OBJECTIVES:The phosphatidylinositol 3-kinase/AKT axis is an important cell-signaling pathway that mediates cell proliferation and survival, two biological processes that regulate malignant cell growth. The phosphatidylinositol 3-kinase CA gene encodes the p110α subunit of the phosphatidylinositol 3-kinase protein. There are phosphatidylinositol 3-kinase CA mutations in several types of human tumors, and they are frequently observed in breast cancer. However, these mutations have not been investigated in Brazilian breast cancer patients.METHODS:PCR-SSCP and direct DNA sequencing were performed to identify phosphatidylinositol 3-kinaseCA exon 9 and exon 20 mutations in 86 patients with sporadic breast cancer. The relationships between PIK3CA mutations and patient clinicopathological characteristics and survival were analyzed. The presence of the TP53 mutation was also examined.RESULTS:Twenty-three (27%) of the 86 primary breast tumors contained PIK3CA mutations. In exons 9 and 20, we identified the hotspot mutations E542K, E545K, and H1047R, and we identified two new missense mutations (I1022V and L1028S) and one nonsense (R992X) mutation. Phosphatidylinositol 3-kinase CA exon 20 mutations were associated with poor overall survival and TP53 gene mutations.CONCLUSIONS:Phosphatidylinositol 3-kinase CA mutations are common in tumors in Brazilian breast cancer patients, and phosphatidylinositol 3-kinase CA and TP53 mutations are not mutually exclusive. Phosphatidylinositol 3-kinase CA exon 20 mutations are associated with poor survival, and they may be useful biomarkers for identifying breast cancer patients with aggressive tumors and for predicting the response to treatment with PI3K pathway inhibitors.
Mechanisms of viral oncogenesis are diverse and include the off‐target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single‐strand DNA editing capability of APOBECs represent a well‐conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single‐nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA‐expression and the APOBEC‐mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation‐signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV‐induced gastric carcinogenesis. After further validation, this EBV‐APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.
Gastric cancer (GC) is the fifth most common type of cancer worldwide with high incidences in Asia, Central, and South American countries. This patchy distribution means that GC studies are neglected by large research centers from developed countries. The need for further understanding of this complex disease, including the local importance of epidemiological factors and the rich ancestral admixture found in Brazil, stimulated the implementation of the GE4GAC project. GE4GAC aims to embrace epidemiological, clinical, molecular and microbiological data from Brazilian controls and patients with malignant and pre-malignant gastric disease. In this letter, we summarize the main goals of the project, including subject and sample accrual and current findings.
We have screened BRCA2 c.156_157insAlu founder mutation in a cohort of 168 women with diagnosis of breast cancer referred for genetic counseling because of risk of being carriers of hereditary breast and ovarian cancer syndrome. Portuguese founder mutation BRCA2 c.156_157insAlu was identified in three unrelated breast cancer probands. Genotyping identified a common haplotype between markers D13S260 and D13S171, and allele sizes were compatible to those described in the Portuguese families. Allele sizes of marker D13S1246, however, were concordant in two families, suggesting that the haplotype may be larger in a subset of families. Tumor phenotypes in Brazilian families seem to reinforce the high prevalence of breast cancer among affected males. However, an apparent excess of gastrointestinal and tongue neoplasias were also observed in these families. Although these tumors are not part of the phenotypic spectrum of hereditary breast and ovarian cancer syndrome, they might be accounted for by other risk alleles contained in the founder haplotype region.
Breast cancer has the highest incidence rate of all malignant neoplasias affecting women. It is a hormone dependent disease with complex and multifactorial etiology. Invasive breast cancer is one of the principal causes of women morbidity and mortality in the world. Breast cancer development and progression are associated with accumulation of various genetic and epigenetic alterations, which result in differential gene expression among normal and tumor cells. Hypoxia could be considered one of the principal hallmarks of solid tumors and the driving force for the tumor cell survival and malignant progression. The tumor suppressor gene PAWR (PKC apoptosis WT1 regulator; also known as PAR-4, prostate apoptosis response-4) has an important role in apoptosis either by intrinsic or extrinsic pathways and could be considered as a target for selective therapy of tumor cells. Some studies, including of our group, have shown the PAR-4 involvement in breast cancer and its role as prognostic and predictive factor in response to chemotherapy. However, little is known about functional role of this gene or the mechanisms involved in PAR-4 expression regulation in mammary gland and in breast tumorigenesis process. In the present study we evaluated the hypoxia effects on PAR-4 expression in MCF10A, MCF7 and MDA-MB-231 cell lines. Therefore, the cells were incubated for time periods of 30 minutes, 1, 2, 6 or 24 hours under controlled environment with 5 % CO 2 , 95% N 2 e 0.2% O 2. PAR-4 expression was evaluated for transcripts, by Real Time PCR, and for protein expression, by western blot. We observed that low oxygen concentration decreases PAR-4 mRNA expression, in periods of 6 and 24 hours, in MCF10A and MCF7 cell lines and in the period of 24 hours in MDA-MB-231 cells. However, when the Par-4 protein levels were evaluated, no significant difference was observed in these cells after incubation under hypoxic conditions. NDRG1 gene expression, which is increased under hypoxia, was used as a control. Our data suggest that the expression of tumor suppressor gene PAR-4 transcripts is inhibited by cell survival mechanisms activated during hypoxia.
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