Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients

Abstract

Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…The findings suggest that loss of Cdh1 promotes aggressive EC phenotypes when cells are initiated by ablation of PTEN. These findings are corroborated by the results of Berg et al (2015) who observed molecular changes in PTEN and PIK3CA in AEH and described transcriptional changes in the PI3K pathway as early events in the invasive step to grade 1 EEC.…”

“…In a recent study, Berg et al (2015) reported preserved ER-A and PR expression in both premalignant endometrial lesions as well as grade 1 EEC. Significant reduction in receptor levels as well as increase in EMT score was detected from grades 2 to 3, suggesting EMT as a late event in endometrial carcinogenesis linked to loss of hormone receptors (Table 1).…”

“…Conditional PTEN ablation and K-ras mutation in mouse uterus dramatically accelerated development of EC as compared to single mutation of either gene . PTEN mutations and loss, mutations in PIK3CA, as well as PI3K and KRAS signaling activation have been suggested as early events in the development from CAH to EEC, while hormone receptor loss and EMT occur during dedifferentiation (Berg et al 2015).…”

Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation

“…Clinical data were collected as described earlier [25, 45]. The patient cohort used for p110β immunohistochemistry is described in detail in Tangen et al [45].…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…However, initial protein microarray data examining alterations in 52 proteins from a small sample of tumours (n = 31) did not show any significantly altered proteins between obese and nonobese subjects after adjustment for false discovery rates, thus preventing translation of these findings into an easily applied tumour protein biomarker panel [53]. In endometrial cancer, gene microarray data revealed different signatures for obese versus nonobese patients with cancer precursor cells, specifically upregulation and activation of the PI3 K pathway in nonobese patients, thus suggesting that different targets are applicable to different patient populations at the same disease site [54]. Loss of the gene encoding tumour suppressor phosphatase and tensin homolog (PTEN) is associated with improved progression-free survival (P < 0.006) in obese (BMI !30 kg/m 2 ) patients (total n = 187 endometrial cancer).…”