Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants.

Germline TP53 splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4-intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACT). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and in silico assays to determine protein stability, splicing, and transcriptional activity of 10 TP53 variants at exon 4-intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of TP53 variants in human cancer and examined individual reports, focusing on family history of cancer. TP53 exon 4-intron 4 junction germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional eight independent TP53 variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project (n = 5,213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization, and loss of function. Clinical case review of carriers of TP53 exon 4-intron 4 junction variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni syndrome. Germline variants involving TP53 exon 4-intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline TP53 variants on the fidelity of splicing, protein structure, and function must be considered in evaluating cancer susceptibility. IMPLICATIONS: Taken together, the data indicate that splice variants at TP53 codon 125 and surrounding bases differentially impacted p53 gene expression and function.

Predictors of peritoneal carcinomatosis in patients with gastric cancer treated at a single institution in Brazil.

BACKGROUND: Peritoneal carcinomatosis is a common pattern of recurrence in gastric cancer and is associated with a poor prognosis. Determining predictive factors for peritoneal recurrence can help the selection of patients suitable for more aggressive treatment strategies. METHODS: A retrospective chart review of 162 patients diagnosed with gastric cancer with no peritoneal carcinomatosis and treated at a single institution in Brazil from January 1994 to December 2004 was carried out. Univariate and multivariate analyses were performed to identify patient and tumor-related characteristics associated with the development of peritoneal metastasis. RESULTS: Twenty-three (14.2%) patients developed peritoneal carcinomatosis. Three independent factors associated with the development of peritoneal metastasis were identified by multivariate analysis: signet-ring cell histology (odds ratio [OR] = 4.9; P = 0.018), the presence of vascular invasion (OR = 4.8; P = 0.022), and the presence of visceral metastasis at diagnosis (OR = 5.1; P = 0.011). Tumor stages T3 or T4 showed a trend towards significance (P = 0.062). CONCLUSIONS: Patients with gastric cancer presenting with signet-ring histology, vascular invasion, or visceral metastasis appear to be at higher risk for the development of peritoneal carcinomatosis.

Factors correlated with peritoneal carcinomatosis and survival in patients with gastric cancer treated at a single institution in Brazil.

BACKGROUND: Gastric cancer is the second leading cause of death due to cancer worldwide and is particularly prevalent in Brazil. Promising new therapeutic agents have already shown activity in some gastrointestinal malignancies and their role in gastric cancer will need to be evaluated. Determining the prognostic factors of survival for patients with gastric cancer can help in identifying patients with a worse prognosis after treatment with the current chemotherapeutic regimens. METHODS: A retrospective chart review of 186 patients diagnosed with gastric cancer and treated at a single institution in Brazil from January 1994 to December 2004 was carried out. Univariate and multivariate analyses were performed to identify patient- and tumor-related characteristics associated with peritoneal metastasis at diagnosis and with overall survival. RESULTS: Of the 186 patients, 76 were alive at the time of this analysis. The median survival for all patients was 30.1 months. Two independent factors associated with the presence of peritoneal metastasis at diagnosis were identified by multivariate analysis: signet-ring cell type (odds ratio [OR], 10.8; 95% confidence interval [CI], 3.1 to 37.5), and visceral metastasis (OR, 51.8; 95% CI, 12.4 to 215.4). The prognostic factors for poor survival were tumor stage T3 or T4 (hazard ratio [HR], 1.87; 95% CI, 1.09 to 3.22) and visceral metastasis (HR, 4.98; 95% CI, 3.02 to 8.20). CONCLUSION: Two factors correlated with peritoneal metastasis and two prognostic factors for survival were identified. These findings may contribute to clinical decision-making, treatment tailoring, and the design of future trials.