Molecular and Cytogenetic Subgroups of Oropharyngeal Squamous Cell Carcinoma

Unit of Experimental Molecular Pathology, Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Italy.
Clinical Cancer Research (Impact Factor: 8.72). 12/2006; 12(22):6643-51. DOI: 10.1158/1078-0432.CCR-06-1759
Source: PubMed


The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches.
Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status.
At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors.
Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.

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Available from: Giulio Cantu, Oct 05, 2015
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    • "For those with locally advanced tumors, the 5-year survival rate is approximately 40%. It is well established that the development of HNSCC is a multi-step process in which the activation of oncogenes and inactivation of tumor suppressor genes, such as inactivation of tumor suppressor genes p53 and p16 and activation of oncogenes cyclin D1 (CCND1) and epidermal growth factor receptor (EGFR), play critical roles [2], [3], [4], [5]. Better understanding the molecular basis of HNSCC should further facilitate development of novel strategies to improve early diagnosis and treatment of the disease. "
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    ABSTRACT: Tripartite motif-containing 24 (TRIM24), a member of the transcriptional intermediary factor 1 family, functions as a co-regulator that positively or negatively modulates the transcriptional activities of several nuclear receptors. The aim of this study was to investigate TRIM24 expression and its clinical significance in head and neck squamous cell carcinoma. The expression levels of TRIM24 variants were examined in head and neck squamous cell carcinoma (HNSCC) samples and cell lines by real-time PCR and WB. The expression levels of TRIM24 measured in 91 locally advanced HNSCC tumors were measured by immunohistochemistry and correlated with clinical and pathological parameters. The functional role of TRIM24 in HNSCC was further investigated by silencing its expression in HNSCC cell lines. TRIM24 variants were up-regulated in 56 HNSCC samples (P<.001) and 9 HNSCC cell lines (P<.05). TRIM24 protein was overexpressed in 6 of 8 HNSCC cell lines and in 2 of 3 HNSCC samples. Furthermore, 54.95% (50/91) of HNSCC samples exhibited remarkably elevated expression of TRIM24 by immunohistochemistry. Univariate analysis revealed that high TRIM24 expression was associated with worse overall survival (P = .020). In multivariate analysis, TRIM24 expression was identified as an independent predictor of overall survival (P = .030), after adjusting for other clinicopathological parameters. Upon TRIM24 silencing, the proliferation of HNSCC cells was notably inhibited due to the induction of apoptosis. These results suggest that aberrant TRIM24 expression may play an important role in the development of HNSCC and is a promising prognostic indicator for patients with locally advanced HNSCC.
    PLoS ONE 05/2013; 8(5):e63887. DOI:10.1371/journal.pone.0063887 · 3.23 Impact Factor
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    • "In agreement with previous studies [48,53], we found that p53 overexpression was a common event in HNSCC. In newest papers immunohistochemically positive cases associate with TP53 mutations in head and neck cancers [48,54,55] and our paper does not contradict this. "
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    ABSTRACT: Although TP53 mutations in human tumours generally have been extensively studied, the significance of p53 in the aetiology of head and neck cancers is still incompletely characterized. In recent years, considerable interest has been focused on mutant forms of p53, the abnormal protein product of TP53 alleles with missense mutation that often accumulate in cancer cells. We compared the nature of TP53 mutations in primary 46 head and neck squamous cell carcinomas (HNSCC) analyzed by PCR-SSCP and sequencing, immunohistochemistry, and using structural information available at IARC p53 database. Sequencing confirmed 36 TP53 mutations in 23 tumours of the 39 mutations in 26 tumours found by PCR-SSCP. Only half (17) putatively affect the function of p53 protein. Of these 8 were in the L2 domain, three affected the LSH motif and three the L3 domain. Three were in other domains. Codon 259 (GAC > GAA) which is a very rare mutation was found in 4 samples in our study. There were indications of p53 aberrations being associated with the combined effect of smoking, alcohol and work history. Patients with a negative family history of cancer had more often TP53 mutations than patients with a positive family history (71% vs. 46%). Our study contributes to the knowledge of cumulative chemical exposure and p53 aberrations in head and neck cancer, an area where literature is scarce.
    Head & Neck Oncology 12/2010; 2(1):36. DOI:10.1186/1758-3284-2-36 · 3.14 Impact Factor
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    • "For permanent staining of the primary tissues, the slides were developed using 3, 3'diaminobenzidine as the chromogen and counterstained with hematoxylin. The staining intensity (1 = weak, 2 = moderate, 3 = strong) and the percentage of positive cells (<1 = 0, 1-20 = 1, 20-50 = 2, 50-80 = 3 and >80 = 4) were detected by two observers independently and by combining the two scores, final evaluation of expression was done (= 2 = low, 3-4 = intermediate, 5-6 = normal, = 7 = high) [20]. The immunocytochemical stained slides of the cell lines was photographed using fluorescence microscope (Nikon Eclipse E600, Japan). "
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    ABSTRACT: To understand the role of two interacting proteins LIMD1 and pRB in development of head and neck squamous cell carcinoma (HNSCC), alterations of these genes were analyzed in 25 dysplastic head and neck lesions, 58 primary HNSCC samples and two HNSCC cell lines. Deletions of LIMD1 and RB1 were analyzed along with mutation and promoter methylation analysis of LIMD1. The genotyping of LIMD1 linked microsatellite marker, hmlimD1, was done to find out any risk allele. The mRNA expression of LIMD1 and RB1 were analyzed by Q-PCR. Immunohistochemical analysis of RB1 was performed. Alterations of these genes were correlated with different clinicopathological parameters. High frequency [94% (78/83)] of LIMD1 alterations was observed in the samples studied. Compare to frequent deletion and methylation, mutation of LIMD1 was increased during tumor progression (P = 0.007). Six novel mutations in exon1 and one novel intron4/exon5 splice-junction mutation were detected in LIMD1 along with a susceptible hmlimD1 (CA)20 allele. Some of these mutations [42% (14/33)] produced non-functional proteins. RB1 deletion was infrequent (27%). Highly reduced mRNA expression of LIMD1 (25.1 +/- 19.04) was seen than RB1 (3.8 +/- 8.09), concordant to their molecular alterations. The pRB expression supported this data. Tumors with LIMD1 alterations in tobacco addicted patients without HPV infection showed poor prognosis. Co-alterations of these genes led the worse patients' outcome. Our study suggests LIMD1 inactivation as primary event than inactivation of RB1 in HNSCC development.
    Molecular Cancer 03/2010; 9:58. DOI:10.1186/1476-4598-9-58 · 4.26 Impact Factor
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