Endometrial cancer is the most common gynecologic malignancy in the United States, where it is the second most common cause of gynecologic cancer deaths. Fortunately, most patients present in early stage and have an excellent prognosis. Disease progression and recurrence are associated with dismal outcomes. The incidence and mortality associated with this disease is on the rise. To date, we are unable to identify patients destined to experience progression and/or recurrence who will ultimately die from this disease. There is an urgent need to develop validated prognostic biomarkers for patients with endometrial cancer. The DNA-damage response gene ATR has an A10 mononucleotide repeat within its coding sequence. This region is a hotspot for mutations in cells with defective mismatch repair. ATR truncating mutations are independently associated with a significantly increased risk of recurrence and mortality among women with endometrioid endometrial cancer. We propose to validate ATR mutation as a prognostic biomarker in this patient population using the Gynecologic Oncology Group Protocol 210 cohort (""""""""A molecular staging study of endometrial carcinoma"""""""").
Two specific aims are proposed:
Specific Aim 1 : Validate the prognostic significance of ATR mutation in patients with endometrioid endometrial cancer. We will test for ATR loss of function mutations in an estimated 508 MSI-positive endometrioid endometrial cancer specimens from patients enrolled in GOG-210 and analyze the relationship between ATR mutation and clinicopathologic variables including disease free and overall survival.
Specific Aim 2 : Determine the relationship between ATR mutation status and response to adjuvant therapy (chemotherapy and/or radiation). Given ATR's important role in DNA damage response pathways, it will be important to determine if prognostic effect(s) vary with specific therapeutic modalities. This large cohort, coupled with complete and detailed data on adjuvant treatment will allow us to test for mutation / therapy interactions, exploring the potential value of ATR mutation to predict response to therapy in patients with endometrioid endometrial cancer (theranostics). We will generate a long-lasting DNA resource for the research community (made available through the GOG) for multiple ongoing and upcoming studies focused on molecular defects related to response to adjuvant therapy in patients with endometrioid endometrial cancer.
This project will validate the prognostic value of ATR mutation and test the theranostic potential of this biomarker in patients with endometrioid endometrial cancer. As part of our characterization of the GOG-210 specimens, we will generate a long-lasting tumor and matched normal tissue DNA resource for the Gynecologic Oncology Group that will be made available for multiple ongoing and upcoming studies on the genetics of endometrial carcinoma.
|Walker, Christopher J; Miranda, Mario A; O'Hern, Matthew J et al. (2016) MonoSeq Variant Caller Reveals Novel Mononucleotide Run Indel Mutations in Tumors with Defective DNA Mismatch Repair. Hum Mutat 37:1004-12|
|Zighelboim, Israel; Ali, Shamshad; Lankes, Heather A et al. (2015) Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 138:614-9|
|Walker, Christopher J; Miranda, Mario A; O'Hern, Matthew J et al. (2015) Patterns of CTCF and ZFHX3 Mutation and Associated Outcomes in Endometrial Cancer. J Natl Cancer Inst 107:|
|Zighelboim, Israel; Mutch, David G; Knapp, Amy et al. (2014) High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers. Hum Mutat 35:63-5|