The objective of Project 2 is to identify epigenetic biomarkers for predicting recurrence of early stage (stages 1 and II) endometrioid endometrial carcinomas (EECs). While this type of cancer usually has a good prognosis, ~10% of patients present with local recurrence or distant metastasis within 3 years of diagnosis. The currently used clinicopathojogical parameters, however, are inadequate for predicting which patients are IiReTy to'recur andlwoijldlnosf beTiefirfrohTup^ Inlhis regardTpfofiIing of molecular markers""""""""~ has recently been shown to be important for improved prognosis and for better stratification of cancer subtypes. Our preliminary studies have found that CpG island hypermethylation, a type of epigenetic alteration in cancer, represents an untapped resource of biomarkers for EECs. To identify these methylation-regulated loci, we will follow a phased-based approach established by the NCI's Early Detection Research Network. In the discovery step (Phase I), an epigenetic microarray approach will be used to comprehensively screen altered methylation of 27,000 human CpG islands in primary tumors of 54 early stage patients who recurred and 54 non-recurrent patients (sample size justified). Global profiling will identify candidate loci that are frequently hypermethylated in the recurrent group, but not in the non-recurrent group. In the validation phase (Phase II), a PCR-based assay, COBRA, will be used to confirm methylation findings in a second cohort of 54 early stage patients who recurred and 54 non-recurrent patients. A final set of 30 loci will then be used for further analysis in 2315 EECs (including all clinical stages and tumor grades) in the Phase III retrospective study. A robust assay, called MassARRAY, can efficiently quantify methylated CpG sites in 384 clinical samples in a single run. This extensive study will determine whether the identified loci are also poor prognostic indicators for some EEC patients. Clinical sensitivity and specificity of promising biomarkers will be calculated and used to assess patients'recurrence, disease-free survival, and other clinicopathological parameters. Such a study lays the foundation for a future prospective clinical trial (Phase IV) designed to test the utility of epigenetic biomarkers for accurate prediction of recurrent EECs.
The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.
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