BRCA1 gene Molecular Alterations in Omani Breast Cancer Patients.

BACKGROUND: Breast cancer (BC) is the most common cancer reported in females in Oman and usually occurs at a relatively younger age, presents at an advanced stage and behaves aggressively. BC occurs in hereditary and sporadic forms. Although germ-line mutations in BRCA1 and BRCA2 genes are rare in sporadic cases compared with hereditary cases, molecular alterations, such as loss of heterozygosity, and CpG methylation, are common. In this study, we investigated the types of molecular alterations associated with hereditary and sporadic BRCA1-associated BC in Omani patients. METHODS: We obtained clinical data and samples from 43 sporadic BC patients. The selection of cases was made based on the following criteria: aged ≤ 40 years, or bilateral breast cancer, or estrogen and progesterone receptor negative status, and HER-2/neu negative (Triple Negative phenotype) status. Screening for molecular alterations was performed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA). RESULTS: Genomic deletions and duplication in the BRCA1 gene were identified in four female patients. Two patients carried exon 1 and 2 deletions and two showed exon 1 and 2 duplication. Screening for mutation by direct sequencing revealed three polymorphisms in exon 11. Two of these polymorphisms are nonsynonymous (rs1800704, rs799917) and one is synonymous (rs1800740). CONCLUSION: The current pilot study detected previously described gene rearrangements and polymorphisms involving the BRCA1 gene and no seemingly pathogenic missense mutations were elucidated. KEYWORDS: BRCA1, breast cancer, mutation, polymorphism, Omani, Arab.

Prognostic significance of cyclooxygenase-2, epidermal growth factor receptor 1, and microvascular density in gastric cancer.

Gastric cancer remains a significant global health burden with poor treatment outcome. New treatment modalities that target inflammation, proliferation, and angiogenesis have been used in various cancers, including gastric cancer. We sought to study the pattern of expression of two important proteins, cyclooxygenase-2 and epidermal growth factor receptor, and their association with microvascular density, clinicopathological features, and survival in Arab Omani patients with gastric cancer. Formalin-fixed, paraffin-embedded tumors were studied by immunohistochemistry using monoclonal antibodies to cyclooxygenase-2, epidermal growth factor receptor, and CD34. The immunohistochemical results were correlated with clinicopathological features and survival. In our study population, we found a male/female ratio of 72:43, a median age of 59 years, stage III and IV incidence of 66.9%, and a median follow-up of 96 months. Positive expression rates of cyclooxygenase-2 and epidermal growth factor receptor were 89.6 and 23.5%, respectively. The median microvascular density value was 52.5. When this value was determined as the cut-off point, 50% of patients were found to have high microvascular density. Epidermal growth factor receptor over-expression correlated with high microvascular density values, advanced lymph node involvement (N3), and TNM stage presentation (III and IV). Similarly, lymph node involvement was associated with cyclooxygenase-2 over-expression and high microvascular density. Univariate analysis showed that epidermal growth factor receptor over-expression, pathological T3 and T4 disease, and overall stage III and IV disease were adverse prognostic factors. On multivariate analysis using a Cox regression model, expression of epidermal growth factor receptor, and advanced TNM stage were significant adverse prognostic factors for overall survival. Expression of epidermal growth factor receptor in Arab Omani patients with gastric cancer correlates with aggressive tumor characteristics and is an independent prognostic factor. Further clinical studies are needed to evaluate the utility of epidermal growth factor receptor immunohistochemistry as a tool for gastric cancer treatment.

The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats.

Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.

The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients.

BACKGROUND: Gastric cancer is the most common cancer in Oman and a leading cause of cancer death. The variation in survival rates between countries and ethnic groups has been attributed to early detection policies, differences in clinicopathological features, treatment approaches, and biological characteristics. There were no previous reports on gastric cancer from Oman and very few studies on Asian Arabs. AIM: To evaluate the impact of clinicopathological and treatment variables on the survival prospects of Omani Arab patients diagnosed with gastric cancer. METHODS: The medical records of 339 Omani Arab patients diagnosed with invasive gastric adenocarcinoma during the period 1993-2004 were retrospectively reviewed. The relative importance of clinicopathological features and surgical and medical treatments were assessed using univariate and multivariate analyses. RESULTS: Most patients had distal ulcerating-type gastric cancer and presented at advanced stages. The median survival time for the entire cohort was 12 months (95% CI 9.7-14.4) with a 5-year overall survival rate of 16.7%. On univariate analysis of 237 patients who underwent surgical resection, the following positive prognostic factors emerged as significant: early overall TNM stage, early T stage, negative lymph nodes, tumor size <5 cm, ulcerating macroscopic appearance, and curative surgical attempt. The independent prognostic factors on multivariate analysis were T stage and lymph node involvement. CONCLUSION: The overall T and N stages are the most important determining factor for survival in Omani Arab patients. More efforts need to be made for the early detection of gastric cancer in developing countries such as Oman, while continuing to employ the standard surgical and medical treatments.

The prognostic significance of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients.

BACKGROUND: The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance. METHODS: Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67. The results were correlated with clinicopathological features and survival. RESULTS: M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow-up = 34.4 months. Positive expression rates of p53, p27 kip1, p21 waf1, Ki67, and HER-2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5 cm (P = 0.01), p27 kip1 and Ki67 expression (P = 0.0001), and HER-2/neu (P = 0.04). p21 waf1 correlated inversely with T-stage (P = 0.008) and Her-2/neu expression correlated with histological grade (P = 0.04) and T-stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (+)/p27 kip1 (-)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival. CONCLUSIONS: The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 kip1 is of added prognostic value.