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1.  Genetic and Expression Analysis of HER-2 and EGFR Genes in Salivary Duct Carcinoma: Empirical and Therapeutic Significance 
Purpose
Salivary duct carcinoma over-expresses epidermal growth factor receptor (EGFR) and HER-2 though underlying mechanisms remain undefined. Because of potential utilization of these markers as treatment targets, we evaluated protein and gene status by several techniques to determine complementary value.
Experimental Design
A tissue microarray of 66 salivary duct carcinomas was used for immunohistochemical analysis of HER-2 and EGFR expression (semiquanititively evaluated into a 3-tiered system), and fluorescence in situ hybridization for gene copy number, and chromosomes 7 and 17 ploidy status. Sequencing of Exons 18, 19 and 21 of the EGFR gene for mutations was performed.
Results
EGFR Forty-six (69.7%) of the 66 tumors showed some form of EGFR expression (17,3+; 17,2+; 12,1+) but none gene amplification. Five (9.4%) of 53 tumors showed mutations in exon 18 (3) and exon 19 (2). Polysomy of chromosome 7(average >2.5 copies per cell) was detected in 15 (25.0%) of 60 tumors (6,3+; 5,2+; 2,1+; 2,0+ expression) and correlated with poor 3-year survival (p=0.015). HER-2: Seventeen (25.8%) of 66 tumors expressed HER-2 (10,3+; 3,2+; 4,1+). Eight tumors showed HER-2 gene amplification (6,3+; 1,1+; 1,0+ protein expression). Chromosome 17 polysomy was found in eight (15.7%) of 51 tumors; two with HER-2 expression (3+; 1+).
Conclusion
Our study shows that salivary duct carcinomas: 1) harbor EGFR gene mutations in a subset of tumors which may guide therapy, 2) pursue aggressive clinical course in cases with Chromosome 7 polysomy and high EGFR expression, and 3) with HER-2 gene amplification and protein high-expression maybe selected for targeted therapy.
doi:10.1158/1078-0432.CCR-09-0238
PMCID: PMC4152860  PMID: 20371674
Salivary duct carcinoma; epidermal growth factor receptor; HER-2; Fluorescence in situ hybridization; polysomy; mutation
2.  Whole exome sequencing of adenoid cystic carcinoma 
The Journal of Clinical Investigation  2013;123(7):2965-2968.
Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.
doi:10.1172/JCI67201
PMCID: PMC3999050  PMID: 23778141
3.  Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras 
The Journal of pathology  2011;225(4):479-489.
Mutations in p53 occur in over 50% of the human head and neck squamous cell carcinomas (SCCHN). The majority of these mutations result in the expression of mutant forms of p53, rather than deletions in the p53 gene. Some p53 mutants are associated with poor prognosis in SCCHN patients. However, the molecular mechanisms that determine the poor outcome of cancers carrying p53 mutations are unknown. Here, we generated a mouse model for SCCHN and found that activation of the endogenous p53 gain-of-function mutation p53R172H, but not deletion of p53, cooperates with oncogenic K-ras during SCCHN initiation, accelerates oral tumour growth, and promotes progression to carcinoma. Mechanistically, expression profiling of the tumours that developed in these mice and studies using cell lines derived from these tumours determined that mutant p53 induces the expression of genes involved in mitosis, including cyclin B1 and cyclin A, and accelerates entry in mitosis. Additionally, we discovered that this oncogenic function of mutant p53 was dependent on K-ras because the expression of cyclin B1 and cyclin A decreased, and entry in mitosis was delayed, after suppressing K-ras expression in oral tumour cells that express p53R172H. The presence of double-strand breaks in the tumours suggests that oncogene-dependent DNA damage resulting from K-ras activation promotes the oncogenic function of mutant p53. Accordingly, DNA damage induced by doxorubicin also induced increased expression of cyclin B1 and cyclin A in cells that express p53R172H. These findings represent strong in vivo evidence for an oncogenic function of endogenous p53 gain-of-function mutations in SCCHN and provide a mechanistic explanation for the genetic interaction between oncogenic K-ras and mutant p53.
doi:10.1002/path.2971
PMCID: PMC4302750  PMID: 21952947
mutant p53; head and neck cancer; mouse model; ras; gain-of-function mutations
4.  Molecular Profiling of Sinonasal Undifferentiated Carcinoma 
Head & neck  2013;36(1):10.1002/hed.23267.
Background
Sinonasal undifferentiated carcinoma remains a poorly characterized malignancy at both the clinical and molecular level, and consequently the optimal treatment strategy remains undefined.
Methods
We utilized a mass spectroscopy-based approach (Sequenom™) to evaluate 95 hallmark single nucleotide variations within 12 oncogenes or tumor suppressor genes (AKT, BRAF, CDK4, Beta-catenin, EGFR, FBXW7, JAK2, c-KIT, KRAS, PDGFR, PI3K, VEGF) in 13 histologically confirmed SNUC cases.
Results
None of the samples demonstrated activating mutations in any of the 95 SNVs.
Conclusions
Select clinically relevant activating genomic mutations were not identified the 13 patient samples. However, polymorphisms were noted within the promoter region of VEGF. These may merit future study as predictive biomarkers for treatment response or overall survival. Additionally, future studies focusing on larger tumor sets and utilizing whole genome or exome sequencing may help define genetic aberrations in SNUC that can be clinically targeted with available or emerging biological agents.
doi:10.1002/hed.23267
PMCID: PMC3874284  PMID: 23633104
SNUC; Sinonasal Undifferentiated Carcinoma; Paranasal sinus tumors; VEGF; Sequenom
5.  Clinical significance of Myb protein and downstream target genes in salivary adenoid cystic carcinoma 
Cancer Biology & Therapy  2011;12(7):569-573.
Adenoid cystic carcinoma (ACC), the second most frequent malignancy of the major and minor salivary glands, comprise of approximately 15–23% of all carcinomas at these locations. ACC is uniquely formed of dual epithelial and myoepithelial cells that give rise to different phenotypic patterns. We hypothesize that the dual myoepithelial/epithelial composition of ACCs underlie their biological heterogeneity and may impact on their therapeutic management. A recurrent reciprocal translocation of t(6;9)(q22–23;p23–24) resulting in fusion gene partners comprising MYB gene the transcription factor NFIB has been reported in ACC of breast, salivary, lachrymal and ceruminal glands. In fusion positive and a subset of fusion negative ACCs, high expression of the transcript Myb was found. However, the role of Myb protein expression and the potential effect on the downstream targets have not been investigated. To investigate the biological and prognostic significance of use of elevated levels of Myb and its downstream target genes (c-kit, cox-2, bcl-2), we analyzed, by immunohistochemistry, the protein expression of these genes in 156 ACCs.
We have found that 55% of ACCs have increased Myb expression mainly confined to myoepithelial cells. We validated Myb expression on a large cohort of ACCs (156 patients). Although no significant effects of the individual Myb and downstream targets c-kit, bcl-2 and cox-2 on survival was noticed, the combinations survival curve for Myb+/c-kit+/cox-2+ showed better survival than combination Myb−/c-kit+/cox-2+. Myb may serve as a new target for the management of this disease, and future therapeutic trials of these tumors may be better based on biomarker stratification and the cellular composition of these tumors.
doi:10.4161/cbt.12.7.17008
PMCID: PMC3218383  PMID: 21785271
adenoid cystic carcinoma; c-kit; cox-2; bcl-2
6.  Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy 
Introduction
The mitogen-activated protein kinase (MAPK) pathway comprises several key signaling components and phosphorylation events that play important role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. Accordingly, these pathways are considered a potential therapeutic target for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials.
Areas covered
This paper focuses on the biological role of the RAS-MAPK pathway, the consequence of its disregulation, and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway will be reviewed here along with a discussion of the application and the results of various inhibitory molecules as anticancer agents in clinical trials.
Expert opinion
The RAS-MAPK pathway mediates cellular responses to growth signals and is often deregulated in human cancer. Activating mutations in the RAS and BRAF genes have been frequently identified in a wide range of cancers. Inhibitors of MEK and particularly of RAF kinases, have been effective in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.
doi:10.1517/14728222.2011.645805
PMCID: PMC3457779  PMID: 22239440
mitogen-activated protein kinase (MAPK); extracellular signal-regulated kinase (ERK); MAP kinase kinase (MEK); RAS; RAF; inhibitors; targeted therapies
7.  Differential gene expression profiling of aggressive and non-aggressive follicular carcinomas 
Human pathology  2011;42(9):1213-1220.
Summary
The classification of follicular thyroid neoplasms requires surgical resection for histologic evaluation of malignancy. As variable clinical behavior exists, genomic expression profiling may lead to the identification of novel markers that facilitate better biological classification. We performed for the first time gene expression analysis on clinically aggressive and non-aggressive follicular carcinomas (FCs) from patients for whom long-term follow-up data were available. We examined matched fresh/frozen tissue from 15 histopathologically diagnosed FCs (7 patients with documented distant metastasis and/or death from disease and 8 patients without recurrence). For categorical comparison, we analyzed 4 follicular adenomas (FAs). The biological control comprised 11 normal thyroid tissue specimens. High-quality RNA was extracted from the tissues, labeled, and hybridized to an Affymetrix oligonucleotide microarray (HG-U133A). With the exceptions of 1 FA and 1 FC, unsupervised hierarchical cluster analysis revealed 2 distinct groups—one containing normal thyroid tissue and FAs and another containing FCs. We identified 421 genes that were differentially expressed between histologically normal thyroid tissues and all follicular neoplasms (P < 0.01; fold-change >2), 94 genes that distinguished FCs from FAs (including PBP and CKS2), and 4 genes that distinguished aggressive FCs from non-aggressive FCs (NID2, TM7SF2, TRIM2 and GLTSCR2). Comparative genomic groupings identified differentially expressed genes that may lead to better classification of follicular thyroid neoplasms. Such genes may be used in future prospective validation studies to establish clinically useful and complementary diagnostic markers.
doi:10.1016/j.humpath.2010.12.006
PMCID: PMC3156288  PMID: 21420716
Follicular neoplasms; follicular carcinoma; gene expression; Affymetrix
8.  Novel Chromosomal Rearrangements and breakpoints at the t(6;9) in Salivary Adenoid Cystic Carcinoma: association with MYB-NFIB chimeric fusion, MYB expression, and clinical outcome 
Objective
To investigate the molecular-genetic heterogeneity associated with the t(6:9) in adenoid cystic carcinoma (ACC) and correlate the findings with patient clinical outcome.
Experimental Design
Multi-molecular and genetic techniques complemented with massive pair-ended sequencing and SNP array analyses were used on tumor specimens from 30 new and 52 previously RT-PCR analyzed fusion transcript negative ACCs. MYB mRNA expression level was determined by quantitative RT-PCR. The results of 102 tumors (30 new and 72 previously reported cases) were correlated with the clinicopathologic factors and patients’ survival.
Results
The FISH analysis showed 34/82 (41.5%) fusion positive tumors and molecular techniques identified fusion transcripts in 21 of the 82 (25.6%) tumors. Detailed FISH analysis of 11 out the 15 tumors with gene fusion without transcript formation showed translocation of NFIB sequences to proximal or distal sites of the MYB gene. Massive pair-end sequencing of a subset of tumors confirmed the proximal translocation to an NFIB sequence and led to the identification of a new fusion gene (NFIB-AIG1) in one of the tumors. Overall, MYB-NFIB gene fusion rate by FISH was in 52.9% while fusion transcript forming incidence was 38.2%. Significant statistical association between the 5′ MYB transcript expression and patient survival was found.
Conclusions
We conclude that: 1) t(6;9) results in a complex genetic and molecular alterations in ACC, 2) MYB-NFIB gene fusion may not always be associated with chimeric transcript formation, 3) non-canonical MYB, NFIB gene fusions occur in a subset of tumors, 4) high MYB expression correlates with worse patient survival.
doi:10.1158/1078-0432.CCR-11-1870
PMCID: PMC3225955  PMID: 21976542
Gene fusion; Gene fusion; chromosomal translocations; salivary gland carcinomas; molecular alterations
9.  Phase II Randomized, Placebo-controlled Trial of Green Tea Extract in Patients with High-risk Oral Premalignant Lesions 
Epidemiologic and preclinical data support the oral-cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPLs) to receive GTE at 500 mg/m2, 750 mg/m2, or 1000 mg/m2 or placebo TID for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n=28; 50%) versus placebo (n=11; 18.2%; p=0.09) but did not reach statistical significance. However, the 2 higher-dose GTE arms (58.8% [750, 1000 mg/m2], 36.4% [500 mg/m2], and 18.2%, [placebo], p=0.03) had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%, p=0.65), though not statistically significant. GTE was well-tolerated although higher doses increased insomnia/nervousness but produced no grade-4 toxicity. Higher mean baseline stromal VEGF correlated with a clinical (p=0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n=5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in non-responsive patients at 12 weeks (versus at baseline). An extended (median 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12 week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.
doi:10.1158/1940-6207.CAPR-09-0121
PMCID: PMC4243312  PMID: 19892663
green tea extract; oral premalignant lesions; chemoprevention
10.  Primary Colonic -Type Adenocarcinoma of the Base of the Tongue: a Previously Unreported Phenotype 
Human Pathology  2009;40(12):1798-1802.
Primary lingual adenocarcinomas are rare and typically of salivary or seromucinous glands origin. Similarly, metastatic adenocarcinoma from distant primary sites to the tongue is an uncommon event, with only three cases from a colonic primary site reported. We present, for the first time, two primary colonic-type adenocarcinomas of the base of the tongue and discuss their putative origin and the clinicopathologic characteristics.
doi:10.1016/j.humpath.2009.01.028
PMCID: PMC3296116  PMID: 19695679
Base of tongue; Primary adenocarcinoma; Intestinal-type; Metastatic carcinoma
11.  Cell-type dependent biomarkers expression in adenoid cystic carcinoma (ACC): biological and therapeutic implications 
Cancer  2010;116(24):5749-5756.
Adenoid cystic carcinoma (ACC), a rare and progressive salivary malignancy, is characterized by cellular, morphologic and clinical heterogeneity. We hypothesize that its dual cellular composition plays an important role in biomarker evaluation, tumor biological behavior and therapy response.
To investigate the differential localization and expression of c-kit and EGFR proteins, we performed immunohistochemical analysis on tissue arrays of 199 tumors and correlated the results with the clinico-pathological factors. The results show c-kit expression to be limited to the inner ductal epithelial cells and the EGFR expression mainly to the outer myoepithelial cells in the majority of tubular and cribriform patterns. In solid ACC, c-kit was uniformly positive while EGFR was consistently negative. Significant statistical correlation was found between c-Kit expression and a poor 3- year outcome, and EGFR expression with a better 3-year outcome. Our findings underscore the importance of cellular subtypes’ localization of biomarkers in the clinical and therapeutic stratification of patients with this entity.
doi:10.1002/cncr.25541
PMCID: PMC2998592  PMID: 20824717
adenoid cystic carcinoma; cellular localization; c-kit; EGFR
12.  Human Papillomavirus and WHO Type I Nasopharyngeal Carcinoma 
The Laryngoscope  2010;120(10):1990-1997.
Objectives
Nasopharyngeal carcinoma (NPC) is a rare cancer in the United States. An association between NPC and Epstein-Barr virus (EBV) is well-established for World Health Organization (WHO) types II and III (WHO-II/III) NPC but less well-established for WHO type I (WHO-I) NPC. Given the rise in oropharyngeal tumors positive for high-risk human papillomavirus (HPV) and the unique biology of WHO-I NPC, we examined the relationship between HPV and WHO-I NPC.
Study Design
Retrospective case-comparison study.
Methods
A search of a large multidisciplinary cancer center tumor registry identified 183 patients seen from January 1999 to December 2008 with incident NPC and no prior cancer. Available paraffin-embedded tumor specimens (N=30) were analyzed for oncogenic HPV status by in-situ hybridization (ISH) and polymerase chain reaction (PCR) for HPV-16 and HPV-18; EBV status by ISH; and p16 expression by immunohistochemistry. Demographic parameters, including race and smoking, were obtained from the medical records.
Results
Among the 18 WHO-I NPC patients, 66% (N=12) were smokers and 17% (N=3) Asian; among the 165 WHO-II/III NPC patients, 44% (N=73) were smokers and 24% (N=39) Asian. Eight WHO-I NPC patients had available paraffin blocks; 5 of 6 were HPV-16-positive by PCR and 4 of 8 were HPV-positive by ISH; only 2 of 8 (25%) were EBV-positive. Twenty-two WHO-II/III NPC patients had available paraffin blocks; only 1 was HPV-positive by ISH, and 13 of 22 (60%) were EBV-positive.
Conclusions
These results suggest that WHO-I NPC is associated with oncogenic HPV, though larger studies are needed to verify these findings.
doi:10.1002/lary.21089
PMCID: PMC4212520  PMID: 20824783
Human papillomavirus; Nasopharyngeal Carcinoma; WHO Type; In-situ hybridization; Polymerase chain reaction
13.  Rheumatoid arthritis mimicking metastatic squamous cell carcinoma 
Head & Neck Oncology  2011;3:26.
We report a case of a cervical rheumatoid nodule in close relation to the hyoid bone mimicking a metastatic carcinoma. A 74-year-old female with a 15-year history of rheumatoid arthritis (RA) on treatment with methotrexate presented with tenderness of the right base of tongue. Imaging demonstrated a 1.4 cm cystic lesion at the hyoid bone. Biopsies were unsuccessful and the patient required surgical resection of the mass. A trans-cervical approach was used. Pathology revealed a necrotizing granuloma compatible with rheumatoid etiology. The clinician should be aware that, in a patient with a neck mass, in the presence of active RA, rheumatoid nodules should be part of the differential diagnosis.
doi:10.1186/1758-3284-3-26
PMCID: PMC3118955  PMID: 21569598
Rheumatoid; arthritis; nodule; hyoid; larynx
14.  Prediction of Neck Dissection Requirement After Definitive Radiotherapy for Head and Neck Squamous Cell Carcinoma 
BACKGROUND
This analysis was undertaken to assess the need for planned neck dissection in patients with a complete response (CR) of involved nodes after irradiation, and to determine the benefit of a neck dissection in those with less than CR by tumor site.
METHODS
Our cohort included 880 patients with T1-4, N1-3M0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx who received treatment between 1994 and 2004. Survival curves were calculated by the Kaplan-Meier Method, comparisons of rates with the log-rank test and prognostic factors by Cox analyses.
RESULTS
Nodal CR occurred in 377 (43%) patients of whom 365 patients did not undergo nodal dissection. The 5-year actuarial regional control rate of patients with CR was 92%. Two hundred sixty-eight of the remaining patients (53%) underwent neck dissections. The 5-year actuarial regional control rate for patients without a CR was 84%. Those who had a neck dissection fared better with 5-year actuarial regional control rates of 90% and 76% for those operated and those not operated (p <.001). Variables associated with poorer regional control rates included higher T and N stage, non-oropharynx cancers, non-CR, both clinical and pathological.
CONCLUSIONS
With 92% 5-year neck control rate without neck dissection after CR, there is little justification for systematic neck dissection. The addition of a neck dissection resulted in higher neck control after partial response though patients with viable tumor on pathology specimens had poorer outcomes. The identification of that subgroup that benefits from additional treatment remains a challenge.
doi:10.1016/j.ijrobp.2011.03.062
PMCID: PMC4124997  PMID: 22284033
Head and Neck Cancer; Neck nodes; Neck Dissection; Radiation therapy
15.  Integrative genomic characterization of oral squamous cell carcinomaidentifies frequent somatic drivers 
Cancer discovery  2013;3(7):10.1158/2159-8290.CD-12-0537.
The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease.
doi:10.1158/2159-8290.CD-12-0537
PMCID: PMC3858325  PMID: 23619168
Integrated genomics; head and neck/oral cancers; NOTCH1; CASP8
16.  Pre-microRNA variants predict HPV16-positive tumors and survival in patients with squamous cell carcinoma of the oropharynx 
Cancer letters  2012;330(2):233-240.
To identify non-tumor biomarkers for prediction of tumor HPV status and prognosis of patients with squamous cell carcinoma of the oropharynx (SCCOP), we evaluated the association of single nucleotide polymorphisms (SNPs) in pre-miRNAs with HPV16 status and survival for SCCOP patients. We analyzed HPV16 status in tumor specimens and genotyped four SNPs in pre-miRNAs (hsa-mir-146a rs2910164 G>C, hsa-mir-149 rs2292832 G>T, hsa-mir-196a2 rs11614913 C>T, and hsa-mir-499 rs3746444 A>G) in 309 SCCOP patients. Unconditional logistic regression models were used for calculation of odds ratio (OR) and 95% confidence intervals (CIs), and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate associations. We found that statistically significant associations with HPV16-positive SCCOP and survival were found for hsa-mir-146a rs2910164 and hsa-mir-196a2 rs11614913, while such similar associations were not observed for hsa-mir-149 rs2292832 and hsa-mir499 rs3746444. Compared with those with corresponding hsa-mir-146a CG/CC and has-mir-196a2 CC genotypes, the hsa-mir-146a GG and hsa-mir-196a2 CT/TT wild-type genotypes were significantly associated with HPV16-positive tumor status (adjusted OR, 2.4; 95% CI, 1.4–4.1 and adjusted OR, 2.1, 95% CI, 1.2–3.6), respectively. Patients having hsa-mir-146a rs2910164 GG and hsa-mir196a2 rs11614913 CT/TT genotypes had significantly better overall, disease-specific, and disease-free survival compared with those having the corresponding CG/CC and CC genotypes, respectively. Furthermore, these genotypes were significantly associated with reduced risk of overall death, death owing to disease, and recurrence after adjustment for important prognostic confounders including HPV status, smoking, and stage. Our findings indicate pre-miRNA polymorphisms may predict tumor HPV16-positive SCCOP cases and may be prognostic biomarkers for SCCOP.
doi:10.1016/j.canlet.2012.11.048
PMCID: PMC3563870  PMID: 23219900
MicroRNA polymorphisms; genetic susceptibility; oropharyngeal cancer; molecular epidemiology; survival
17.  Multispectral optical imaging device for in vivo detection of oral neoplasia 
Journal of biomedical optics  2008;13(2):024019.
A multispectral digital microscope (MDM) is designed and constructed as a tool to improve detection of oral neoplasia. The MDM acquires in vivo images of oral tissue in fluorescence, narrowband (NB) reflectance, and orthogonal polarized reflectance (OPR) modes, to enable evaluation of lesions that may not exhibit high contrast under standard white light illumination. The device rapidly captures image sequences so that the diagnostic value of each modality can be qualitatively and quantitatively evaluated alone and in combination. As part of a pilot clinical trial, images are acquired from normal volunteers and patients with precancerous and cancerous lesions. In normal subjects, the visibility of vasculature can be enhanced by tuning the reflectance illumination wavelength and polarization. In patients with histologically confirmed neoplasia, we observe decreased blue/green autofluorescence and increased red autofluorescence in lesions, and increased visibility of vasculature using NB and OPR imaging. The perceived lesion borders change with imaging modality, suggesting that multimodal imaging has the potential to provide additional diagnostic information not available using standard white light illumination or by using a single imaging mode alone.
doi:10.1117/1.2904658
PMCID: PMC3970814  PMID: 18465982
oral cancer; diagnosis; noninvasive; optical imaging; fluorescence; decreased autofluorescence; reflectance; polarized; orthogonal; porphyrin; vasculature; monochromatic
18.  Molecular Heterogeneity in Mucoepidermoid Carcinoma: Conceptual and Practical Implications 
Head and Neck Pathology  2013;7(1):23-27.
Mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy of the upper aerodigestive tract and tracheobronchial tree, is also known for its considerable cellular heterogeneity including epidermoid, intermediate and mucin producing cells. Despite this structural and cellular heterogeneity, MEC is uniquely characterized by a specific translocation t(11; 19) (q12; p13), resulting in a fusion between the MECT1 and the MAML2 genes. Although the incidence of this fusion in MEC varies, it is generally accepted that more than 50 % of this entity manifest the MECT1-MAML2. Fusion-positive cases showed significantly better survival than fusion-negative cases, suggesting that MECT1-MAML2 represents a specific prognostic molecular marker in MEC. We contend that fusion in MEC represents a distinct mechanism in the development of this entity. In that context, fusion positive MEC, regardless of grade, manifest a more stable genome and better clinical behaviour, while fusion negative MEC represent a distinctly different pathway characterized by marked genomic instability and relatively aggressive tumors.
doi:10.1007/s12105-013-0432-5
PMCID: PMC3597160  PMID: 23459841
Mucoepidermoid carcinoma; t(11; 19) (q12; p13); Fusion transcript; MECT1-MAML2
19.  Early postoperative epidermal growth factor receptor inhibition is safe and effective in inhibiting microscopic residual of oral squamous cell carcinoma in vivo 
Head & neck  2012;35(3):10.1002/hed.22961.
Background
The local-regional failure of advanced oral squamous cell carcinoma (OSCC) after surgery results from the re-growth of residual tumor cells that may be stimulated by epidermal growth factor receptor (EGFR) ligands during the wound-healing process.
Methods
The level of EGFR ligands in human drain fluids from OSCC resection and remote flap donor site were determined. A mouse model of microscopic residual OSCC was established and treated with cetuximab to measure tumor growth, survival, and cervical lymph node metastases. A mouse model of wound-healing was also established to assess the effect of an EGFR antibody on the wound-healing process.
Results
EGFR ligands are found in sites from OSCC resection. EGFR targeted therapy can delay tumor re-growth in a microscopic residual disease model of OSCC without significant effects on local wound-healing.
Conclusion
These results provide a strong rationale for clinical evaluation of this approach to treat patients with local-regionally advanced OSCC.
doi:10.1002/hed.22961
PMCID: PMC3836367  PMID: 22367702
recurrence of oral squamous cell carcinoma; epidermal growth factor receptor (EGFR) ligands; postoperative EGFR inhibition; wound healing; in vivo model of microscopic residual disease
20.  Phase II Trial of Induction Chemotherapy Followed by Surgery for Squamous Cell Carcinoma of the Oral Tongue in Young Adults 
Head & neck  2011;34(9):1255-1262.
Background
We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults.
Methods
From September 2001 to October 2004, 23 patients aged 18–49 years with clinical T2-3N0-2M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy.
Results
On final surgical pathology, 9 (39%) patients had a complete/major (2 complete) histologic response at the primary tumor site; 8 (35%) had no response or progression. Similarly, 9 (39%) patients had a complete response in the neck or remained node negative; 6 (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 (43%) patients developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (P = .029), poor histologic differentiation (P = .012), and multiple adverse features on final surgical pathology (P = .040).
Conclusions
Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults.
doi:10.1002/hed.21906
PMCID: PMC3893095  PMID: 22009800
Oral tongue cancer; Young adults; Induction chemotherapy
21.  Highly prevalent TERT promoter mutations in aggressive thyroid cancers 
Endocrine-related cancer  2013;20(4):603-610.
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
doi:10.1530/ERC-13-0210
PMCID: PMC3782569  PMID: 23766237
TERT promoter mutations; thyroid cancers; BRAF V600E mutation; telomerase reverse transcriptase; thyroid tumorigenesis
22.  A Comparison of the Demographics, Clinical Features, and Survival of Patients with Adenoid Cystic Carcinoma of Major and Minor Salivary Glands Versus Less Common Sites within the SEER Registry 
Cancer  2011;118(16):3945-3953.
Objectives
The scientific literature to date lacks population-based studies on the demographics, clinical features, and survival of patients with adenoid cystic carcinoma (ACC) of different anatomic sites.
Methods
We identified 5349 ACC cases in major salivary glands (N=1850), minor salivary glands (N=2077), breast (N=696), skin (N=291), lung and bronchus (N=203), female genital system (N=132), and eye and orbit (N=100) from the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in demographics, clinical features, and survival of patients were assessed.
Results
ACC of the eye and orbit was associated with younger age at presentation (mean=49.9 years). ACC of the skin or breast tended to present with less aggressive prognostic features, while ACC of the lung and bronchus or eye and orbit tended to present with more aggressive prognostic features. In multivariate survival analysis of patients presenting with localized disease, patients with ACC of breast (HR=0.40) or skin (HR=0.40) had a significantly lower risk death than patients with ACC of major salivary glands, while patients with ACC of lung and bronchus (HR=3.72) or eye and orbit (HR=3.67) had a significantly higher risk. For patients presenting with regional disease, the only clear prognostic difference in multivariate analysis was that patients with ACC of skin did significantly better.
Conclusions
The demographics and clinical features of ACC differ by disease site. Site may be an important predictor of survival for patients presenting with localized disease but is less important for patients presenting with regional disease.
doi:10.1002/cncr.26740
PMCID: PMC3412946  PMID: 22179977
Adenoid Cystic Carcinoma; SEER; Epidemiology; Site; Survival
23.  MicroRNA Profiling of Salivary Adenoid Cystic Carcinoma: Association of miR-17-92 Upregulation with Poor Outcome 
PLoS ONE  2013;8(6):e66778.
Background
Salivary adenoid cystic carcinoma (ACC) is a rare relentlessly progressive malignant tumor. The molecular events associated with ACC tumorigenesis are poorly understood. Variable microRNAs (miRNA) have been correlated with tumorigenesis of several solid tumors but not in ACC. To investigate the association of miRNAs with the development and/or progression of ACC, we performed a comparative analysis of primary ACC specimens and matched normal samples and a pooled salivary gland standard and correlated the results with clinicopathologic factors and validated selected miRNAs in a separate set of 30 tumors.
Methods
MiRNA array platform was used for the identification of target miRNAs and the data was subjected to informatics and statistical interrelations. The results were also collected with the MYB-NFIB fusion status and the clinicopathologic features.
Results
Differentially dysregulated miRNAs in ACC were characterized in comparison to normal expression. No significant differences in miRNA expression were found between the MYB-NFIB fusion positive and -negative ACCs. Of the highly dysregulated miRNA in ACC, overexpression of the miR-17 and miR-20a were significantly associated with poor outcome in the screening and validation sets.
Conclusion
Our study indicates that the upregulation of miR-17-92 may play a role in the biology of ACC and could be potentially targeted in future therapeutic studies.
doi:10.1371/journal.pone.0066778
PMCID: PMC3692530  PMID: 23825564
24.  p53 mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer 
Cancer Cell  2012;21(6):793-806.
SUMMARY
Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53-mutant tumors failed to arrest proliferation leading to abnormal mitoses and cell death, while p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines that exhibited autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of a heterozygous p53 point mutation or absence of p21. Thus, we show wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.
doi:10.1016/j.ccr.2012.04.027
PMCID: PMC3376352  PMID: 22698404
25.  Developmental transcription factor EN1- novel biomarker in human salivary gland adenoid cystic carcinoma 
Cancer  2011;118(5):1288-1292.
Background
Adenoid cystic carcinoma (ACC), a rare and progressive salivary malignancy, is characterized by histogenetic, morphologic and clinical heterogeneity. Extensive efforts to characterize molecular events associated with these tumors include the identification of biomarkers for prognostication and post therapy assessment. Our previous study of genome-wide methylation screening identified a limited number of differentially methylated gene regions in ACC, and significant hypermethylation was found at the transcriptional start site (TSS) of genes that encode for transcription factor EN1. Our clinicopathologic correlation analysis showed that the EN1 methylation status correlated with the histological tumor grade, tumor location and final outcome of the patient.
Methods
To ascertain definitively whether aberrant EN1 expression accompanies human salivary ACC, we used an immunohistochemical technique to directly evaluate EN1 protein expression in ACC of the salivary gland.
Results
Our data show increased EN1 protein expression in solid type ACC, which correlated with a significantly lower survival rate.
Conclusions
we validated EN1 as a potential biomarker in a large cohort of salivary ACC. Immunohistochemical analysis of EN1 in biopsy specimens obtained for diagnostic purposes and/or surgically resected material may show that EN1 is a biological predictor of poor prognosis in salivary ACC patients.
doi:10.1002/cncr.26412
PMCID: PMC3208084  PMID: 21800291
adenoid cystic carcinoma; methylation; EN1; cellular localization

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