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.
Base of tongue; Primary adenocarcinoma; Intestinal-type; Metastatic carcinoma
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.
TERT promoter mutations; thyroid cancers; BRAF V600E mutation; telomerase reverse transcriptase; thyroid tumorigenesis
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.
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.
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.
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.
Adenoid Cystic Carcinoma; SEER; Epidemiology; Site; Survival
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.
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.
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.
Our data show increased EN1 protein expression in solid type ACC, which correlated with a significantly lower survival rate.
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.
adenoid cystic carcinoma; methylation; EN1; cellular localization
Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since 1980s. While the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid cancer (DTC). Therefore, we explored the association between sporadic DTC and family history of cancer.
In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer.
The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR = 4.1, 95% CI: 1.7–9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR = 4.6, 95 CI%: 1.9–11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR = 7.4, 95% CI: 1.8–30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs. 35.5%, p = 0.01).
Our study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC.
Differentiated thyroid carcinoma; papillary thyroid carcinoma; benign thyroid disease; multifocal; family history of cancer
Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAbs), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual RTKs, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had co-expression of total and phosphorylated IGF-1R and EGFR at high levels compared to paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mammalian target of rapamycin (mTOR), resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.
EGFR; IGF-IR; head and neck squamous cell carcinoma; survivin; cixutumumab
p53 levels are tightly regulated in normal cells, and thus the wild-type p53 protein is nearly undetectable until stimulated through a variety of stresses. In response to stress, p53 is released from its negative regulators, mainly Mdm2, allowing p53 to be stabilized to activate cell cycle arrest, senescence, and apoptosis programs. Many of the upstream signals that regulate wild type p53 are known; however, limited information for the regulation of mutant p53 exists. Previously, we demonstrated that wild-type and mutant p53R172H are regulated in a similar manner in the absence of Mdm2 or p16. Additionally, this stabilization of mutant p53 is responsible for the gain-of-function metastatic phenotype observed in the mouse. In this report, we examined the role of oncogenes, DNA damage, and reactive oxygen species, signals that stabilize wild type p53, on the stabilization of mutant p53 in vivo and the consequences of this expression on tumor formation and survival. These factors stabilized mutant p53 protein which often times contributed to exacerbated tumor phenotypes. These findings, coupled with the fact that patients carry p53 mutations without stabilization of p53, suggest that personalized therapeutic schemes may be needed for individual patients depending on their p53 status.
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.
adenoid cystic carcinoma; c-kit; cox-2; bcl-2
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.
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.
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.
mitogen-activated protein kinase (MAPK); extracellular signal-regulated kinase (ERK); MAP kinase kinase (MEK); RAS; RAF; inhibitors; targeted therapies
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.
Follicular neoplasms; follicular carcinoma; gene expression; Affymetrix
DNA methylation is a fundamental epigenetic event associated with physiologic and pathologic conditions including cancer. Hypermethylation of CpG islands at active gene promoters lead to transcriptional repression while hypomethylation is associated with gene overexpression. The aim of this study was to identify genes in adenoid cystic carcinoma (ACC) of salivary gland strongly deregulated by epigenetic CpG island methylation, to validate selected genes by conventional techniques, and to correlate the findings with clinico-pathologic factors.
We analyzed 16 matched normal and tumor tissues for aberrant DNA methylation using the methylated CpG island amplification and microarray (MCAM) method, and the pyrosequencing technique.
Microarray analysis showed hypomethylation in seven, and hypermethylation in 32 CpG islands. Hypomethylation was identified in CpG islands near FBXO17, PHKG1, LOXL1, DOCK1 and PARVG. Hypermethylation was identified near genes encoding predominantly transcription factors (EN1, FOXE1, GBX2, FOXL2, TBX4, MEIS1, LBX2, NR2F2, POU3F3, IRX3, TFAP2C, NKX2-4, PITX1, NKX2-5), and 13 genes with different functions (MT1H, EPHX3, AQPEP, BCL2L11, SLC35D3, S1PR5, PNLIPRP1, CLIC6, RASAL, XRN2, GSTM5, FNDC1, INSRR). Four CpG islands by EN1, FOXE1, TBX4, and PITX1 were validated by pyrosequencing.
The highly methylated genes in tumor versus normal are linked to developmental, apoptotic and other fundamental cellular pathways, suggesting that downregulation of these genes is associated with ACC development and progression. With EN1 hypermethylation showing potential as possible biomarker for ACC in salivary gland, the biological and therapeutic implications of our findings require further preclinical investigations.
adenoid cystic carcinoma; epigenetics; CpG island methylation; MCAM; pyrosequencing
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.
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.
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.
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.
Gene fusion; Gene fusion; chromosomal translocations; salivary gland carcinomas; molecular alterations
No studies have evaluated roles of insulin-like growth factor binding protein 5 (IGFBP-5) polymorphisms in risk of squamous cell carcinoma of the head and neck (SCCHN).
A hospital-based study of 1082 SCCHN patients and 1120 cancer-free controls was performed to investigate associations between two functional polymorphisms -1195T>C and -709G>C in the IGFBP5 promoter region and SCCHN risk.
We demonstrated that the transcription factor AP-1 differentially bound to T or C variants at -1195 in the promoter to regulate the IGFBP5 promoter activity and that the C variant genotypes were associated with deferential risk of late-stage SCCHN, compared with the TT genotype, particularly for HPV-unrelated sites (adjusted OR, 2.21; 95% CI, 1.19-4.11 for CC vs. TT).
The IGFBP5 -1195T>C polymorphism is functional and may potentially be a biomarker for susceptibility to late-stage SCCHN.
IGFBP5; head neck cancer; TNM stage; polymorphism; association
Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. The majority of the ~250,000 cases occurring annually in the United States are small, non-aggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and have increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve outcomes for patients with aggressive CSCC.
We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-IGF-IR antibody, A12, alone or in combination with an anti-EGF-R antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC.
Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of SCC cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) as well as increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92% respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = 0.044 and p < 0.001 respectively).
These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.
Insulin-like growth factor receptor I (IGF-IR); epidermal growth factor receptor (EGFR); squamous cell carcinoma; orthotopic model; preclinical study
Patients with oral preneoplastic lesion (OPL) have high risk of developing oral cancer. Although certain risk factors such as smoking status and histology are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer-free survival and used to develope multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinico-pathological risk factors. Based on the gene expression profile data, we also identified 2182 transcripts significantly associated with oral cancer risk associated genes (P-value<0.01, single variate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomes components as the top gene sets associated with oral cancer risk. In multiple independent datasets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention.
gene expression profiling; oral cancer; oral leukoplakia; biomarker
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.
adenoid cystic carcinoma; cellular localization; c-kit; EGFR
This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer.
We examined IQGAP1 copy gain and its relationship with clinicopathological outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process.
We found IQGAP1 copy number gain ≥ 3 in 1/30 (3%), 24/74 (32%), 44/107 (41%), 8/16 (50%), and 27/41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell PTC, and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of copy number ≥ 4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50–60% rate of multifocality and recurrence of BRAF mutation-positive PTC (P = 0.01 and 0.02, respectively). siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Co-immunoprecipitation assay demonstrated direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was up-regulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions.
IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer.
thyroid cancer; IQGAP1; gene copy gain; E-cadherin; BRAF mutation
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papilloma virus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA and HRAS, we identified mutations in FBXW7 and NOTCH1. Interestingly, nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
The impact of tumor differentiation on the behavior and response of sinonasal neuroendocrine carcinoma is unknown.
We performed a retrospective review of the patients treated for neuroendocrine carcinoma (NEC) of the nasal cavity or paranasal sinuses from 1992 to 2008 at MDACC.
The results of our study suggest that pathologic differentiation may not be a critical factor in the clinical management of patients with NEC of the sinonasal tract. This is in contrast to laryngeal and lung NEC for which pathological differentiation has traditionally guided clinical management.
Mutlimodality approach should be the cornerstone of treating sinonasal NEC regardless of their differentiation. Specifically, RT may provide durable local control for patients with moderately differentiated NEC if resection is not feasible or desirable, while surgical resection can benefit patients with chemo-resistant or radio-resistant disease.
Neuroendocrine carcinoma; carcinoid tumor; poorly differentiated carcinoma; sinonasal tumor
Leukoplakia is the most common premalignant lesion of the oral cavity. Epidermal growth factor receptor (EGFR) abnormalities are associated with oral tumorigenesis and progression. We hypothesized that EGFR expression and gene copy number changes are predictors of the risk of an oral premalignant lesion (OPL) for progressing to oral squamous cell carcinoma (OSCC). A formalin-fixed, paraffin-embedded OPL biopsy specimen was collected from each of 162 patients in a randomized controlled clinical trial. We assessed EGFR expression by immunohistochemistry with two methods: a semi-quantitative analysis (145 evaluable specimens) and an automated quantitative analysis (127 evaluable specimens). EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) in a subset of 49 OPLs with high EGFR expression defined by the semi-quantitative analysis. We analyzed EGFR abnormalities for associations with OSCC development. High EGFR expression occurred in 103 (71%) of the 145 OPLs and was associated with a nonsignificantly higher risk of OSCC (P = 0.10). Twenty (41%) of 49 OPLs assessed by FISH had an increased EGFR gene copy number (FISH-positive). Patients with FISH-positive lesions had a significantly higher incidence of OSCC than did patients with FISH-negative (a normal copy number) lesions (P = 0.0007). Of note, 10 of 11 OSCCs that developed at the site of the examined OPL were in the FISH-positive group, leaving only one FISH-negative OPL that did so (P < 0.0001). Our data indicate that an increased EGFR gene copy number is common in and associated with OSCC development in patients with OPLs expressing high EGFR, particularly OSCC developing at the site of a high-expression OPL; they also suggest that EGFR inhibitors may prevent oral cancer in patients with OPLs having an increased EGFR gene copy number.
epithelial growth factor receptor; oral cancer; oral leukoplakia; immunohistochemistry; fluorescence in situ hybridization; biomarker
We conducted a hospital-based study of 1110 SCCHN cases and 1129 controls to replicate the associations reported by a recent large European study between two potentially functional single nucleotide plymorphisms (SNPs) of the alcohol dehydrogenases genes, ADH1B R48H (rs1229984: G>A) and ADH7 A92G (rs1573496: C>G), and risk of squamous cell carcinoma of the head and neck (SCCHN).
Multivariate logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (95% CI). False-positive report probabilities were also calculated for significant findings.
We found that the ADH7A92G GG and combined CG+GG genotypes were associated with a decreased risk of SCCHN (adjusted OR, 0.32; 95% CI, 0.13-0.82 for GG and adjusted OR, 0.74; 95% CI, 0.59-0.94 for CG+GG; FPRP, .098) compared with the CC genotype. This association was also evident in subgroups of older (> 57 years) subjects, males, former smokers, oral cancer, and N0 lymph node metastasis (P < .05 for all); however, such associations were not observed for the ADH1B R48H SNP.
Our results support the ADH7 A92G SNP as a marker for risk of SCCHN in non-Hispanic White populations.
ADH7; genetic variant; genetic susceptibility; head and neck cancer; molecular epidemiology
Tumor hypoxia regulates many cytokines and angiogenic factors (CAFs) and is associated with worse prognosis in head and neck squamous cell cancer (HNSCC). Serum CAF profiling may provide information regarding the biology of the host and tumor, prognosis, and response to therapy. We investigated 38 CAFs in HNSCC patients receiving induction therapy on a Phase II trial of carboplatin, paclitaxel, and cetuximab. CAFs were measured by multiplex bead assay and enzyme-linked immunosorbent assay in 32 patients. Baseline and post-induction CAF levels were correlated with disease progression (PD) and human papilloma virus (HPV) status by Wilcoxon rank sum test. Baseline levels of 8 hypoxia-regulated CAFs (the “high-risk signature” including vascular endothelial growth factor, interleukins-4 and -8, osteopontin, growth-related oncogene-α (Gro-α), eotaxin, granulocyte-colony stimulating factor, and stromal cell derived factor-1α) were associated with subsequent PD. Elevation in ≥6/8 factors was strongly associated with shorter time to progression (p=0.001) and was 73% specific and 100% sensitive for PD. Rising Gro-α from baseline to week six was also associated with PD. Progression free and overall survival were shorter in patients with HPV-negative tumors (p=0.012 and 0.046, respectively), but no individual CAF was associated with HPV-status. However, among 14 HPV-negative patients, the high-risk CAF signature was seen in all 6 patients with PD, but only 2/14 without PD. In conclusion, serum CAF profiling, particularly in HPV-negative patients, may be useful for identifying those at highest risk for recurrence.
head and neck squamous cell cancer; serum markers; hypoxia
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.
Rheumatoid; arthritis; nodule; hyoid; larynx
Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population.
Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR.
BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years).
Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.