Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation

Abstract

Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.amplification ͉ endometrial cancer ͉ prognosis ͉ comparative genomic hybridization ͉ stathmin expression W ith a 2% to 3% lifetime risk among women, endometrial cancer is the most common pelvic gynecologic malignancy in industrialized countries, and the incidence is increasing (1). Approximately 75% of cases are diagnosed with the tumor confined to the uterine corpus (1, 2), but after primary surgery 15% to 20% of these tumors recur and have limited response to systemic therapy. In light of these recurrences, patients who have localized endometrial cancer have 2 major needs: (1) adjuvant therapies that will reduce the recurrence rate, and (2) the ability to target these therapies to the patients in whom disease is most likely to recur. In addition, women who have metastatic disease require effective systemic therapy.The needs for effective systemic therapies and for reliable prognostic markers have been addressed only partly. The most common basis for determining risk of recurrent disease has been the categorization of endometrial cancer into 2 subtypes. The majority are type I, associated with good prognosis, low stage and grade, and endometrioid histology. In contrast, type II cancers are characterized by high stage and grade, nonendometrioid histology, and poor prognosis. The prognostic value of this distinction is ...

Establishment of a nine‐gene prognostic model for predicting overall survival of patients with endometrial carcinoma

“…Among them, partial genes have been previously reported to be associated with EC prognosis, such as TP53 23, 24, PIK3CA 25, CDKN2A 26, 27, and PTEN 17. By performing KEGG enrichment analysis (Fig.…”

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…Stathmin protein expression has been associated with PI3Kinase activity in breast and endometrial cancers. 96,118 The latter found STMN1 overexpressed in 15% of Type I cancers compared to 64% for Type II. 96 Other oncogenes have also been reported as altered in endometrial cancer; Drug sensitive mutations in the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene have been reported in 12% of endometrial carcinomas.…”

“…96,118 The latter found STMN1 overexpressed in 15% of Type I cancers compared to 64% for Type II. 96 Other oncogenes have also been reported as altered in endometrial cancer; Drug sensitive mutations in the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene have been reported in 12% of endometrial carcinomas. 119 Nuclear accumulation of ȕ-catenin (CTNNB1), only partially explained by mutations, is detected more frequently in Type I compared to Type II cancers.…”

“…95 The searching for better treatment regimens has prompted investigation of underlying molecular alterations important in endometrial carcinogenesis. 96 Exploration of tumour biology, uncovering dysregulation in several cellular pathways, is one way of identifying novel treatment strategies. Several of such molecular approaches to new therapy are now being explored in clinical phase I and II trials.…”

“…111 In endometrial cancer, mutations in the PI3CA, coding for the catalytic subunit; PI3CA, is found in 30% of Type I cancers and 20 % of Type II, while PI3CA amplifications are seen in 2-14 % and 46% of Type I and Type II respectively. 96,97 However mutation of the regulatory unit PI3R1…”