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Kimmo J Hatanpaa

Publications and source records attributed to Kimmo J Hatanpaa.

7 recordsLinked to original sources
PubMed2006

Human postmortem tissue: what quality markers matter?

Postmortem human brain tissue is used for the study of many different brain diseases. A key factor in conducting postmortem research is the quality of the tissue. Unlike animal tissue, whose condition at death can be controlled and influenced, human tissue can only be collected naturalistically. This introduces potential confounds, based both on pre- and postmortem conditions, that may influence the quality of tissue and its ability to yield accurate results. The traditionally recognized confounds that reduce tissue quality are agonal factors (e.g., coma, hypoxia, hyperpyrexia at the time of death), and long postmortem interval (PMI). We measured tissue quality parameters in over 100 postmortem cases collected from different sources and correlated them with RNA quality (as indicated by the RNA Integrity Number (RIN)) and with protein quality (as measured by the level of representative proteins). Our results show that the most sensible indicator of tissue quality is RIN and that there is a good correlation between RIN and the pH. No correlation developed between protein levels and the aforementioned factors. Moreover, even when RNA was degraded, the protein levels remained stable. However, these correlations did not prove true under all circumstances (e.g., thawed tissue, surgical tissue), that yielded unexpected quality indicators. These data also suggest that cases whose source was a Medical Examiner's office represent high tissue quality.

Adult↗
PubMed2006

Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-alpha (TGF-alpha) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-alpha and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma.

Autocrine Communication↗
PubMed2005

Chromosome 22q deletions in atypical teratoid/rhabdoid tumors in adults.

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, malignant brain tumors that usually occur in the posterior fossa. Both AT/RT and the analogous tumor outside the brain, malignant rhabdoid tumor, share a polyphenotypic immunoprofile and frequent 22q deletions with inactivation of the IN11/hSNF5 gene. Reports, so far, indicate that AT/RTs occur almost exclusively in children, most of whom are 5-years-old or less. The rarity of the tumor and the polyphenotypic immunoprofile, characterized by antigen expression that is often patchy, make diagnosis in adults difficult and controversial. We describe three AT/RTs in adults in which the diagnoses were supported by detection of 22q11.2 deletions, INI1 mutation and/or loss of INI1 protein expression. Two patients were female, ages 20 and 31 and one was male, age 45. Two tumors occurred in the sella or sellar region and one in the cerebellum. In all cases, fluorescence in situ hybridization with probes to the BCR (22q11.2) and NF2 (22q12) regions of chromosome 22 revealed single copy deletions of BCR with normal dosages of NF2 and, in all cases, immunohistochemistry demonstrated loss of INI1 protein expression. In one case, a single base pair deletion was detected in the INI1/hSNF5 gene. These molecular findings confirm the occurrence of AT/RTs in adults. Although rare, AT/RT should be considered in the differential diagnosis of poorly differentiated intracranial tumors in adults.

Adult↗
PubMed2004

Atypical teratoid/rhabdoid tumor: cytology and differential diagnosis in adults.

Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant intracranial neoplasms that usually occur in the posterior fossa of children. They are characterized by cells with paranuclear rhabdoid inclusions, a mesenchymal and epithelial immunohistochemical profile, and 22q deletions with inactivation of the INI1/hSNF5 gene. Although they usually occur in young children, AT/RTs are being recognized in adults with increasing frequency. We report the cytologic features of an AT/RT from the cerebellum of a 45-year-old man and discuss the differential diagnosis in adults.

Cerebellar Neoplasms↗
PubMed2004

Molecular diagnosis of metastasizing oligodendroglioma: a case report.

We report the case of a suspicious parotid mass in which molecular determination of loss of heterozygosity (LOH) of chromosome arms 1p and 19q in combination with cytologic and immunohistochemical analysis defined the tumor to be metastatic oligodendroglioma. The patient was a 41-year-old woman who developed a World Health Organization grade II oligodendroglioma in her right frontal lobe at age 32, for which no adjuvant chemo- or radiotherapy was administered. Five years following this diagnosis, radiological assessment revealed a 10-centimeter mass in the tumor bed, suspicious for a recurrence. Resection of this lesion revealed an anaplastic oligodendroglioma (grade III) and adjuvant radiotherapy was given. Eleven months after this surgery the patient presented with a 5.5-cm subcutaneous, non-mobile, non-tender mass in the region of the right parotid gland. Fine needle aspiration (FNA) yielded highly cellular material, morphologically and immunohistochemically suspicious for oligodendroglioma. Molecular analysis of microsatellite loci residing on chromosome arms 1p and 19q was performed using DNA extracted from the patient's recurrent brain oligodendroglioma and the FNA specimen. This analysis revealed evidence of LOH at all eight of the microsatellite loci tested. The combination of cytologic and molecular findings defined the extracranial tumor to be metastatic oligodendroglioma.

Adult↗
PubMed2003

Molecular diagnosis of oligodendroglioma in paraffin sections.

Distinction of oligodendrogliomas from other gliomas is clinically important, but the histologic diagnosis of oligodendroglioma has been a difficult and notoriously subjective task. Testing for loss of heterozygosity (LOH) on chromosomal arms 1p and 19q, the genetic signature of oligodendroglioma, has emerged as a useful, objective adjunct to the traditional histologic evaluation. However, LOH testing of glioma specimens has not yet been widely implemented, presumably because of a lack of a practical LOH assay. We describe a 1p and 19q LOH assay suitable for routine diagnostics. In contrast to traditional microsatellite-based LOH analysis, we show that detection of LOH is usually possible even without normal tissue or blood from the same patient. A small area of tumor on a single paraffin section is sufficient for the assay. The assay protocol consists of a one-step DNA extraction, multiplex PCR for microsatellites on 1p and 19q, and capillary electrophoresis of the PCR products. LOH is detected by analysis of the allelic patterns and by integration of data from multiple highly polymorphic microsatellites. In a validation study on 19 gliomas, the results were concordant with results obtained by established methods and correlated well with histologic diagnoses. Because only a paraffin section is required, the pathologist can perform both the traditional histopathologic evaluation and this supporting molecular assay from the material at hand.

Brain Neoplasms↗