In contrast, studies using reverse-transcription polymerase chain reaction (RT-PCR) detected fusion transcripts resulting from that translocation in an average of 8.2% of adenomas. The aim of this study was to determine the frequency of the PAX8-PPARG fusion in follicular adenomas and to use the HMGA2 mRNA level of such tumors as an indicator of malignancy. In cytogenetic studies of 192 follicular adenomas, the t(2;3)(q13;p25) has been identified in only two cases described herein. Histopathology revealed no evidence of malignancy in either case, and, concordantly, HMGA2 mRNA levels were not elevated. In summary, the fusion is a rare event in follicular adenomas and its prevalence may be overestimated in many RT-PCR–based studies.
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