PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients

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.

TP53 mutations and loss of heterozygosity of chromosome 17 in colorectal tumors

Este trabalho teve como objetivo determinar a incidência de mutaçöes no gene TP53 e de perdas de heterozigose (LOH) no cromossomo 17 em carcinomas coloretais de pacientes brasileiros. Analisamos amostras de DNA do tumor e da mucosa normal de 39 pacientes com câncer coloretal. As mutaçöes no gene TP53 foram analisadas pela técnica de PCR-SSCP (polimorfismo decorrente da conformaçäo da fita simples de DNA) e a análise de perda de heterozigose para o cromossomo 17 foi feita com a utilizaçäo de seis marcadores de DNA polimórfico do tipo microsatélite e uma sonda para minisatélite. Mutaçöes no gene TP53 foram observadas em 15/39 dos casos analisados. As mutaçöes observadas estäo distribuídas por todos os exons examinados (exons 5 a 8), sendo a maioria das mutaçöes transiçöes G/C A/T. Perdas de heterozigose nos segmentos cromossômicos 17p e 17q foram observadas em 70 e 46 por cento dos tumores, respectivamente. Observamos uma associaçäo significativa entre a ocorrência de mutaçöes para o gene TP53 e as perdas de heterozigose nos segmentos cromossômicos 17p (P=0,0035) e 17q (P=0,03). Embora nenhuma correlaçäo estatisticamente significativa tenha sido observada entre a ocorrência de alteraçöes genéticas no gene TP53 e as características clinicopatológicas dos pacientes, a associaçäo entre a ocorrência de mutaçäo no gene TP53 e a perda de heterozigose em ambos os braços do cromossomo 17 pode indicar que em um subgrupo de tumores coloretais a inativaçäo do gene TP53 resulte em células com maior instabilidade genética.