Publications by authors named "Susanne M Gollin"

63 Publications

A porcine model of phenylketonuria generated by CRISPR/Cas9 genome editing.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, and Universityof Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Phenylalanine hydroxylase-deficient (PAH-deficient) phenylketonuria (PKU) results in systemic hyperphenylalaninemia, leading to neurotoxicity with severe developmental disabilities. Dietary phenylalanine (Phe) restriction prevents the most deleterious effects of hyperphenylalaninemia, but adherence to diet is poor in adult and adolescent patients, resulting in characteristic neurobehavioral phenotypes. Thus, an urgent need exists for new treatments. Additionally, rodent models of PKU do not adequately reflect neurocognitive phenotypes, and thus there is a need for improved animal models. To this end, we have developed PAH-null pigs. After selection of optimal CRISPR/Cas9 genome-editing reagents by using an in vitro cell model, zygote injection of 2 sgRNAs and Cas9 mRNA demonstrated deletions in preimplantation embryos, with embryo transfer to a surrogate leading to 2 founder animals. One pig was heterozygous for a PAH exon 6 deletion allele, while the other was compound heterozygous for deletions of exon 6 and of exons 6-7. The affected pig exhibited hyperphenylalaninemia (2000-5000 μM) that was treatable by dietary Phe restriction, consistent with classical PKU, along with juvenile growth retardation, hypopigmentation, ventriculomegaly, and decreased brain gray matter volume. In conclusion, we have established a large-animal preclinical model of PKU to investigate pathophysiology and to assess new therapeutic interventions.
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http://dx.doi.org/10.1172/jci.insight.141523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605535PMC
October 2020

Interlaboratory study to validate a STR profiling method for intraspecies identification of mouse cell lines.

PLoS One 2019 20;14(6):e0218412. Epub 2019 Jun 20.

National Institute of Standards and Technology, Biosystems and Biomaterials Division, Gaithersburg, Maryland, United States of America.

The Consortium for Mouse Cell Line Authentication was formed to validate Short Tandem Repeat (STR) markers for intraspecies identification of mouse cell lines. The STR profiling method is a multiplex polymerase chain reaction (PCR) assay comprised of primers targeting 19 mouse STR markers and two human STR markers (for interspecies contamination screening). The goals of the Consortium were to perform an interlaboratory study to-(1) validate the mouse STR markers to uniquely identify mouse cell lines (intraspecies identification), (2) to provide a public database of mouse cell lines with the National Institute of Standards and Technology (NIST)-validated mouse STR profiles, and (3) to publish the results of the interlaboratory study. The interlaboratory study was an international effort that consisted of 12 participating laboratories representing institutions from academia, industry, biological resource centers, and government. The study was based on 50 of the most commonly used mouse cell lines obtained from the American Type Culture Collection (ATCC). Of the 50 mouse cell lines, 18 had unique STR profiles that were 100% concordant (match) among all Consortium laboratory members, and the remaining 32 cell lines had discordance that was resolved readily and led to improvement of the assay. The discordance was due to low signal and interpretation issues involving artifacts and genotyping errors. Although the total number of discordant STR profiles was relatively high in this study, the percent of labs agreeing on allele calls among the discordant samples was above 92%. The STR profiles, including electropherogram images, for NIST-validated mouse cell lines will be published on the NCBI BioSample Database (https://www.ncbi.nlm.nih.gov/biosample/). Overall, the interlaboratory study showed that the multiplex PCR method using 18 of the 19 mouse STR markers is capable of discriminating at the intraspecies level between mouse cell lines. Further studies are ongoing to refine the assay including (1) development of an allelic ladder for improving the accuracy of allele calling and (2) integration of stutter filters to identify true stutter.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218412PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586308PMC
February 2020

Genomic and Transcriptomic Characterization Links Cell Lines with Aggressive Head and Neck Cancers.

Cell Rep 2018 10;25(5):1332-1345.e5

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. Electronic address:

Cell lines are important tools for biological and preclinical investigation, and establishing their relationship to genomic alterations in tumors could accelerate functional and therapeutic discoveries. We conducted integrated analyses of genomic and transcriptomic profiles of 15 human papillomavirus (HPV)-negative and 11 HPV-positive head and neck squamous cell carcinoma (HNSCC) lines to compare with 279 tumors from The Cancer Genome Atlas (TCGA). We identified recurrent amplifications on chromosomes 3q22-29, 5p15, 11q13/22, and 8p11 that drive increased expression of more than 100 genes in cell lines and tumors. These alterations, together with loss or mutations of tumor suppressor genes, converge on important signaling pathways, recapitulating the genomic landscape of aggressive HNSCCs. Among these, concurrent 3q26.3 amplification and TP53 mutation in most HPV(-) cell lines reflect tumors with worse survival. Our findings elucidate and validate genomic alterations underpinning numerous discoveries made with HNSCC lines and provide valuable models for future studies.
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http://dx.doi.org/10.1016/j.celrep.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280671PMC
October 2018

Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation.

Haematologica 2018 10 28;103(10):1688-1697. Epub 2018 Jun 28.

Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA

The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.
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http://dx.doi.org/10.3324/haematol.2018.188227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165797PMC
October 2018

A prolonged response to platinum-based therapy in a patient with metastatic urothelial carcinoma harboring a single rearranged and truncated NF2 gene.

Genes Chromosomes Cancer 2018 08 30;57(8):430-433. Epub 2018 Mar 30.

Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Tumor genome sequencing has become an invaluable resource in determining targets for new therapies. In this report, we describe the case of a patient with metastatic urothelial carcinoma with sarcomatoid features. Sarcomatoid differentiation is a rare histologic subtype that confers a more aggressive course. The first-line treatment for patients with urothelial carcinoma is platinum-based chemotherapy. Next generation tumor sequencing performed using the FoundationOne assay revealed loss of one NF2 allele and an unbalanced der(22)t(10;22)(p11.22;q12.2) chromosomal rearrangement involving the other NF2 allele, resulting in truncation and predicted loss of function. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of one NF2 signal. NF2 mutations have been found in a variety of cancers and result in activation of the mTOR pathway. As such, the use of mTOR inhibitors, such as everolimus are thought to be particularly effective in the case of NF2 loss. Our patient had a dramatic response to first-line chemotherapy, but unfortunately experienced subsequent progression of his cancer and could not tolerate everolimus. Although our patient's tumor demonstrated unique acquired genetic features including both loss of heterozygosity and truncation of the NF2 locus, he still achieved a meaningful response to platinum-based chemotherapy.
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http://dx.doi.org/10.1002/gcc.22537DOI Listing
August 2018

Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines.

Head Neck 2017 05 25;39(5):840-852. Epub 2017 Feb 25.

Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. The purpose of this study was to evaluate viral oncogene expression and viral integration sites in HPV16- and HPV18-positive squamous cell carcinoma lines.

Methods: E6/E7 alternate transcripts were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites.

Results: All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 head and neck squamous cell carcinoma (HNSCC) lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration.

Conclusion: HPV integration into cancer-related genes occurred in 7 of 9 HPV-positive cell lines and of these 6 were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors. © 2017 Wiley Periodicals, Inc. Head Neck 39: 840-852, 2017.
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http://dx.doi.org/10.1002/hed.24729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392184PMC
May 2017

The Genomic Landscape of PAX5, IKZF1, and CDKN2A/B Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia.

Cytogenet Genome Res 2016 18;150(3-4):242-252. Epub 2017 Feb 18.

Center for Clinical Genetics and Genomics, Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment. Furthermore, all cases with IKZF1 deletions also had additional genomic alterations, including BCR-ABL1 gene fusions, PAX5 deletions, CDKN2A/B deletions, and FLT3 amplification. Deletions of CDKN2A/B represented the most frequent abnormalities in our group of patients. Our study demonstrates the high incidence of PAX5, IKZF1, and CDKN2A/B alterations in B-ALL detected by aCGH analysis. Due to the small size and variability in the deletion breakpoints, FISH studies showed false-negative results in 10, 40, and 28% of the samples tested for the IKZF1,PAX5, and CDKN2A/B gene deletions, respectively. The PAX5 and IKZF1 abnormalities are highly specific to B-ALL and can be used as diagnostic markers. Moreover, IKZF1 alterations frequently coexist with a BCR-ABL gene fusion. Our study revealed multiple additional B-ALL-specific genomic alterations and showed that aCGH is a more sensitive method than FISH, allowing whole genome profiling and identification of aberrations of diagnostic and prognostic significance in patients with B-ALL.
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http://dx.doi.org/10.1159/000456572DOI Listing
April 2017

Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients.

Carcinogenesis 2017 02 26;38(2):218-229. Epub 2016 Dec 26.

Department of Otorhinolaryngology-Head and Neck Surgery, GROW Institute, Maastricht University Medical Centre, Maastricht, The Netherlands.

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.
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http://dx.doi.org/10.1093/carcin/bgw203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191086PMC
February 2017

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas.

Exp Cell Res 2016 Oct 9;348(1):75-86. Epub 2016 Sep 9.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15261, United States of America.

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens. We show that spheroid enrichment of CSC from early and short-term HNSCC cell cultures was associated with increased expression of CD44, CD133, SOX2 and BMI1 compared with normal oral epithelial cells. On immunophenotyping, five of 12 SC/CSC markers were homogenously expressed in all tumor cultures, while one of 12 was negative, four of 12 showed variable expression, and two of the 12 were expressed heterogeneously. We showed that irradiated CSCs survived and retained their self-renewal capacity across different ionizing radiation (IR) regimens. Fluorescence in situ hybridization (FISH) analyses of parental and clonally-derived tumor cells revealed different chromosome copy numbers from cell to cell, suggesting the presence of chromosomal instability in HNSCC CSC. Further, our in vitro and in vivo mouse engraftment studies suggest that CD44+/CD66- is a promising, consistent biomarker combination for HNSCC CSC. Overall, our findings add further evidence to the proposed role of HNSCC CSCs in therapeutic resistance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056028PMC
http://dx.doi.org/10.1016/j.yexcr.2016.09.003DOI Listing
October 2016

Cell division patterns and chromosomal segregation defects in oral cancer stem cells.

Genes Chromosomes Cancer 2016 09 23;55(9):694-709. Epub 2016 Jun 23.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.

Oral squamous cell carcinoma (OSCC) is a serious public health problem caused primarily by smoking and alcohol consumption or human papillomavirus. The cancer stem cell (CSC) theory posits that CSCs show unique characteristics, including self-renewal and therapeutic resistance. Examining biomarkers and other features of CSCs is critical to better understanding their biology. To this end, the results show that cellular SOX2 immunostaining correlates with other CSC biomarkers in OSCC cell lines and marks the rare CSC population. To assess whether CSC division patterns are symmetrical, resulting in two CSC, or asymmetrical, leading to one CSC and one cancer cell, cell size and fluorescence intensity of mitotic cells stained with SOX2 were analyzed. Asymmetrical SOX2 distribution in ≈25% of the mitoses analyzed was detected. Chromosomal instability, some of which is caused by chromosome segregation defects (CSDs), is a feature of cancer cells that leads to altered gene copy numbers. We compare chromosomal instability (as measured by CSDs) between CSCs (SOX2+) and non-CSCs (SOX2-) from the same OSCC cell lines. CSDs were more common in non-CSCs (SOX2-) than CSCs (SOX2+) and in symmetrical CSC (SOX2+) mitotic pairs than asymmetrical CSC (SOX2+/SOX2-) mitotic pairs. CSCs showed fewer and different types of CSDs after ionizing radiation treatment than non-CSCs. Overall, these data are the first to demonstrate both symmetrical and asymmetrical cell divisions with CSDs in OSCC CSC. Further, the results suggest that CSCs may undergo altered behavior, including therapeutic resistance as a result of chromosomal instability due to chromosome segregation defects. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22371DOI Listing
September 2016

Correlation of Classic and Molecular Cytogenetic Alterations in Soft-Tissue Sarcomas: Analysis of 46 Tumors With Emphasis on Adipocytic Tumors and Synovial Sarcoma.

Appl Immunohistochem Mol Morphol 2017 03;25(3):168-177

*Department of Pathology, Presbyterian-Shadyside Hospitals ‡Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital, University of Pittsburgh Medical Center †Department of Pathology, University of Pittsburgh School of Medicine §Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.

Introduction: Sarcomas are heterogeneous, and their treatment and prognosis are driven by the morphologic subtype and the clinical stage. Classic cytogenetics and fluorescence in situ hybridization (FISH) analysis play an important role in their diagnostic work up.

Materials And Methods: Forty-six cases of soft-tissue sarcoma were reviewed that underwent karyotyping and simultaneous FISH analysis at initial diagnosis. They included 10 dedifferentiated liposarcomas, 10 myxoid liposarcomas, and 14 synovial sarcomas. Six tumors were investigated for EWSR1 rearrangement. Six high-grade miscellaneous sarcomas were also examined.

Results: The dedifferentiated liposarcoma had complex karyotypes and MDM2 amplification by FISH, and of these, 5 tumors with myxoid changes also had complex signals for DDIT3. All but 4 myxoid liposarcomas had complex karyotypes, in addition to the characteristic translocation. FISH analysis displayed DD1T3 rearrangement. All synovial sarcomas except 1 recurrence had a t(X;18) translocation by karyotyping and FISH. The EWSR1 rearrangement was present in all extraskeletal myxoid chondrosarcomas, angiomatoid fibrous histiocytoma, atypical Ewing sarcoma, and a clear-cell sarcoma, all of which had characteristic karyotypes. Seven high-grade sarcomas had no specific karyotype or rearrangements for DDIT3, SS18, and EWSR1 by FISH.

Conclusions: There is good correlation between karyotyping and FISH. Complex FISH signals found in dedifferentiated liposarcomas may be related to an increased chromosome 12 copy number and ploidy. Karyotyping is an important baseline standard for the quality assurance of newly developed FISH probes. It also provides a global view of chromosomal changes and the opportunity to investigate the role of other genetic alterations and potential therapeutic targets.
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http://dx.doi.org/10.1097/PAI.0000000000000294DOI Listing
March 2017

Integration of microarray analysis into the clinical diagnosis of hematological malignancies: How much can we improve cytogenetic testing?

Oncotarget 2015 Aug;6(22):18845-62

Pittsburgh Cytogenetics Laboratory, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

Purpose: To evaluate the clinical utility, diagnostic yield and rationale of integrating microarray analysis in the clinical diagnosis of hematological malignancies in comparison with classical chromosome karyotyping/fluorescence in situ hybridization (FISH).

Methods: G-banded chromosome analysis, FISH and microarray studies using customized CGH and CGH+SNP designs were performed on 27 samples from patients with hematological malignancies. A comprehensive comparison of the results obtained by three methods was conducted to evaluate benefits and limitations of these techniques for clinical diagnosis.

Results: Overall, 89.7% of chromosomal abnormalities identified by karyotyping/FISH studies were also detectable by microarray. Among 183 acquired copy number alterations (CNAs) identified by microarray, 94 were additional findings revealed in 14 cases (52%), and at least 30% of CNAs were in genomic regions of diagnostic/prognostic significance. Approximately 30% of novel alterations detected by microarray were >20 Mb in size. Balanced abnormalities were not detected by microarray; however, of the 19 apparently "balanced" rearrangements, 55% (6/11) of recurrent and 13% (1/8) of non-recurrent translocations had alterations at the breakpoints discovered by microarray.

Conclusion: Microarray technology enables accurate, cost-effective and time-efficient whole-genome analysis at a resolution significantly higher than that of conventional karyotyping and FISH. Array-CGH showed advantage in identification of cryptic imbalances and detection of clonal aberrations in population of non-dividing cancer cells and samples with poor chromosome morphology. The integration of microarray analysis into the cytogenetic diagnosis of hematologic malignancies has the potential to improve patient management by providing clinicians with additional disease specific and potentially clinically actionable genomic alterations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662459PMC
http://dx.doi.org/10.18632/oncotarget.4586DOI Listing
August 2015

Concerning consequences of blocking Notch signaling in satellite muscle stem cells.

Front Cell Dev Biol 2015 18;3:11. Epub 2015 Feb 18.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health Pittsburgh, PA, USA.

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http://dx.doi.org/10.3389/fcell.2015.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332377PMC
March 2015

Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: a next generation window to the biology of disease.

Authors:
Susanne M Gollin

Genes Chromosomes Cancer 2014 Dec 3;53(12):972-90. Epub 2014 Sep 3.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Departments of Otolaryngology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA.

Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14-15, 8q11-12, and 20q12-13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21-24, 11q14-23, 13q12-14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC.
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http://dx.doi.org/10.1002/gcc.22214DOI Listing
December 2014

Viral load, gene expression and mapping of viral integration sites in HPV16-associated HNSCC cell lines.

Int J Cancer 2015 Mar 14;136(5):E207-18. Epub 2014 Aug 14.

Department of Otorhinolaryngology and Head and Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands; Department of Molecular Cell Biology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.

HPV-related HNSCC generally have a better prognosis than HPV-negative HNSCC. However, a subgroup of HPV-positive tumors with poor prognosis has been recognized, particularly related to smoking, EGFR overexpression and chromosomal instability. Viral integration into the host genome might contribute to carcinogenesis, as is shown for cervical carcinomas. Therefore, all HPV16-positive HNSCC cell lines currently available have been carefully analyzed for viral and host genome parameters. The viral integration status, viral load, viral gene expression and the presence of aneusomies was evaluated in the cell lines UD-SCC-2, UM-SCC-047, UM-SCC-104, UPCI:SCC090, UPCI:SCC152, UPCI:SCC154 and 93VU147T. HPV integration was examined using FISH, APOT-PCR and DIPS-PCR. Viral load and the expression of the viral genes E2, E6 and E7 were determined via quantitative PCR. All cell lines showed integration-specific staining patterns and signals indicating transcriptional activity using FISH. APOT- and DIPS-PCR identified integration-derived fusion products in six cell lines and only episomal products for UM-SCC-104. Despite the observed differences in viral load and the number of viral integration sites, this did not relate to the identified viral oncogene expression. Furthermore, cell lines exhibited EGFR expression and aneusomy (except UPCI:SCC154). In conclusion, all HPV16-positive HNSCC cell lines showed integrated and/or episomal viral DNA that is transcriptionally active, although viral oncogene expression was independent of viral copy number and the number of viral integration sites. Because these cell lines also contain EGFR expression and aneusomy, which are parameters of poor prognosis, they should be considered suitable model systems for the development of new antiviral therapies.
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http://dx.doi.org/10.1002/ijc.29112DOI Listing
March 2015

Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss.

Genes Chromosomes Cancer 2014 Feb 25;53(2):129-43. Epub 2013 Nov 25.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA.

Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage-fusion-bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR-CHEK1 pathway, and that knocking down the ATR-CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR-CHEK1 pathway and flow cytometry showed G2 M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR-CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF-00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR-CHEK1 pathway inhibition.
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http://dx.doi.org/10.1002/gcc.22125DOI Listing
February 2014

Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas.

Genes Chromosomes Cancer 2014 Jan 21;53(1):25-37. Epub 2013 Oct 21.

Department of Internal Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA.

The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.
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http://dx.doi.org/10.1002/gcc.22115DOI Listing
January 2014

The p53-PUMA axis suppresses iPSC generation.

Nat Commun 2013 ;4:2174

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.

Mechanisms underlying the reprogramming process of induced pluripotent stem cells remain poorly defined. Like tumorigenesis, generation of induced pluripotent stem cells was shown to be suppressed by the Trp53 (p53) pathway, at least in part via p21Cdkn1a (p21)-mediated cell cycle arrest. Here we examine the role of PUMA, a pro-apoptotic mediator of p53, during somatic reprogramming in comparison to p21 in the p53 pathway. Using mouse strains deficient in these molecules, we demonstrate that PUMA is an independent mediator of the negative effect of p53 on induced pluripotent stem cell induction. PUMA deficiency leads to a better survival rate associated with reduced DNA damage and fewer chromosomal aberrations in induced pluripotent stem cells, whereas loss of p21 or p53 results in an opposite outcome. Given these new findings, PUMA may serve as a distinct and more desirable target in the p53 pathway for induced pluripotent stem cell generation, thereby having important implications for potential therapeutic applications of induced pluripotent stem cells.
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http://dx.doi.org/10.1038/ncomms3174DOI Listing
January 2014

Longitudinal bone marrow evaluations for myelodysplasia in patients with myeloma before and after treatment with lenalidomide.

Leuk Lymphoma 2013 Sep 28;54(9):1965-74. Epub 2013 Jan 28.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Lenalidomide (LEN) treatment in multiple myeloma (MM) results in a superior outcome. However, there is concern for increased myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) associated with LEN. Thus, bone marrow morphology and cytogenetics studies from 40 patients were evaluated for early signs of MDS prior to therapy, during therapy and at follow-up. Newly diagnosed patients with MM treated with LEN and dexamethasone (LD) alone or followed by autologous stem cell transplant (LD/ASCT), or patients with relapsed/refractory MM treated with LEN, bendamustine and dexamethasone (BLD) were included. One patient developed MDS. Baseline prevalence of mild morphologic myelodysplasia was highest in pretreated patients with MM (BLD, 71%), but was also seen in newly diagnosed patients (LD and LD/ASCT, 17%). The prevalence of myelodysplasia did not increase over time. Thus, this study did not reveal rapidly emerging MDS in 39 of 40 patients with MM treated with LEN. The development of MDS in one patient suggests that longer follow-up is needed for all.
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http://dx.doi.org/10.3109/10428194.2012.755177DOI Listing
September 2013

TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression.

Cancer Res 2012 Jul 7;72(13):3270-81. Epub 2012 May 7.

Department of Otolaryngology, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine and Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213, USA.

Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0475-TDOI Listing
July 2012

Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.

Mol Cell Proteomics 2011 Dec 28;10(12):M111.011635. Epub 2011 Sep 28.

Chair of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.

Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10-20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.
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http://dx.doi.org/10.1074/mcp.M111.011635DOI Listing
December 2011

Myeloperoxidase-dependent oxidation of etoposide in human myeloid progenitor CD34+ cells.

Mol Pharmacol 2011 Mar 19;79(3):479-87. Epub 2010 Nov 19.

Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34(+) myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34(+) cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34(+) cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34(+) cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.
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http://dx.doi.org/10.1124/mol.110.068718DOI Listing
March 2011

Polymorphisms in DNA damage response genes and head and neck cancer risk.

Biomarkers 2010 Aug;15(5):379-99

Department of Epidemiology, State University of New York Downstate Medical Center, NY, USA.

Background: Polymorphisms in DNA repair genes have been reported contributing factors in head and neck cancer risk but studies have shown conflicting results.

Objective: To clarify the impact of DNA repair gene polymorphisms in head and neck cancer risk.

Method: A meta-analysis including 30 case-control studies was performed.

Results: Marginally statistically significant association was found for XRCC1 codon 399 (for Caucasians only), XPD Asp312Asn and XRCC1 codon 194 variants and head and neck cancer.

Conclusion: Assessments of the effects of smoking, alcohol, human papillomavirus and race/ethnicity on the association between DNA repair gene polymorphisms and head and neck cancer are needed.
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http://dx.doi.org/10.3109/13547501003797664DOI Listing
August 2010

Defining the borders of splenic marginal zone lymphoma: a multiparameter study.

Hum Pathol 2010 Apr 11;41(4):540-51. Epub 2009 Dec 11.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Classic splenic marginal zone lymphomas are CD5-, CD10-, CD23-, CD43-, and usually IgD+ with biphasic white pulp nodules. However, the 2008 World Health Organization classification accepts splenic marginal zone lymphomas with monophasic marginal zone-like white pulp nodules and recognizes a group of unclassifiable splenic small B-cell lymphomas. To explore the relationship of classic splenic marginal zone lymphomas to these other less well-defined splenic lymphomas, a multiparameter study of 47 splenic marginal zone lymphomas and unclassifiable splenic small B-cell lymphomas was performed. Seventeen of 31 splenic marginal zone lymphomas were biphasic, and 14 were monophasic (90%-100% marginal zone-like white pulp nodules). Sixteen cases were unclassifiable splenic small B-cell lymphomas, most lacking a marginal zone-type component. There were many clinical similarities between the 3 groups, including similar survivals. Monophasic and unclassifiable cases were less likely to have a typical splenic marginal zone lymphoma phenotype (28.6%, 23.1%) compared with biphasic cases (86.7%), usually because of IgD negativity (P < .003). Thirty-four of 42 (81%) cases had cytogenetic abnormalities by fluorescence in situ hybridization; and 17 of 20 (85%), by classical cytogenetics. The most frequent fluorescence in situ hybridization abnormalities among the splenic marginal zone lymphomas were del(7)(q31) (26%), +12 (25%), and +3q27 (27%); and among the unclassifiable cases, +12 (50%) and +3q27 (36%). Five of 6 unclassifiable cases with exclusively small non-marginal zone-like lymphocytes involving both white and red pulp had +12 compared with 9 of 34 other cases (P < .02). CDK6 (2 cases) and BCL3 (1 case) rearrangements were only seen in the unclassifiable group. These results support including both biphasic and monophasic cases as splenic marginal zone lymphomas, but suggest that the lack of a non-marginal zone-like population in the monophasic group is associated with some biologic differences. They also demonstrate a relatively large proportion of unclassifiable cases, including a group with frequent +12.
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http://dx.doi.org/10.1016/j.humpath.2009.09.007DOI Listing
April 2010

Sheddase activity of tumor necrosis factor-alpha converting enzyme is increased and prognostically valuable in head and neck cancer.

Cancer Epidemiol Biomarkers Prev 2009 Nov 20;18(11):2913-22. Epub 2009 Oct 20.

Departments of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-1863, USA.

Tumor necrosis factor alpha converting enzyme (TACE) is a sheddase overexpressed in cancers that generates cancer cell growth and survival factors, and is implicated in carcinogenesis and tumor growth. This indicates that TACE could be a potentially important cancer biomarker. Unexpectedly, TACE expression in cancer tissues does not correlate with cancer stage or invasiveness. Although TACE sheddase activity is a more direct and potentially better indicator of TACE biology and might be a better cancer biomarker than TACE expression, it has not been studied in cancer tissues. In the present study, we developed a reliable specific assay for quantification of TACE sheddase activity, investigated TACE activity and TACE protein expression in head and neck cancer (HNC) tissues, and examined the correlation of the results with HNC clinical stages and likelihood to recur. We found that HNC cell lines and tissues contained remarkably higher quantities of TACE activity and TACE protein than normal keratinocytes or oral mucosa. siRNA silencing of TACE resulted in the inhibition of release of the tumorogenic factors amphiregulin and transforming growth factor alpha, and tumor protective factors tumor necrosis factor receptors from HNC cells. Importantly, TACE activity, but not TACE protein expression, was significantly higher in large, T3/T4, primary tumors relative to small, T1/T2, primary tumors, and especially in primary tumors likely to recur relative to those unlikely to recur. These data show that increased TACE activity in cancer is biologically and clinically relevant, and indicate that TACE activity could be a significant biomarker of cancer prognosis.
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http://dx.doi.org/10.1158/1055-9965.EPI-08-0898DOI Listing
November 2009

Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation.

BMC Cancer 2009 Oct 6;9:354. Epub 2009 Oct 6.

University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.

Background: Biomarkers that predict clinical response, tumor recurrence or patient survival are severely lacking for most cancers, particularly for oral and pharyngeal cancer. This study examines whether gene-promoter methylation of tumor DNA correlates with survival and recurrence rates in a population of patients with oral or pharyngeal cancer.

Methods: The promoter methylation status of the DNA repair gene MGMT and the tumor suppressor genes CDKN2A and RASSF1 were evaluated by methylation-specific PCR in 88 primary oral and pharyngeal tumors and correlated with survival and tumor recurrence. Quantitative MGMT methylation was also assessed.

Results: 29.6% of the tumors presented with MGMT methylation, 11.5% with CDKN2A methylation and 12.1% with RASSF1 methylation. MGMT promoter methylation was significantly associated with poorer overall and disease-free survival. No differences in methylation status of MGMT and RASSF1 with HPV infection, smoking or drinking habits were observed. A significant inverse trend with the amount of MGMT methylation and overall and disease-free survival was observed (ptrend = 0.002 and 0.001 respectively).

Conclusion: These results implicate MGMT promoter methylation as a possible biomarker for oral and pharyngeal cancer prognosis. The critical role of MGMT in DNA repair suggests that defective DNA repair may be correlative in the observed association between MGMT promoter methylation and tumor recurrence. Follow-up studies should include further quantitative MSP-PCR measurement, global methylation profiling and detailed analysis of downstream DNA repair genes regulated by promoter methylation.
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http://dx.doi.org/10.1186/1471-2407-9-354DOI Listing
October 2009

Decreased expression of miR-125b and miR-100 in oral cancer cells contributes to malignancy.

Genes Chromosomes Cancer 2009 Jul;48(7):569-82

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.

Altered microRNA (miRNA) expression profiles have been observed in numerous malignancies, including oral squamous cell carcinoma (OSCC). However, their role in disease is not entirely clear. Several genetic aberrations are characteristic of OSCC, with amplification of chromosomal band 11q13 and loss of distal 11q being among the most prevalent. It is not known if the expression levels of miRNAs in these regions are altered or whether they play a role in disease. We hypothesize that the expression of miRNAs mapping to 11q are altered in OSCC because of loss or amplification of chromosomal material, and that this contributes to the development and progression of OSCC. We found that miR-125b and miR-100 are down-regulated in OSCC tumor and cell lines, and that transfecting cells with exogenous miR-125b and miR-100 significantly reduced cell proliferation and modified the expression of target and nontarget genes, including some that are overexpressed in radioresistant OSCC cells. In conclusion, the down-regulation of miR-125b and miR-100 in OSCC appears to play an important role in the development and/or progression of disease and may contribute to the loss of sensitivity to ionizing radiation.
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http://dx.doi.org/10.1002/gcc.20666DOI Listing
July 2009

Comparisons of high-risk cervical HPV infections in Caribbean and US populations.

Infect Agent Cancer 2009 Feb 10;4 Suppl 1:S9. Epub 2009 Feb 10.

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, USA.

Background: Disparities in cervical cancer incidence and mortality rates exist among women of African ancestry (African-American, African-Caribbean and African). Persistent cervical infection with Human papillomavirus (HPV) is associated with cervical dysplasia and if untreated, could potentially progress to invasive cervical cancer. Very few studies have been conducted to examine the true prevalence of HPV infection in this population. Comparisons of cervical HPV infection and the type-specific distribution of HPV were performed between cancer-free Caribbean and US women.

Results: The Caribbean population consisted of 212 women from Tobago and 99 women from Jamaica. The US population tested, consisted of 82 women from Pittsburgh. The majority of the US subjects was Caucasian, 74% (61/82) while 12% (10/82) and 13% (11/82) were African-American or other ethnic groups, respectively. The age-adjusted prevalence of any HPV infection among women from Tobago was 35%, while for Jamaica, it was 81% (p < 0.0001). The age-adjusted prevalence of HPV infection for Caribbean subjects was not statistically significantly different from the US (any HPV: 47% vs. 39%, p > 0.1; high-risk HPVs: 27% vs. 25%, p > 0.1); no difference was observed between US-Blacks and Jamaicans (any HPV: 92% vs. 81%, p > 0.1; high-risk HPV: 50% vs. 53%, p > 0.1). However, US-Whites had a lower age-adjusted prevalence of HPV infections compared to Jamaican subjects (any HPV: 29% vs. 81%, p < 0.0001; high-risk HPV: 20% vs. 53%, p < 0.001). Subjects from Jamaica, Tobago, and US-Blacks had a higher proportion of high-risk HPV infections (Tobago: 20%, Jamaica: 58%, US-Blacks: 40%) compared to US-Whites (15%). Similar observations were made for the presence of infections with multiple high-risk HPV types (Tobago: 12%, Jamaica: 43%, US-Blacks: 30%, US-Whites: 8%). Although we observed similar prevalence of HPV16 infections among Caribbean and US-White women, there was a distinct distribution of high-risk HPV types when comparisons were made between the ethnic groups.

Conclusion: The higher prevalence of cervical HPV infections and multiple high-risk infections in Caribbean and US-Black women may contribute to the high incidence and prevalence of cervical cancer in these populations. Evaluation of a larger sample size is currently ongoing to confirm the distinct distribution of HPV types between ethnic groups.
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http://dx.doi.org/10.1186/1750-9378-4-S1-S9DOI Listing
February 2009

Knowledge about human papillomavirus and the HPV vaccine--a survey of the general population.

Infect Agent Cancer 2009 Feb 10;4 Suppl 1:S10. Epub 2009 Feb 10.

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.

Background: The United States (US) Food & Drug Administration (FDA) recently approved a human papillomavirus (HPV) vaccine with the purpose of reducing the risk of cervical cancers caused by HPV 16 and HPV 18. It is important that the general population be educated about HPV and the HPV vaccine in order to make the appropriate decision whether or not to vaccinate against this virus. Participants from the adult US general population of Pittsburgh, Pennsylvania, USA and Hampton, Virginia, USA (18+ years old) were surveyed to determine their knowledge about HPV and the HPV vaccine, and to evaluate their perception of the vaccine efficacy and safety.

Results: We report herein preliminary data for 202 participants. Fifty-five percent (55%) of the study population was White, 45% Black, and 1% was from other ethnic groups or did not disclose their ethnicity. A large proportion of participants had heard of the human papillomavirus (overall population: 93.6%; Pittsburgh: 95%; Hampton: 90%). Participants of African descent were slightly less aware of HPV than Whites (Black 89% vs. Whites 97%, p > 0.1). Although the majority of participants knew that HPV caused cervical cancer (84%), Whites were more informed than Black participants (91% vs. 73%, p = 0.044). Eighty-seven percent (87%) of participants had heard of the HPV vaccine (Pittsburgh: 92% and Hampton: 74%, p = 0.029); a higher proportion of Whites were aware of the vaccine when compared with Blacks (93% vs. 76%, p = 0.031). However, only 18% of the population knew that the current FDA-approved vaccine protected against genital warts and most cervical cancer (20% of Blacks and 16% of Whites, p > 0.1).

Conclusion: These data suggest that although the general population might be aware of HPV and the HPV vaccine, knowledge of the benefits of the HPV vaccination may not be apparent. Knowledge of HPV and the HPV vaccine could result in a likely choice of HPV vaccination and would subsequently reduce the incidence of cervical cancer.
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http://dx.doi.org/10.1186/1750-9378-4-S1-S10DOI Listing
February 2009
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