BackgroundSquamous cell carcinoma of tongue (SCCT) is expected to harbor unique clinico-pathological and molecular genetic features since a significant proportion of patients are young and exhibit no association with tobacco or alcohol.MethodsWe determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival.ResultsOur results revealed a significantly higher incidence of p53 nuclear stabilization in early (as against late) onset SCCOT. FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use. Samples harboring mutation in p53 DNA binding domain or exhibiting p53 nuclear stabilization, were significantly associated with poor survival.ConclusionOur study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.
BACKGROUND We wanted to investigate as to which variable like age, weight, stage, prior chemotherapy, radiation therapy etc. had a significant association with the patient developing collection of serous fluid in the axilla in the post-operative period following axillary lymph node clearance. METHODS This is a retrospective study. All patients who underwent axillary clearance were included in the study including elective and therapeutic indications. All relevant clinical data was extracted from these patients. The clinical variables were studied to reveal the most significant variable associated with formation of seroma RESULTS Axillary dissection was carried out in 133 patients, 70 patients as a part of modified radical mastectomy for carcinoma breast, 39 patients as a part of breast conserving surgery for carcinoma breast, 12 patient as a part of completion surgery for patients who underwent mastectomy elsewhere for carcinoma breast in which axilla was not addressed, 6 patient with melanoma of the upper limb and 4 for squamous cell carcinoma of upper limb and 2 for sarcoma for the upper limb. Incidence of seroma was 43.47 in >60 yrs. vs 31.04 in <60 yrs., 80% in males vs 33.60% in females, 29.14% for tumour size of 2 cm vs 37.25% for 2-5 cm, vs 41.97% for > 5 cms, 38.46% nodal metastasis vs 28.57 no nodal metastasis, 34.28% in MRM vs 23.07% in BCS vs 41.66% in Completion Mastectomy, neoadjuvant chemotherapy had 54.84% vs 29.41% in no prior chemotherapy, infection/flap necrosis 83.33% vs 30.58 in no infection/ flap necrosis, 85.71% when drainage duration 5 days vs 75% when 5 to 10 days vs 20.40% when more than 10 days. Melanoma and sarcoma histology had higher incidence of seroma formation. CONCLUSIONS Male sex, older age, larger tumour size, nodal involvement, completion surgery or re-surgery, histology like melanoma or sarcoma, neoadjuvant chemotherapy, prior irradiation, infection or flap necrosis, and early removal of drain is associated with higher incidence of post-operative seroma formation.
Squamous cell carcinoma of tongue (SCCT) is a common form of head and neck squamous cell carcinoma (HNSCC) in developing countries, mainly in India. In the last few decades, a steady increase in incidence rate of SCCT has been reported across the world. More importantly, though SCCT is considered to be a tobacco-related late-onset cancer, recent reports indicate an increase in incidence of SCCT in the young and in non-smokers. We analyzed the status of known tumorigenic pathways/genes including TP53, epidermal growth factor receptor (EGFR), microsatellite instability (MSI), CDKN2A, FHIT and human papilloma virus (HPV) infection in 120 surgically resected primary oral SCCT (SCCOT) samples and correlated with clinico-pathological variables and disease specific survival. 78 of 121 (65%) samples exhibited p53 nuclear stabilization confirming earlier reports. Interestingly, p53 nuclear stabilization was more common in young (36/46; 78%) than in older (44/75; 56%) patients (p = 0.0184). Further, PCR based mutation screening of exons 5-8 (encoding the DNA binding domain of p53) revealed mutations in ten of nineteen samples (52.6%) that exhibited p53 nuclear stabilization and in three of fifteen tumors (20%) that did not. We identified a novel 33bp deletion, c.616-648del33, located in exon 5 in a p53 positive tumor from a chronic tobacco chewer. Case control analysis revealed that Proline at TP53 codon 72 increased the risk of SCCOT. Majority of samples (97/121; 80%) exhibited significant EGFR expression though HPV infection was rare (14/106; 13%). MSI was observed in 14/106 (13%) samples, a frequency higher than reported for other populations. Loss of Heterozygosity (LOH) was more frequently observed in CDKN2A (28%) and FHIT (26%). In addition, LOH at FHIT locus was significantly associated with p53 nuclear stabilization (p = 0.0508), especially in non-smokers. A significant difference in survival rate between p53 positive and negative group (p = 0.0056) (Hazard ratio 2.5595) was observed. Though associated with p53 stabilization, FHIT loss did not exhibit significant effect on patient survival. Interestingly, patients exhibiting p53 nuclear stabilization as well as FHIT loss exhibited worse survival. We performed genome-wide DNA copy number and transcript profiling in several SCCOT samples. Interestingly, there was no significant difference in extent and profile of chromosomal instability in p53 positive and negative tumors. Amplifications were detected at chromosomal regions 3q26.1 (PIK3CA), 5p, 8q22 (MYC, RUNX1T1), 11q13 (CCND1) and 20q13 (HNFα). Genome-wide transcript profiling identified novel pathways that appear to drive tumorigenesis in tumors not exhibiting p53 inactivation. Our comprehensive analysis has therefore revealed important insights into the molecular basis for SCCOT and identified prognostic indicators in patients not associated with tobacco use. Citation Format: Raju S. Adduri, Viswakalyan Kotapalli, Rajender K K, Swarnalata Gowrishankar, Saumyadipta Pyne, Mukta Srinivasulu, Subramanyeshwar Rao, Shantveer G. Uppin, Mohammed Mujtaba Ali, Umanath K. Nayak, Snehalatha Dhagam, Mohana Vamsy Chigurupati, Murali D. Bashyam. Clinical and molecular genetic analysis of squamous cell carcinoma of the oral tongue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1883. doi:10.1158/1538-7445.AM2014-1883
The p53 oncoprotein is a tumor suppressor that is stabilized upon various forms of cellular stresses to induce transcription of genes regulating cell cycle arrest or apoptosis. TP53 is the most frequently mutated gene in human cancers and majority of mutations are located in the region encoding the DNA binding domain compromising thereby its transcription activation ability and resulting in loss of function. Recent studies however suggest mutant p53 proteins to exhibit a gain of function property. Specific p53 missense mutations can result in an altered transcription program causing positive regulation of cell proliferation, metastasis and chemoresistance. In our previous studies, we performed comprehensive characterization of squamous cell carcinoma of the oral tongue (SCCOT) with respect to p53, EGFR, Wnt, MSI, LoH of several tumor suppressor loci and HPV status. Mutant p53 was a significant predictor of overall survival and the TP53 codon 72 Proline allele was significantly associated with SCCOT. In order to dissect the role of mutant p53 in tongue cancer, we performed genome wide DNA and RNA profiling of 26 and 40 SCCOT samples, respectively. Both mutant and wild type tumor samples appeared to exhibit comparable levels of DNA copy number alterations. Transcriptome data analyses using a combination of single sample gene set enrichment analysis and comparative marker selection revealed gene sets that could significantly distinguish p53 mutant and wild type tumor samples. Significance analysis of microarrays performed on all genes constituting the differentially enriched gene sets surprisingly identified only two genes to be upregulated in p53 mutant samples at a false discovery rate significantly lower than 10% namely TP53 itself and SMARCD1; the latter a member of the SWI/SNF chromatin remodelling complex. Elevated levels of TP53 transcript in tumors harbouring mutant p53 significantly correlated with levels of ZMAT3, itself induced by p53 and known to stabilize the TP53 transcript. In addition, the analysis revealed several known (ATF3 and others) and novel (GCHFR and others) targets of wild type p53. Differential expression of all targets was validated in additional tongue cancer samples. Ectopic expression of certain (but not all) p53 mutant proteins in p53 null cells induced SMARCD1 (but not canonical wild type p53 targets) while expression of wild type p53 induced GCHFR, ATF3, CDKN1A, etc. (but not SMARCD1). In contrast, p53 stabilization in cells harboring wild type p53 caused elevation of GCHFR, ATF3, CDKN1A, etc., but not of SMARCD1. Validation of novel targets using promoter-luciferase constructs, chromatin immunoprecipitation PCR and a tongue cancer tissue microarray is underway. This is perhaps the first evidence from Head and Neck tumor samples for a gain of function activity of mutant p53. Thus wild type and mutant p53 may support distinct transcription programs in tongue cancer. Citation Format: Raju SR Adduri, Padmavathi Kavadipula, Viswakalyan Kotapalli, Leena Bashyam, Anupama Shirke, Arun kumar Paripati, Swarnalata Gowrishankar, Mukta Srinivasulu, Mohammed Mujtaba Ali, Subramanyeshwar Rao, Snehalatha Dhagam, Mohana Vamsy Chigurupati, Shantveer G. Uppin, Vijaya Tourani, Murali D. Bashyam. Transcriptome analysis of oral tongue cancer reveals novel insights into wild type and mutant TP53 transcription program. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3692.
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