Phosphatidylinositol 3-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P ‫؍‬ 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.

FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25

Mutation of PIK3CA, the gene coding for the p110a catalytic subunit of phosphoinositide 3-kinase (PI3K), has been reported in a limited range of human tumors. We now report that PIK3CA is also mutated in esophageal tumors. Single-strand conformational polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) were used to screen all 20 exons of PIK3CA in 101 samples from 95 individuals with esophageal cancer and/or Barrett's esophagus. Somatic mutation of PIK3CA was detected in 4 of 35 (11.8%) of esophageal squamous cell carcinomas (SCC) and 3 of 50 (6%) adenocarcinomas. No mutations were detected in any of 17 samples of Barrett's esophagus. For PIK3CB, we screened exons 11 and 22, which code for the regions corresponding to the exon 9 and 20 mutational ÔhotspotsÕ of PIK3CA. No somatic changes were detected in PIK3CB This study extends previous observations in other tumor types by demonstrating the presence of somatic PIK3CA mutations in both SCC and adenocarcinoma of the esophagus, thus implicating the PI3K pathway in the initiation and/or progression of esophageal cancers. ' 2005 Wiley-Liss, Inc.Key words: phosphatidylinositide 3 0 -kinase; mutation; oncogene; esophageal cancer; Barrett's esophagus Phosphatidylinositide 3-kinases (PI3K) are a ubiquitous family of lipid kinases that catalyse the phosphorylation of phosphatidylinositol (PI), PI(4)P and PI(4,5)P 2 forming PI(3)P, PI(3,4)P 2 and PI(3,4,5)P 3 , respectively. 1 These lipid products are then able to activate a variety of downstream targets that regulate a wide range of important cellular processes, including cell proliferation, migration and survival, oncogenic transformation and intracellular trafficking of proteins. Of the PI3Ks, the most extensively studied are the class 1A sub-group, which exist as heterodimers consisting of a unique catalytic subunit (p110a, b, and d) along with one of a number of shared regulatory subunits (p85a, p85b and p55g). 1,2 Numerous genetic and functional studies have clearly established a fundamental role for the PI3K pathway in the development of neoplasia. Amplification of the PIK3CA gene (which codes for the p110a catalytic subunit of PI3K) has been reported in a number of different tumor types. 3,4 We have previously reported activating somatic mutations in the p85a regulatory subunit of PI3K (PIK3R1) in primary ovarian and colon tumors, 5 while more recently we, and others, have demonstrated a high frequency of somatic mutations in PIK3CA in a limited selection of tumor types. [6][7][8][9][10][11] Therapeutic strategies that target PI3K or its downstream targets such as Akt and mTOR are beginning to show considerable promise as potential new anticancer treatments. [12][13][14] In addition, there is increasing evidence that PI3K inhibitors can enhance the efficacy of conventional chemotherapeutic agents in both in vitro and in vivo models. 13,14 Since tumors harbouring mutations in PI3K are likely to be more susceptible to the therapeutic actions of agents that target the PI3K pathway, it i...

Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands onTcells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. Experimental Design: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positiveTcells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. Results: Regressing tumor tissue was infiltrated with CD8-positiveT cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A^specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A^specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A^expressing tumor cells. Conclusions: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

No abstract