Publications by authors named "Aaron D Bossler"

31 Publications

PTCH1-GLI1 Fusion-Positive Ovarian Tumor: Report of a Unique Case With Response to Tyrosine Kinase Inhibitor Pazopanib.

J Natl Compr Canc Netw 2021 09 20;19(9):998-1004. Epub 2021 Sep 20.

Department of Pathology, and.

Recurrent GLI1 gene fusions have been recently described in a subset of soft tissue tumors showing a distinct monotonous epithelioid morphology with a rich capillary network and frequent S100 protein expression. Three different fusion partners-ACTB, MALAT1, and PTCH1-have been reported with the PTCH1-GLI1 fusion from 2 patients only, both with head and neck tumors. Herein, we report for the first time a PTCH1-GLI1 fusion in a primary ovarian tumor from a female patient aged 54 years who presented with a 21-cm right ovarian mass and mesenteric metastasis. The tumor was diagnosed as "favor malignant melanoma" based on histologic examination and extensive immunohistochemistry studies. The patient received 4 cycles of pembrolizumab and 2 cycles of trabectedin but developed multiple metastases. A next-generation sequencing-based assay detected a PTCH1-GLI1 fusion, which led to a revised pathologic diagnosis and a change of the patient's management. The patient was switched to the tyrosine kinase inhibitor (TKI) pazopanib to target the sonic hedgehog pathway. Her disease was stable 49 months post TKI therapy. Our case report is the first to show that a tumor with GLI1 oncogenic activation was sensitive to a TKI. The morphologic and immunohistochemistry similarities of our patient's tumor to other recently described tumors harboring GLI1 fusions suggest that these tumors may all belong to the same entity of GLI1 fusion-positive neoplasms and may be treated similarly.
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http://dx.doi.org/10.6004/jnccn.2021.7058DOI Listing
September 2021

Validation of Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy.

J Mol Diagn 2021 Aug 9. Epub 2021 Aug 9.

Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address:

The molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD) relies on detecting contractions of the unique D4Z4 repeat array at the chromosome 4q35 locus in the presence of a permissive 4q35A haplotype. Long, intact DNA molecules are required for accurate sizing of D4Z4 repeats. We validated the use of optical genome mapping to determine size and haplotype of D4Z4 alleles for FSHD analysis. The cohort included 36 unique DNA specimens from fresh blood samples or archived agarose plugs. High-molecular- weight DNA underwent sequence-specific labeling followed by separation and image analysis with data collection on the Saphyr system. D4Z4 allele sizes were calculated and haplotypes determined from the labeling patterns. Each specimen had previous diagnostic testing using restriction enzyme digests with EcoRI, EcoRI/BlnI, XapI, or HindIII, followed by pulsed field gel electrophoresis and Southern blot analysis with appropriate probes. Optical genome mapping detected 4q35 and 10q26 alleles ranging from 1 to 79 D4Z4 repeats and showed strong correlation with Southern blot allele sizing (R = 0.95) and haplotyping (133 of 134; 99.4% haplotype match). Analysis of inter-assay and intra-assay runs showed high reproducibility (0.03 to 0.94 %CV). Subsequent optical genome mapping for routine clinical testing from 315 clinical FSHD cases compared favorably with historical result trends. Optical genome mapping is an accurate and highly reproducible method for chromosomal abnormalities associated with FSHD.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.021DOI Listing
August 2021

Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2-4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45-0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32-0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.
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http://dx.doi.org/10.3390/cancers13071489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037963PMC
March 2021

CLIA Laboratory Testing for Facioscapulohumeral Dystrophy: A Retrospective Analysis.

Neurology 2021 02 21;96(7):e1054-e1062. Epub 2020 Dec 21.

From the Departments of Pathology (A.R., A.D.B., S.A.M.) and Pediatrics and Neurology (A.R., K.D.M.), Carver College of Medicine, The University of Iowa, Iowa City.

Objective: To summarize facioscapulohumeral muscular dystrophy (FSHD) diagnostic testing results from the University of Iowa Molecular Pathology Laboratory.

Methods: All FSHD tests performed in the diagnostic laboratory from January 2015 to July 2019 were retrospectively reviewed. Testing was by restriction enzyme digestion and Southern blot analysis with sequencing of , if indicated. Cases were classified as FSHD1 (4q35 EcoRI size ≤40 kb; 1-10 D4Z4 repeats), FSHD2 (permissive 4q35A allele, D4Z4 hypomethylation, and pathogenic variant), or non-FSHD1,2. We also noted cases with borderline EcoRI fragment size (41-43 kb; 11 D4Z4 repeats), cases that meet criteria for both FSHD1 and FSHD2, somatic mosaicism, and cases with hybrid alleles that add complexity to test interpretation.

Results: Of the 1,594 patients with FSHD tests included in the analysis, 703 (44.1%) were diagnosed with FSHD. Among these positive tests, 664 (94.5%) met criteria for FSHD1 and 39 (5.5%) met criteria for FSHD2. Of all 1,594 cases, 20 (1.3%) had a 4q35 allele of borderline size, 23 (1.5%) were somatic mosaics, and 328 (20.9%) had undergone translocation events. Considering only cases with at least 1 4q35A allele, D4Z4 repeat number differed significantly among groups: FSHD1 cases median 6.0 (interquartile range [IQR] 4-7) repeats, FSHD2 cases 15.0 (IQR 12-22) repeats, and non-FSHD1,2 cases 28.0 (IQR 19-40) repeats.

Conclusion: FSHD1 accounts for 94.5% of genetically confirmed cases of FSHD. The data show a continuum of D4Z4 repeat numbers with FSHD1 samples having the fewest, FSHD2 an intermediate number, and non-FSHD1,2 the most.
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http://dx.doi.org/10.1212/WNL.0000000000011412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055331PMC
February 2021

Multivariable Analysis of 169 Cases of Advanced Cutaneous Melanoma to Evaluate Antibiotic Exposure as Predictor of Survival to Anti-PD-1 Based Immunotherapies.

Antibiotics (Basel) 2020 Oct 27;9(11). Epub 2020 Oct 27.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.

Recently antibiotic exposure has been associated with worse outcomes in patients undergoing treatment with antibodies directed against programmed cell death protein-1 (PD-1). We reviewed data of 1264 patients enrolled at Melanoma Skin and Ocular Tissue Repositories at University of Iowa Hospitals and Clinic. Reviewed data included patient demographics, prior medical history, baseline hematologic and disease parameters and outcomes including progression-free survival (PFS) and overall survival (OS). Cox regression models were used to determine predictive markers. Overall, 169 patients with advanced cutaneous melanoma received anti-PD-1 based therapies. Median follow up was 18.46 (range 0.89 to 62.52) months. On multivariable analysis brain metastasis, higher absolute neutrophil count (ANC) and lower absolute lymphocyte count were associated with poorer PFS while brain and liver metastasis and lower albumin were associated with poorer OS. Prior antibiotics, radiation as well as age, gender, basal metabolic index (BMI), smoking status, mutation, line of therapy (first or latter), prior treatments (ipilimumab or BRAF inhibitors), hemoglobin, neutrophil-to-lymphocyte ratio, white blood cell, platelet and eosinophil counts were not associated with PFS or OS in multivariable analysis. Contrary to some prior studies BMI, radiation, and antibiotics were not associated with PFS or OS.
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http://dx.doi.org/10.3390/antibiotics9110740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692514PMC
October 2020

Exploration of PCORnet Data Resources for Assessing Use of Molecular-Guided Cancer Treatment.

JCO Clin Cancer Inform 2020 08;4:724-735

Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA.

Purpose: Examine the ability of PCORnet data resources to investigate molecular-guided cancer treatment.

Patients And Methods: Patients (N = 86,154) had single primary solid tumors (diagnosed 2013-2017) from hospital oncology registries linked to the PCORnet Common Data Model (CDM) at 11 medical institutions. Molecular and anatomic test procedures and oral and infused therapies were identified with Current Procedural Terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes, RxNorm Concept Unique Identifier, and National Drug Codes from CDM tables. Chart review (2 institutions, n = 213) for advanced colorectal cancer and Medicare claims linkages (7 institutions, n = 1,731) for breast cancer explored options for increasing electronic data capture.

Results: Molecular testing prevalence detected via analyte-specific molecular CPT/HCPCS codes was 5.5% (n = 4,784); for the nonspecific anatomic pathology codes, for which only some testing is performed to guide therapy selection, it was an additional 44.8% (n = 38,610). Molecular-guided therapy prevalence was 5% (n = 4,289). Testing and treatment were most common with stage IV disease and varied across cancer types and study institutions (testing, 0%-10.4%; treatment, 0.8%-8.4%). Therapy-concordant test results were found in charts for all 36 treated patients with colorectal cancer at the 2 institutions, 3 (8.3%) of whom received treatment outside the institution. Breast cancer Medicare claims linkage increased rates of identified testing from 62.7%-98.9% and treatment from 3.9%-8.2%.

Conclusion: Although a minority of patients received molecular-guided therapies, the majority had testing that could guide cancer treatment. Claims data extended electronic data capture for therapies and test orders but often was uninformative for types of test ordered. Test results continue to require text data curation from narrative pathology reports.
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http://dx.doi.org/10.1200/CCI.19.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469597PMC
August 2020

Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events.

J Oncol 2019 25;2019:1856594. Epub 2019 Jul 25.

Division of Hematology, Oncology and Blood & Marrow Transplantation, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242, USA.

Introduction: Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes.

Materials And Methods: Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin & Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS).

Results: Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause).

Discussion: Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.
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http://dx.doi.org/10.1155/2019/1856594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683789PMC
July 2019

Urothelial carcinoma with an rearrangement and response to targeted therapy.

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.

Although mutations are commonly identified in many solid tumors and the response of p.V600E-positive tumors to targeted therapy is well documented, rearrangements are less frequent and are predominantly found in low-grade glioma, melanoma, lung, colorectal, and thyroid carcinoma. Preclinical and clinical studies have demonstrated effectiveness of multiple therapies (RAF-targeted, ERK-targeted, or MEK-targeted) targeting -fusion harboring tumors. We report a rare fusion with novel breakpoints, identified by next-generation sequencing-based assay, from a 69-year-old man with metastatic urothelial carcinoma (UC) of the renal pelvis and his initial clinical response to a second-generation MEK inhibitor, trametinib, before stopping the medication because of adverse side effects. The fusion has only been reported in a single case of anaplastic pleomorphic xanthoastrocytoma, and rearrangement has never been reported in UC.
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http://dx.doi.org/10.1101/mcs.a003848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549557PMC
June 2019

fusion in a low-grade glioma with distinctive morphology and unexpected aggressive behavior.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Department of Pathology, University of Iowa, Iowa City, Iowa 52242, USA.

A 52-yr-old man was found to have a 6.6-cm left frontotemporal mass. Biopsy revealed a low-grade astrocytic neoplasm with significant infiltration and an unusual morphologic appearance. Only rare mitotic figures were seen and the Ki-67 proliferative index was very low. Unexpectedly, the low-grade astrocytoma showed rapid progression within a short time, but subsequent resection showed similar histologic findings to the original biopsy with only slightly more mitoses and a marginally increased Ki-67 proliferative index. Molecular testing performed on the tumor showed no alterations in the , , , or genes by sequencing, intact 1p/19q by FISH, and a novel fusion transcript by reverse transcription and anchored multiplex PCR. The patient underwent standard-of-care therapy, both first and second line, for a high-grade glioma because of the aggressive behavior, but the glioma continued to progress despite treatment, and the patient died within 13.5 mo of the original diagnosis. At the time of diagnosis, the fusion transcript had not been described in solid tumors; however, a recent publication described this fusion transcript in two glioblastomas. Although no approved therapy was available for this patient, FDA approval has now been given for solid tumors with any gene family fusions. This unexpected molecular finding in a deceptively low-grade-appearing glioma supports the use of expanded molecular testing in gliomas and solid tumors, particularly in instances where targeted therapies are available.
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http://dx.doi.org/10.1101/mcs.a003855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549568PMC
April 2019

Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma.

Melanoma Res 2019 12;29(6):643-647

Departments of Hematology, Oncology, and Blood and Marrow Transplantation.

Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.
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http://dx.doi.org/10.1097/CMR.0000000000000592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717692PMC
December 2019

Toxicities with targeted therapies after immunotherapy in metastatic melanoma.

Melanoma Res 2018 12;28(6):600-604

Internal Medicine, Division of Hematology, Oncology and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine.

Over the last decade, melanoma treatment has taken rapid strides with the advent of immunotherapies and targeted agents. With these new agents, there has been a significant improvement in patient survival. However, these new treatment options may sometimes lead to unanticipated side effects that make these treatments challenging to administer and monitor. In preclinical studies, BRAF and MEK inhibitors have shown to modulate tumor microenvironment and potentiate immunotherapies. Therefore, some patients who had prior treatment with immunotherapies can develop immune toxicities even with these targeted agents due to the long half-life of these monoclonal antibodies. Herein, we present our institutional experience with regard to these unexpected toxicities with targeted agents in patients who had previous treatment with immunotherapies. This case series lays out the various side effects along with details of their management, outcomes, and patient response.
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http://dx.doi.org/10.1097/CMR.0000000000000493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436382PMC
December 2018

TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy.

Skelet Muscle 2018 05 31;8(1):17. Epub 2018 May 31.

Department of Pathology Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.

Background: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation.

Case Presentation: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual.

Conclusion: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.
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http://dx.doi.org/10.1186/s13395-018-0163-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984345PMC
May 2018

Biallelic TP53 gain of function mutations in rapidly progressing solid tumors.

Cancer Genet 2018 04 24;222-223:20-24. Epub 2018 Feb 24.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City 52241, IA, USA . Electronic address:

Recent studies are discovering TP53 mutations with gain of function (GOF) properties that promote tumorigenesis via a variety of mechanisms. To our knowledge, all reported compound mutations are allelic. We identified two patients with biallelic GOF TP53 mutations in their tumors and a third with allelic compound variants. The correlation with p53 expression was also examined. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and mutational analysis was performed using Ion AmpliSeq™Cancer HotSpot Panel V2. Biallelic GOF mutations (p.R273H and p.R273C) were identified in a 19-year-old male with glioblastoma (allele frequencies 94% and 48%) and a 54-year-old with pT3 penile squamous cell carcinoma (allele frequencies 19% and 27%). Immunohistochemistry showed nuclear accumulation of p53. The third patient, a 62-year-old female with metastatic lung adenocarcinoma, had allelic p.P278S (GOF) and p.R283L (non-GOF) variants at frequencies of 61% but with null staining for p53. Germline testing for Patient 1 confirmed wildtype TP53. No other variants were discovered among the genes tested in these cases. All patients succumbed within two years of diagnosis despite aggressive treatment. In conclusion, implementation of TP53 mutation analysis in clinical practice may predict patient outcome, and inhibition of GOF p53 could represent an attractive target for therapy.
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http://dx.doi.org/10.1016/j.cancergen.2018.02.001DOI Listing
April 2018

Correction to: Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy.

BMC Cancer 2018 04 12;18(1):413. Epub 2018 Apr 12.

Cellworks Group, Inc., 2033 Gateway Place Suite 500, San Jose, CA, 95110, USA.

It has been highlighted that in the original manuscript [1] Table S3 'An example of the predictive computational modeling process. Specific details on an annexure section of the PD-L1 pathway show the step-by-step reactions, mechanisms, and reaction equations that occur. Such reactions also occurred in all of the other pathways' was omitted and did not appear in the Additional files and that the Additional files were miss-numbered thereafter. This Correction shows the correct and incorrect Additional files. The original article has been updated.
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http://dx.doi.org/10.1186/s12885-018-4200-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898039PMC
April 2018

Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy.

BMC Cancer 2018 02 27;18(1):225. Epub 2018 Feb 27.

Cellworks Group, Inc., 2033 Gateway Place Suite 500, San Jose, CA, 95110, USA.

Background: Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses.

Methods: We used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses.

Results: Expression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses.

Conclusions: Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies.
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http://dx.doi.org/10.1186/s12885-018-4134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897943PMC
February 2018

Simultaneous detection of single-nucleotide variant, deletion/insertion, and fusion in lung and thyroid carcinoma using cytology specimen and an RNA-based next-generation sequencing assay.

Cancer Cytopathol 2018 03 24;126(3):158-169. Epub 2018 Jan 24.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

Background: Molecular testing for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion is routinely performed in patients with stage IV lung adenocarcinoma to assess their eligibility for targeted therapy. Fine-needle aspiration (FNA)-derived material frequently is the only pathologic material available. The identification of genomic aberrations in thyroid nodules from FNA smears may help stratify cancer risk and spare patients from a second surgery. In the current study, the authors tested nucleic acid extracted from the cytology smears of lung and thyroid carcinomas for simultaneous detection of single-nucleotide variant, insertion/deletion, and gene fusion using an RNA-based next-generation sequencing assay.

Methods: A total of 27 cases (17 lung and 10 thyroid carcinomas, the majority of which had known variants) were tested. Areas of interest were scrapped from stained smears using a scalpel. Total nucleic acid was extracted. Gene fusion and mutational analysis was performed using the Comprehensive Thyroid and Lung FusionPlex Assay. Data were analyzed using the analysis pipeline provided by the vendor. Eleven cases with available formalin-fixed, paraffin-embedded (FFPE) tissue were tested in parallel.

Results: Gene fusions were detected in 6 cases; common single-nucleotide variants in EGFR, RAS, and BRAF in 14 cases; and in-frame deletions within EGFR in 3 cases. A concordance rate of 100% was observed between FNA and FFPE tissue.

Conclusions: Cytology preparations can be a reliable source for the detection of both DNA and RNA aberrations. The ability to simultaneously detect multiple types of genomic variants is crucial for patients with advanced cancer and maximizes the usefulness of cytology specimens. Cancer Cytopathol 2018;126:158-69. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.21963DOI Listing
March 2018

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study.

Oncotarget 2017 Oct 26;8(51):89182-89193. Epub 2017 Sep 26.

Department of Hematology, Oncology and Blood and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Introduction: Epigenetic modifications play an important role in progression and development of resistance in BRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with BRAF positive metastatic melanoma with or without any prior treatment.

Experimental Design: The study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line.

Results: Fourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity.

Conclusions: The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in BRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.
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http://dx.doi.org/10.18632/oncotarget.21269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687680PMC
October 2017

Anchored multiplex PCR for targeted next-generation sequencing reveals recurrent and novel USP6 fusions and upregulation of USP6 expression in aneurysmal bone cyst.

Genes Chromosomes Cancer 2017 04 2;56(4):266-277. Epub 2016 Dec 2.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242.

Primary aneurysmal bone cyst (ABC) is a neoplastic process due to recurrent translocations involving the USP6 gene. By fluorescence in situ hybridization, up to 69% of primary ABCs harbored USP6 translocations; no USP6 translocation was found in secondary ABC or giant cell tumor of bone (GCT). GCT can recur locally, metastasize to the lungs in some cases, and rarely undergo malignant transformation. Differentiating primary ABC from its mimics is important for treatment and prognosis. We evaluated USP6 fusion and expression in 13 cases of primary and 1 case of secondary ABC, and 9 cases of GCT using nucleic acid extracted from formalin-fixed, paraffin-embedded tissue and a next generation sequencing (NGS)-based assay. USP6 fusions including 7 novel fusions and USP6 transcripts were identified in all 13 primary ABCs. Nine cases with strong evidence of fusions showed high levels of USP6 transcripts by reverse transcription-PCR (RT-PCR). The remaining four had no detectable USP6 expression by a first-round of RT-PCR but the presence of USP6 transcripts was identified by a second-round, nested PCR. The major fusions were confirmed by RT-PCR followed by Sanger sequencing. No USP6 fusion or transcript was detected in any of the GCTs or the case of secondary ABC by NGS or by two rounds of PCR. All USP6 translocations resulted in fusion of the entire USP6 coding sequence with promoters of the fusion gene leading to upregulation of USP6 transcription, which is likely the underlying mechanism for ABC oncogenesis. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22432DOI Listing
April 2017

The NAB2-STAT6 gene fusion in solitary fibrous tumor can be reliably detected by anchored multiplexed PCR for targeted next-generation sequencing.

Cancer Genet 2016 Jul-Aug;209(7-8):303-12. Epub 2016 May 24.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. Electronic address:

Solitary fibrous tumor (SFT) is a mesenchymal tumor of fibroblastic origin, which can affect any region of the body. 10-15% of SFTs metastasize and metastatic tumors are uniformly lethal with no effective therapies. The behavior of SFT is difficult to predict based on morphology. Recently, an intrachromosomal gene fusion between NAB2 and STAT6 was identified as the defining driving genetic event of SFT and different fusion types correlated with tumor histology and behavior. Due to the proximity of NAB2 and STAT6 on chromosome 12, this fusion may be missed by fluorescence in-situ hybridization. We evaluated 12 SFTs from 10 patients. All tumors showed strong nuclear staining for STAT6 by immunohistochemistry (IHC). The same formalin-fixed, paraffin-embedded blocks for IHC were used for gene fusion detection by a next-generation sequencing (NGS)-based assay. Targeted RNA fusion sequencing for gene fusions was performed using the Universal RNA Fusion Detection Kit, the Archer(™) FusionPlex(™) Sarcoma Panel and the Ion Torrent PGM, and data were analyzed using the Archer Analysis Pipeline 3.3. All tumors were positive for NAB2-STAT6 fusion. Six types of fusions were detected: NAB2ex4-STAT6ex2, NAB2ex2-STAT6ex5, NAB2ex6-STAT6ex16, NAB2ex6-STAT6ex17, NAB2ex3-STAT6ex18 and NAB2intron6-STAT6Ex17. The NGS findings were confirmed by RT-PCR followed by Sanger sequencing. No STAT6 fusion was detected in selected morphologic mimics of SFT. The assay also allows for detection of novel fusions and can detect NAB2-STAT6 fusions at a single-base resolution.
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http://dx.doi.org/10.1016/j.cancergen.2016.05.071DOI Listing
May 2017

Genomic Sequencing Procedure Microcosting Analysis and Health Economic Cost-Impact Analysis: A Report of the Association for Molecular Pathology.

J Mol Diagn 2016 05 13;18(3):319-328. Epub 2016 Apr 13.

Genomic Sequencing Procedures Pricing Project Oversight Committee, a Working Group of the Association for Molecular Pathology Economic Affairs Committee, Bethesda, Maryland; Department of Pathology, University of Iowa, Iowa City, Iowa.

The increasing use of advanced nucleic acid sequencing technologies for clinical diagnostics and therapeutics has made vital understanding the costs of performing these procedures and their value to patients, providers, and payers. The Association for Molecular Pathology invested in a cost and value analysis of specific genomic sequencing procedures (GSPs) newly coded by the American Medical Association Current Procedural Terminology Editorial Panel. Cost data and work effort, including the development and use of data analysis pipelines, were gathered from representative laboratories currently performing these GSPs. Results were aggregated to generate representative cost ranges given the complexity and variability of performing the tests. Cost-impact models for three clinical scenarios were generated with assistance from key opinion leaders: impact of using a targeted gene panel in optimizing care for patients with advanced non-small-cell lung cancer, use of a targeted gene panel in the diagnosis and management of patients with sensorineural hearing loss, and exome sequencing in the diagnosis and management of children with neurodevelopmental disorders of unknown genetic etiology. Each model demonstrated value by either reducing health care costs or identifying appropriate care pathways. The templates generated will aid laboratories in assessing their individual costs, considering the value structure in their own patient populations, and contributing their data to the ongoing dialogue regarding the impact of GSPs on improving patient care.
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http://dx.doi.org/10.1016/j.jmoldx.2015.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212689PMC
May 2016

Germline mutations predisposing to non-small cell lung cancer.

Fam Cancer 2015 Sep;14(3):463-9

Department of Internal Medicine, University of Iowa College of Medicine, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA, 52242, USA,

Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well.
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http://dx.doi.org/10.1007/s10689-015-9796-xDOI Listing
September 2015

A simple and cost-effective method of DNA extraction from small formalin-fixed paraffin-embedded tissue for molecular oncologic testing.

BMC Clin Pathol 2014 7;14:30. Epub 2014 Jul 7.

Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, BT6008GH, Iowa City, IA 52242, USA.

Background: Extraction of DNA from formalin-fixed, paraffin-embedded (FFPE) tissue is a critical step in molecular oncologic testing. As molecular oncology testing becomes more important for prognostic and therapeutic decision making and tissue specimens become smaller due to earlier detection of suspicious lesions and the use of fine needle aspiration methods for tissue collection, it becomes more challenging for the typical molecular pathology laboratory to obtain reliable test results. We developed a DNA extraction method to obtain sufficient quantity and high quality genomic DNA from limited FFPE tissue for molecular oncology testing using a combination of H&E stained slides, a matrix capture method and the Qiagen DNA column.

Methods: THREE DNA EXTRACTION METHODS WERE COMPARED: our standard procedure of manually scraping tissue from unstained slides followed by DNA extraction using the QIAamp FFPE column (Qiagen, Valencia, CA), a glue capture method (Pinpoint Solution, Zymo Research Corp, Inc) on H&E stained slides followed by DNA extraction using either the QIAamp column or the column included with the Pinpoint kit (Zymo Research). The DNA extraction protocol was optimized. Statistical analysis was performed using the paired two-sample student's t-test.

Results: The combination of the matrix capture method with the QIAamp column gave an equivalent amount of DNA as our standard extraction method using the unstained slides and a 4.6-fold higher DNA yield than using the Zymo column included in the Pinpoint Slide Solution kit. Several molecular tests were performed and DNA purified using the new method gave the same results as for the previous methods.

Conclusions: Using H&E stained slides allows visual confirmation of tumor cells during microdissection. The Pinpoint solution made removal of specific tissue from the slides easier and reduced the risk of contamination and tissue loss. This DNA extraction method is simple, cost-effective, and blends with our current workflow requiring no additional equipment.
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http://dx.doi.org/10.1186/1472-6890-14-30DOI Listing
July 2014

Evaluation of the Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry systems for identification of nonfermenting gram-negative bacilli isolated from cultures from cystic fibrosis patients.

J Clin Microbiol 2012 Jun 11;50(6):2034-9. Epub 2012 Apr 11.

Univ. of Iowa Health Care, Iowa City, Iowa, USA.

The Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) instruments were evaluated for the identification of nonfermenting gram-negative bacilli (NFGNB) by a blinded comparison to conventional biochemical or molecular methods. Two hundred NFGNB that were recovered from cultures from cystic fibrosis patients in the University of Iowa Health Care (UIHC) Microbiology Laboratory between 1 January 2006 and 31 October 2010 were sent to Mayo Clinic for analysis with the Bruker Biotyper (software version 3.0) and to bioMérieux for testing with Vitek MS (SARAMIS database version 3.62). If two attempts at direct colony testing failed to provide an acceptable MALDI-TOF identification, an extraction procedure was performed. The MS identifications from both of these systems were provided to UIHC for comparison to the biochemical or molecular identification that had been reported in the patient record. Isolates with discordant results were analyzed by 16S rRNA gene sequencing at UIHC. After discrepancy testing, the Bruker Biotyper result agreed with the biochemical or molecular method, with 72.5% of isolates to the species level, 5.5% to the complex level, and 19% to the genus level (3% not identified). The level of agreement for Vitek MS was 80% species, 3.5% complex, 6% genus, and 3.5% family (7% not identified). Both MS systems provided rapid (≤3 min per isolate) and reliable identifications. The agreement of combined species/complex/genus-level identification with the reference method was higher for the Bruker Biotyper (97% versus 89.5%, P = 0.004) but required an extraction step more often. Species-level agreement with the reference method was similar for both MS systems (72.5% and 80%, P = 0.099).
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http://dx.doi.org/10.1128/JCM.00330-12DOI Listing
June 2012

Muscle-Eye-Brain disease.

J Clin Neuromuscul Dis 2010 Mar;11(3):124-6

Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

A term female infant was evaluated for global developmental delay, hypotonia, hyporeflexia, diffuse weakness including facial muscles, and visual impairment with optic nerve hypoplasia. In the absence of family history or perinatal concerns, an extensive investigation was performed, including lab studies, muscle biopsy, brain MRI and focused genetic testing. This revealed elevated serum CK, a structurally abnormal brain, and a dystrophic-appearing muscle biopsy with evidence of a glycosylation defect in the alpha-dystroglycan complex. Of the 6 known related genes, testing of the POMGnT1 gene showed three heterozygous missense mutations. Thus her history, examination, biopsy specimen, imaging, laboratory, and genetic studies are all consistent with the diagnosis of Muscle-Eye-Brain (MEB) disease. MEB is one of an emerging spectrum of congenital disorders that involve both central and peripheral nervous systems, described further in this case report.
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http://dx.doi.org/10.1097/CND.0b013e3181c5054dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925645PMC
March 2010

Human papillomavirus (HPV) type 18 induces extended growth in primary human cervical, tonsillar, or foreskin keratinocytes more effectively than other high-risk mucosal HPVs.

J Virol 2009 Nov 9;83(22):11784-94. Epub 2009 Sep 9.

Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, IA 52246, USA.

Mucosal high-risk (HR) human papillomaviruses (HPVs) that cause cervical and other anogenital cancers also are found in approximately 25% of head and neck carcinomas (HNCs), especially those arising in the oropharynx and the tonsils. While many HR HPV types are common in anogenital cancer, over 90% of HPV-positive HNCs harbor HPV type 16 (HPV-16). Using a quantitative colony-forming assay, we compared the ability of full-length mucosal HPV genomes, i.e., the low-risk HPV-11 and HR HPV-16, -18, and -31, to persist in and alter the growth of primary human keratinocytes from the foreskin, cervix, and tonsils. The HR HPV types led to the formation of growing keratinocyte colonies in culture independent of the site of epithelial origin. However, HPV-18 induced colony growth in all keratinocytes >4-fold more effectively than HPV-16 or HPV-31 and >20-fold more efficiently than HPV-11 or controls. HPV-11-transfected or control colonies failed to expand beyond 32 to 36 population doublings postexplantation. In contrast, individual HR HPV-transfected clones exhibited no apparent slowdown of growth or "crisis," and many maintained HPV plasmid persistence beyond 60 population doublings. Keratinocyte clones harboring extrachromosomal HR HPV genomes had shorter population doubling times and formed dysplastic stratified epithelia in organotypic raft cultures, mirroring the pathological features of higher-grade intraepithelial lesions, yet did not exhibit chromosomal instability. We conclude that, in culture, the HR HPV type, rather than the site of epithelial origin of the cells, determines the efficacy of inducing continued growth of individual keratinocytes, with HPV-18 being the most aggressive mucosal HR HPV type tested.
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http://dx.doi.org/10.1128/JVI.01370-09DOI Listing
November 2009

Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1.

Carcinogenesis 2009 Aug 18;30(8):1336-44. Epub 2009 Jun 18.

Veterans Affairs Medical Center, Iowa City, IA 52246, USA.

Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis, to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-beta synthesis and downregulate genes induced by IFN. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-beta as a potential boost in infection. Treatment with low levels of human IFN-beta induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to 6-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic interferon regulatory factor (IRF) expression in transfection experiments using IRF-1(-/-), IRF-2(-/-) and dual knockout cell lines determined that these responses are due to the activation of IRF-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of IFN therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signaling molecules in infection and therapy.
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http://dx.doi.org/10.1093/carcin/bgp150DOI Listing
August 2009

The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth.

J Virol 2008 Mar 26;82(5):2493-500. Epub 2007 Dec 26.

University of Iowa Department of Otolaryngology-Head and Neck Surgery, Iowa City, IA 52242, USA.

The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras(v12), resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.
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http://dx.doi.org/10.1128/JVI.02188-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258903PMC
March 2008

Deletion of the PDZ motif of HPV16 E6 preventing immortalization and anchorage-independent growth in human tonsil epithelial cells.

Head Neck 2008 Feb;30(2):139-47

Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.

Background: Human papillomavirus 16 (HPV16) has been associated with head and neck squamous cell carcinoma (HNSCC) in up to 60% of sampled specimens.

Methods: To understand better the viral genes required to transform human tonsil epithelial cells (HTEC), we isolated HTEC's and transduced them with retroviral vectors containing HPV16 E6 and E7.

Results: Immortalization and anchorage-independent growth of HTEC's only occurred with expression of E6 and E7 with resultant degradation of p53. However, cells expressing E6 lacking the PSD-95/disc-large/Zo-1 (PDZ) motif did not immortalize or grow anchorage independent. Telomerase activity and degradation of p53 were similar for wild-type and mutant E6.

Conclusion: The mechanism of oncogenic transformation by E6 in HTEC's is dependent on the PDZ binding motif. Identification of pathways affected by the interaction of E6 and PDZ domain containing proteins will further our understanding of how HPV causes HNSCC and will provide potential therapeutic targets.
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http://dx.doi.org/10.1002/hed.20673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600880PMC
February 2008

A novel t(3;8)(q27;q24.1) simultaneously involving both the BCL6 and MYC genes in a diffuse large B-cell lymphoma.

Cancer Genet Cytogenet 2007 Jan;172(1):45-53

Department of Pathology and Laboratory Medicine, School of Medicine, Hospital of the University of Pennsylvania, 7.103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19014-4284, USA.

Diffuse large B-cell lymphomas (DLBCLs) are a clinically and biologically heterogeneous group of hematologic malignancies. Specific genetic aberrations underlie some of this heterogeneity. These genetic events include distinct and separate translocations resulting in the dysregulated expression of either BCL6 protein with the t(3;14)(q27;q32) or c-MYC protein with the t(8;14)(q24;q32), as a consequence of the juxtaposition of these oncogenes with heterologous promoters or enhancers, such as those of the immunoglobulin heavy chain gene. Here, we report the case of a patient with DLBCL with a unique t(3;8)(q27;q24.1) that involves the BCL6 and MYC genes. We know of no previous report of this translocation in DLBCL, which simultaneously affects two key genes implicated in lymphomagenesis and may reflect a novel genetic mechanism in neoplastic transformation.
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http://dx.doi.org/10.1016/j.cancergencyto.2006.07.016DOI Listing
January 2007

Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma.

J Immunother 2006 Sep-Oct;29(5):558-68

Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.

Oligodeoxynucleotides containing CpG motifs (CpG ODN) can alter various immune cell subsets important in antibody therapy of malignancy. We undertook a phase I trial of CPG 7909 (also known as PF-3512676) in patients with previously treated lymphoma with the primary objective of evaluating safety across a range of doses, and secondary objectives of evaluating immunomodulatory effects and clinical effects. Twenty-three patients with previously treated non-Hodgkin lymphoma received up to 3 weekly 2-hour intravenous (IV) infusions of CPG ODN 7909 at dose levels 0.01 to 0.64 mg/kg. Evaluation of immunologic parameters and clinical endpoints occurred for 6 weeks. Infusion-related toxicity included grade 1 nausea, hypotension, and IV catheter discomfort. Serious adverse hematologic events observed more than once included anemia (2=Gr3, 2=Gr4), thrombocytopenia (4=Gr3), and neutropenia (2=Gr3), and were largely judged owing to progressive disease. Immunologic observations included: (1) The mean ratio of NK-cell concentrations compared with pretreatment at day 2 was 1.44 (95% CI=0.94-1.94) and at day 42 was 1.53 (95% CI=1.14-1.91); (2) NK activity generally increased in subjects; and (3) Antibody-dependent cellular cytotoxicity activity increased in select cohorts. No clinical responses were documented radiographically at day 42. Two subjects demonstrated late response. We conclude CpG 7909 can be safely given as a 2-hour IV infusion to patients with previously treated non-Hodgkin lymphoma at doses that have immunomodulatory effects.
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http://dx.doi.org/10.1097/01.cji.0000211304.60126.8fDOI Listing
November 2006
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