P53 nuclear stabilization is associated with FHIT loss and younger age of onset in squamous cell carcinoma of oral tongue.

BACKGROUND: Squamous 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. METHODS: We 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. RESULTS: Our 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. CONCLUSION: Our study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.

Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India.

Two genetic instability pathways viz. chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for >90% of late-onset colorectal cancer (CRC). Our understanding of early-onset sporadic CRC is however comparatively limited. In addition, most seminal studies have been performed in the western population and analyses of tumorigenesis pathway(s) causing CRC in developing nations have been rare. We performed a comparative analysis of early and late-onset CRC from India with respect to common genetic aberrations including Wnt, KRAS, and p53 (constituting the classical CRC progression sequence) in addition to MSI. Our results revealed the absence of Wnt and MSI in a significant proportion of early-onset as against late-onset CRC in India. In addition, KRAS mutation frequency was significantly lower in early-onset CRC indicating that a significant proportion of CRC in India may follow tumorigenesis pathways distinct from the classical CRC progression sequence. Our study has therefore revealed the possible existence of non-canonical tumorigenesis pathways in early-onset CRC in India.

Distinct genetic aberrations in oesophageal adeno and squamous carcinoma.

BACKGROUND: The two main oesophageal cancer subtypes namely adenocarcinoma and squamous cell carcinoma exhibit interesting clinical, pathological and geographical variations with the former being more common in the West and the latter in Asia. MATERIALS AND METHODS: We evaluated status of p53, EGFR, Wnt and HPV in addition to microsatellite instability and loss of heterozygosity of several chromosomal loci in the two oesophageal cancer subtypes from India. The comparative analysis was extended to two oesophageal adenosquamous mixed cancer samples. RESULTS: Our results reveal a high frequency of EGFR overexpression in ESCC as against EAC, while Wnt activation was a significantly more common event in EAC as against ESCC. Frequencies of p53 perturbations were not significantly different in the two subtypes. Interestingly, the EGFR and Wnt status in adenocarcinoma and squamous components of the two oesophageal adenosquamous cancer samples were identical to primary tumours. In addition, no common molecular aberration (including instability and loss of heterozygosity) in several microsatellites was detected in DNA isolated from the two components in both adenosquamous cancer samples. CONCLUSIONS: Our results reveal the presence of distinct aberrations in oesophageal adenocarcinoma and squamous cell carcinoma which are replicated in the respective components of adenosquamous cancers. The study therefore suggests perhaps an independent origin of the two components of oesophageal adenosquamous mixed cancer.

Her-2/neu status: a neglected marker of prognostication and management of breast cancer patients in India.

BACKGROUND: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. MATERIALS AND METHODS: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. RESULTS: In the present study, the ages ranged from 20-87 years with a mean of 50.0±12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. CONCLUSIONS: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India.

PNUTS functions as a proto-oncogene by sequestering PTEN.

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.

Overexpression of aldose reductase in human cancer tissues.

BACKGROUND: Aldose reductase (AR) belongs to the aldo-keto reductase (AKR) super family and catalyzes the conversion of aldoses to the corresponding alcohol. Some recent studies have shown overexpression of AR and AR-like proteins in human liver cancers and some cancer cell lines such as HepG2 and HeLa cells. However, apart from hepatic cancer tissue, the status of AR expression has not been reported in other human cancer tissues. Therefore, in this preliminary report, the expression of AR in a few other commonly occurring cancer tissues was investigated. MATERIAL/METHODS: Fresh post-surgical tumor tissues of breast, ovary, cervix, and rectum were collected from subjects who were admitted for surgical therapy of tumors. Tumor area and tumor characteristics were determined by histopathological analysis. The expression and activity of AR in tumor and non-tumor areas was carried out by immunohistochemical, immunoblotting, and enzyme activity studies. RESULTS: Immunoblotting results indicated overexpression of AR in breast, ovarian, cervical, and rectal cancerous tissues. Furthermore, biochemical data revealed that the specific activity of AR was higher in tumor areas than in non-tumor regions of these tissues. The overexpression of AR in tumor tissue was further validated by immunohistochemistry in the case of breast tissue. CONCLUSIONS: These preliminary results suggest overexpression and increased activity of AR in different human cancers. However, the incidence of AR overexpression and its role in drug resistance needs to be established with a large number of samples of various cancers.