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Biomedical subjects

Jennifer L Hunt

Publications and source records attributed to Jennifer L Hunt.

At least 19 recordsLinked to original sources
PubMed2007

Down-regulation of S100A2 in lymph node metastases of head and neck cancer.

BACKGROUND: Our cDNA microarray analysis of squamous cell carcinoma of the head and neck (SCCHN) previously identified that S100A2 was down-regulated in highly metastatic 686LN-M3s cell lines established through in vivo selection using a metastatic xenograft mouse model. S100A2, a putative tumor suppressor, has been found to be down-regulated in several types of primary tumor as compared with the normal tissue. Only a few reports have explored its expression status and function in metastasis. METHODS: To further confirm down-regulation of S100A2 in human metastasis, we examined S100A2 expression using immunohistochemical analysis of paraffin-embedded SCCHN tissues. The samples included primary SCCHN tumors (Tu-1) and involved lymph nodes (Met-1) from the same patients, and primary tumors in node-negative patients (Tu-2). RESULTS: Most of these tumors expressed S100A2 but lymph node metastases showed a pattern of reduced staining for S100A2 compared with primary tumors. A similar expression pattern of S100A2 was also observed in several SCCHN cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting. Particularly, S100A2 expression was lower in 686LN than Tu686 and hardly detectable in the metastatic derivatives 686LN-M3s. Further study of S100A2 promoter showed higher methylation intensity in these metastatic derivatives than in Tu686 and 686LN. CONCLUSIONS: S100A2 was down-regulated in lymph node metastasis of SCCHN, suggesting that instead of being a putative tumor suppressor, S100A2 may play a role in the metastasis of SCCHN.

Carcinoma, Squamous Cell↗
PubMed2007

Epithelial-myoepithelial carcinoma: a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract.

To further define the clinicopathologic spectrum of epithelial-myoepithelial carcinoma (EMCa), we report the gross, histologic, and immunophenotypic characteristics of 61 tumors seen within a 30-year-period. The mean age at presentation was 60.9 years, with a female predominance (1.5:1). The most common sites were parotid (62.1%), sinonasal mucoserous glands (10.3%), palate (8.6%), and submandibular (8.6%). Most EMCas showed a characteristic nodular/multinodular growth pattern and classic biphasic tubular histology. However, new morphologies in EMCa such as ancient change (8.2%), "Verocay"-like change (3.3%), and sebaceous differentiation (13.1%) were noted. Specific histologic variants were dedifferentiated EMCa (3.3%), oncocytic EMCa (8.2%), EMCa ex pleomorphic adenoma (1.6%), double-clear EMCa (3.3%), and EMCa with myoepithelial anaplasia (3.3%). All cytokeratin cocktails selectively highlighted the epithelial component well. Of the myoepithelial markers, p63, smooth muscle actin and vimentin performed best. Bcl-2 and c-kit were frequently positive (66.7% and 69.2%, respectively). p53 was highly expressed only in 1 dedifferentiated EMCa. The recurrence rate was 36.3% (median disease-free survival 11.34 y), but death was rare with 5-year and 10-year disease-specific survivals of 93.5% and 81.8%, respectively. The most important univariate predictors of recurrence were margin status (log rank P=0.006), angiolymphatic invasion (P=0.002), tumor necrosis (P=0.004), and myoepithelial anaplasia (P=0.038). Thus, EMCa is generally a low-grade tumor with a broader morphologic spectrum than previously thought, with several key features predictive of recurrence. Immunohistochemistry can aid diagnosis by highlighting the biphasic nature of the tumor.

Adolescent↗
PubMed2007

Microsatellite instability is uncommon in lymphoepithelioma-like carcinoma of the lung.

Primary lymphoepithelioma-like carcinoma of the lung (LELC) shares some morphologic and clinical characteristics with malignancies associated with microsatellite instability (MSI). The aims of our study were to determine the MSI status in LELC and compare these findings with stage I non-small cell lung carcinoma (NSCLC) with marked lymphocytic host response (MLHR). We assessed MSI by a DNA-based polymerase chain reaction assay using mononucleotide (BAT25 and BAT26) and dinucleotide (D2S123, D5S346, and D17S250) repeats. MSI was detected in 2 (29%) of 7 LELC cases with only 1 marker (D17S250), and in 3 (19%) of 16 NSCLC cases with MLHR with only 2 markers (1D2S123 and 2 D17S250). Loss of heterozygosity (LOH) was detected at 1 or 2 of 3 dinucleotide repeats in 11 NSCLC cases (69%) with MLHR and 3 LELC cases (43%) (P = .36). The overall frequencies of LOH in NSCLC with MLHR were 29% and 19% in LELC (P = .55). MSI is very uncommon in LELC, indicating that MSI is not an important event in carcinogenesis for this tumor subtype. The presence of LOH suggests a probable role of tumor suppressor genes in LELC carcinogenesis.

Aged↗
PubMed2006

Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.

PURPOSE: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. EXPERIMENTAL DESIGN: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. RESULTS: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. CONCLUSIONS: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

Adult↗
PubMed2006

Comparison of allelic losses in chondroblastoma and primary chondrosarcoma of bone and correlation with fluorescence in situ hybridization analysis.

Chondroblastoma (CBL) is a benign neoplasm of bone for which the genomic characteristics remain unclear. We compared the status of allelic losses of CBL with that seen in a set of chondrosarcomas (CS) to determine whether differences in their natural history and behavior are also reflected genetically. Eleven cases of CBL and 10 cases of CS of different grades were included. Tumors were subjected to microdissection and polymerase chain reaction using 17 markers located near genes on chromosomes 5, 9, 11, 13, 17, and 19. The selected chromosomes are known to be involved in several mesenchymal neoplasms. Fluorescence in situ hybridization was also performed on tumors displaying allelic losses, with dual-color probes for 9p, 17p, and 13q. Fractional allelic losses per gene ranged from 18.2% to 63.7% in CBLs and from 28.6% to 66.7% in CSs. Loss of heterozygosity (LOH) of 5q, 9p, 11p, 13q, and 19q occurred in both CBLs and CSs. Loss of heterozygosity of 17p (p53 locus) occurred in 7 of 11 CBLs and in only 1 case of recurrent CS. The pattern of allelic loss was similar in low-grade CSs and CBLs. Loci with LOH in both tumor types suggest possible involvement of the genes p53, RB1, CDKN2/p16, ERC, and XRCC in tumorigenesis. Overall correlation between LOH and fluorescence in situ hybridization results was 90% with 17p13, 80% with 9p, and 60% with 13q. The role of p53 in CBL is uncertain; however, given the benign behavior of this tumor, it is probably unrelated to tumor progression.

Adolescent↗
PubMed2006

Malignant mixed tumors of the salivary gland: a study of loss of heterozygosity in tumor suppressor genes.

Carcinosarcomas and carcinoma ex pleomorphic adenoma of the salivary glands are rare tumors that fit into the broader category of malignant mixed tumors. Although most evidence has suggested that the different morphologic components arise from a common clonal origin, there are very few studies that have provided molecular evidence for this clonality. In this study, we examined a set of seven carcinosarcomas and four carcinomas ex pleomorphic adenoma for tumor suppressor gene loss of heterozygosity, in order to assess the clonal patterns in the varying components. Microdissection was performed to obtain each morphological component and tumor suppressor gene loci on 3p, 5q, 9p, 17p, 17q, and 18q were analyzed. The fractional allelic loss (FAL) was calculated for each area, and the different targets were compared for their molecular profile. The overall mean FAL of the malignant targets was 42%. In carcinosarcomas, the sarcomatous targets had a higher mean FAL than the carcinomatous targets (68 vs 46%, respectively) and in carcinomas ex pleomorphic adenoma, the mean FAL in the benign component was 11 vs 46% seen in the carcinomatous component. The most frequently lost genetic loci were p53 (17p13, 73%), nm23-H1 (17q21, 55%), and DCC (18q21, 50%). Loss of heterozygosity of 17q21 and 9p21 only occurred in carcinosarcomas and not in carcinomas ex pleomorphic adenoma. Within the carcinosarcomas, the mutational profiles were conserved between epithelial and sarcomatous areas. In carcinomas ex pleomorphic adenoma, loss of heterozygosity was uncommon in the benign component, but the mutations were conserved in the corresponding malignant areas. These results support the hypothesis that the carcinomatous and sarcomatous components of carcinosarcomas are clonally related. Furthermore, these data support prior studies that suggest a common clonal origin for the benign and malignant components of carcinomas ex pleomorphic adenoma.

Adult↗
PubMed2006

Fractional allelic loss of tumor suppressor genes identifies malignancy and predicts clinical outcome in follicular thyroid tumors.

Thyroid follicular tumors can be challenging diagnostically and clinically, because the cytologic and histologic features can be subtle and prognosis is also difficult to predict. In this study, we analyzed thyroid follicular tumors with known long-term follow-up for a molecular panel of tumor suppressor genes to determine whether this molecular approach has prognostic significance. Microdissection and DNA extraction were performed from tumor and normal tissue. Polymerase chain reaction (PCR) was performed for 13 short tandem repeats at or near tumor suppressor genes. PCR product was detected using semiquantitative capillary gel electrophoresis and fractional allelic loss (FAL) was calculated. We included eight adenomas, three minimally invasive carcinomas, four angioinvasive carcinomas, and three widely invasive carcinomas with a mean follow-up of 77 months. Three patients died of disease and an additional two are alive with disease recurrence/metastasis. The mean FAL for benign tumors (14%) was significantly different from that of malignant tumors (56%, p < 0.001). Patients with a follicular tumor who had no evidence of disease recurrence had a mean FAL of 22% and those with disease recurrence or death from disease had a mean of 78% (p < 0.002). Based on these results, a tumor suppressor gene panel for allelic imbalance in follicular-derived tumors (FTT) may correlate with both malignancy and outcome in patients with follicular-derived carcinomas of the thyroid.

Adenoma↗
PubMed2006

NM-23 gene loss of heterozygosity and protein expression in high-stage laryngeal squamous cell carcinomas.

Tumor suppressor genes that reduce metastatic potential have been described in a variety of different tumor types. One of the main tumor metastasis suppressor genes is nm-23, which is a nucleoside diphosphate kinase. Two isotypes, nm-23H1 and nm-23H2, have been cloned and map to chromosome 17q21.3. In a variety of tumors, including colon cancer and breast cancer, loss of expression of nm-23 is associated with lymph node metastasis. In other organ systems, however, this relationship is not seen. In head and neck squamous cell carcinomas (HNSCC), there have been conflicting results regarding the association between nm-23 protein expression and metastatic potential. To further explore the tumor metastasis suppressor function of nm-23 in HNSCC, we studied high-stage laryngeal carcinomas, tumors with and without cervical lymph node metastasis for nm-23 protein expression and loss of heterozygosity of the gene locus. Twenty-five cases were included (11 cases with and 14 cases without metastasis). Loss of heterozygosity for the nm-23 gene locus was seen in 7 of 22 (32%) informative tumors. Using immunohistochemistry, most tumors expressed nm-23, though decreased expression was seen in 10 of 25 (40%) cases. Only 2 tumors showed negative expression. We did not find a correlation between either protein expression or loss of heterozygosity with metastatic disease or any other adverse prognostic factors in this group of high-stage laryngeal squamous cell carcinomas. These data imply that nm-23 may be tumor suppressor gene involved in HNSCC but that it may not function as a tumor metastasis suppressor in high-stage laryngeal carcinoma.

Adult↗
PubMed2006

Assessment of microsatellite instability in very small microdissected samples and in tumor samples that are contaminated with normal DNA.

Microsatellite instability (MSI) testing is important for the management of young patients with colonic adenocarcinoma. Biopsies can be small and can be contaminated by normal cells. It is not known how sample size or contamination by non-neoplastic cell populations affects the interpretation of MSI assays. Serial microdissection targets (0.75 to 5.5 mm) were obtained from cases with high-level MSI. Polymerase chain reaction was performed for the standard National Cancer Institute recommended markers and products were analyzed by capillary electrophoresis. DNA from a patient with a BAT25 polymorphism was used to determine the sensitivity of detecting an aberrant allele in otherwise normal DNA. In small targets, MSI was seen sporadically in the setting of low DNA concentration. The results for small targets ranged from 1/4 to 5/5 loci with MSI, secondary to allelic dropout. In the sensitivity study, the aberrant allele was detected only when present at a concentration of above 10%. Allelic dropout can lead to under-estimation of the presence of MSI in small tissue samples or samples with low DNA concentration. Contaminating normal cell DNA can mask the presence of MSI. MSI testing on tissue fragments that are <5.5 mm can lead to a false-negative MSI test.

Alleles↗
PubMed2006

Analysis of allelic loss as an adjuvant tool in evaluation of malignancy in uterine smooth muscle tumors.

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are difficult both from the diagnostic and patient management standpoint because they cannot be classified as benign or malignant by conventional histologic criteria. This study's aim was to determine the diagnostic utility of allelic imbalance (AI) analysis in uterine smooth muscle tumors. Using microdissection and genotyping, we tested 5 leiomyomas, 6 STUMPs, and 10 leiomyosarcomas with follow-up for AI across a panel of seven tumor suppressor genes (p16, p21, p53, VHL, XRCC3, RB, and NM-23). None of the 6 patients with STUMP experienced recurrent disease, whereas 8 of the 10 patients diagnosed with leiomyosarcoma died of disease at follow-up. The mean frequency of allelic loss (FAL) for leiomyomas (18%) was not significantly different from that of STUMPs (21%) (P = 1), whereas leiomyosarcomas displayed a significantly higher FAL (52%) than both leiomyomas (P = 0.001) and STUMPs (P = 0.002). Loss of NM-23, a reported tumor metastasis suppressor gene, was found only in leiomyosarcomas (5 of 9, or 56%), and 4 of 5 (80%) of these were the only cases that demonstrated distant metastases (P = 0.04). Additionally, an FAL of >50% correlated with both NM-23 loss (P = 0.008) and distant metastatic disease (P = 0.04). In conclusion, leiomyomas and STUMPs displayed similar mean FALs and all were clinically benign, whereas uterine leiomyosarcomas had significantly higher frequencies of allelic loss than both leiomyomas and STUMPs. Molecular profiling may thus provide a valuable tool in assessment of malignancy in uterine smooth muscle tumors. Additionally, NM-23 is a promising candidate gene for determination of metastatic potential in these tumors.

Diagnosis, Differential↗
PubMed2006

Microsatellite instability in nasopharyngeal and lymphoepithelial carcinomas of the head and neck.

Lymphoepithelial carcinoma (LEC) is a descriptive diagnosis for an undifferentiated carcinoma that has a typical morphologic appearance of large vesicular cells with prominent nucleoli and infiltrating lymphocytes. Tumors with this histopathologic appearance in the head and neck can be categorized as either those that occur in endemic areas, such as Southeast Asia and are associated with Epstein-Barr virus (EBV) infection, or those that occur in other countries and are less commonly associated with EBV. The molecular changes in endemic EBV-related LEC have been fairly well studied and include both alterations in tumor suppressor genes and 1 report of high levels of microsatellite instability. In nonendemic LECs arising in western countries, there is very little data related to molecular mutational profiles. In this study, we examined 19 cases of LEC from the United States for evidence of microsatellite instability at the DNA level and for alterations in the DNA mismatch repair (MMR) system at the immunohistochemical staining level. Only 3/19 cases showed high-level microsatellite instability and only 1 of these showed an alteration in the DNA MMR protein expression hMLH1. These data suggest that alterations in DNA MMR system are not a common mechanism of tumorigenesis in LEC of the head and neck in a nonendemic country.

Adult↗
PubMed2006

Tumor suppressor gene alterations in respiratory epithelial adenomatoid hamartoma (REAH): comparison to sinonasal adenocarcinoma and inflamed sinonasal mucosa.

Respiratory epithelial adenomatoid hamartoma (REAH) is an unusual benign sinonasal glandular proliferation. REAH is not considered a neoplasm, although, no molecular evidence exists to support or refute this possibility. Microdissection of 10 cases of REAH, 9 cases of sinonasal adenocarcinoma (SNAC) and 10 cases of chronic sinusitis was performed. DNA was extracted and polymerase chain reaction performed using fluorescently labeled primers flanking known tumor suppressor genes on chromosomes 9p (CDKN2/p16), 11p (H-ras), 17p (p53), and 18q (DCC/DPC4). Polymerase chain reaction products were analyzed semiquantitatively by capillary electrophoresis. Allele ratios were calculated using the peak height from the shorter allele divided by the peak height from the longer allele. The loss of heterozygosity (LOH) ratio was calculated as the allele ratio from tumor tissue divided by the allele ratio from normal tissue. The fractional allelic loss (FAL) was calculated as the percentage of loci that harbored LOH divided by the number of loci that were informative. REAH demonstrated an intermediate FAL of 31% compared with SNAC (64%) and chronic sinusitis (2%). REAH and SNAC had the highest LOH for multiple loci located on 9p (p16) and 18q (DCC/DPC4). The molecular profile of REAH shows a mean FAL of 31%, which would be considered unusually high for a non-neoplastic entity. Appreciable allelic loss within REAH suggests the possibility that REAH may be a benign neoplasm rather than a hamartoma.

Adenocarcinoma↗
PubMed2006

Repeat thyroid nodule fine-needle aspiration in patients with initial benign cytologic results.

Fine-needle aspiration (FNA) is the standard of care for the initial workup of thyroid nodules, but there is no consensus algorithm to manage patients with benign results. We examined performance characteristics of initial and repeat satisfactory FNAs for all 402 patients who underwent thyroid surgery during a recent 22-month period. Of these patients, 267 had at least 1 satisfactory FNA and 70 had 2 or more. After an initial benign FNA, 1 repeat FNA correctly identified an unsuspected malignancy in 2 of 70 patients and was indeterminate in 17; of these, 7 of 17 were identified as malignant in the final pathologic diagnosis. Overall, the use of 1 repeat FNA increased the sensitivity for malignancy from 81.7% to 90.4% and decreased the false-negative rate from 17.1% to 11.4%. With more than 1 repeat FNA, there was no improvement in performance characteristics. These data make a strong argument for 1 repeat FNA following an initial benign FNA diagnosis.

Biopsy, Fine-Needle↗
PubMed2006

Allelic loss of 3 different tumor suppressor gene loci in benign and malignant endothelial tumors of the head and neck.

CONTEXT: Angiosarcomas are rare malignancies that commonly arise in the head and neck. No definitive precursor lesion or etiological link between hemangiomas and angiosarcoma has been postulated. Evidence at the cell culture level suggests that loss of heterozygosity of 13q might be involved in tumorigenesis of endothelial cells. Although overexpression of p53 and WT-1 has been found in angiosarcoma, little is known about the molecular changes involved. OBJECTIVE: This study compared the molecular profile of angiosarcoma with that in some benign vascular lesions. DESIGN: Specimens from 6 cases of angiosarcoma, 5 of hemangioma, and 5 of granulation tissue were microdissected. DNA extraction and polymerase chain reaction amplification for 11 microsatellite markers on chromosomes 11p13, 13q14, and 17p13 (WT-1, RB, p53) were performed. Loss of heterozygosity of amplification products was assessed by capillary electrophoresis. Allelic loss and fractional allelic loss were calculated. RESULTS: The mean fractional allelic loss was 43% for angiosarcomas and 29% for hemangiomas. Eighty-three percent of angiosarcomas had allelic loss at 17p13, 66% at 13q14, and 50% at 11p13. Allelic loss was seen in 60% of hemangiomas at 13q14 and 17p13, but only in 20% at 11p13. Two cases of hemangioma and all the granulation tissue cases had no allelic losses. CONCLUSIONS: In our study, 11p13, 13q14, and 17p13 allelic losses were present in both hemangiomas and angiosarcomas. This supports the cell culture-based theories that tumorigenesis in endothelial cells likely involves these chromosomes and provides some insight into the potential pathogenesis of angiosarcomas and benign hemangiomas.

Chromosomes, Human, Pair 11↗
PubMed2006

Warthin tumors do not have microsatellite instability and express normal DNA mismatch repair proteins.

CONTEXT: Warthin tumors are controversial entities with a poorly understood etiology. Although some investigators have suggested a neoplastic origin, others have supported a developmental anomaly. A recent study described the absence of staining for hMLH1 and hMSH2 proteins in the epithelial component of Warthin tumors, suggesting that they arise secondary to defects in the DNA mismatch repair system. OBJECTIVE: To determine if Warthin tumors exhibit evidence of DNA mismatch repair defects. DESIGN: Immunostains for hMLH1 and hMSH2 were performed using a standard approach. Microdissection of the epithelial component was followed by DNA extraction from the tissue fragments. Polymerase chain reaction and capillary electrophoresis analyses were performed for the following 5 National Cancer Institute-recommended microsatellites: D2s123, D5s346, D17s250, BAT25, and BAT26. PATIENTS: Twelve patients with Warthin tumors were included. RESULTS: The immunostains for hMLH1 and hMSH2 showed preserved expression in the nuclei of the epithelial component of all Warthin tumors. No microsatellite instability was detected, and no loss of heterozygosity was seen. CONCLUSIONS: These results are not concordant with previously reported results showing loss of expression of the hMLH1 and hMSH2 DNA mismatch repair enzymes in the epithelial component of Warthin tumors. Furthermore, no microsatellite instability was detected in the 5 loci tested for each tumor in this series. These data demonstrate that Warthin tumors do not have evidence of DNA mismatch repair defects at the genomic or protein expression level.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor.

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.

Adenocarcinoma↗