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Originally published as JCO Early Release 10.1200/JCO.2009.22.2125 on May 26 2009 © 2009 American Society of Clinical Oncology.
ATR Mutations in Endometrial Cancer: A Window Into the Role of Mismatch Repair DefectsClinical Genetics Service, Department of Medicine, and Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Since the initial identification that defects in mismatch repair (MMR) lead to the phenotype of microsatellite instability (MSI) in colorectal and endometrial cancer in 1993,1–4 it has become well recognized that this feature is present in 15% to 20% of colorectal5 and 20% to 25% of endometrial cancers.6 In addition, multiple studies have suggested that colorectal tumors with high-level microsatellite instability (MSI-H) have improved prognosis compared to colorectal tumors that are microsatellite stable (MSS).7,8 Perhaps more importantly, several of these studies have also suggested that defective MMR is an important biomarker that may be used to predict lack of response to fluorouracil-based chemotherapy regimens.9,10 The prognostic and therapeutic implications of MMR defects in endometrial cancer, however, have been less clear. In 2006, Cohn et al11 evaluated 294 endometrial cancers and demonstrated that tumors with defective MMR, as evidenced by loss of MLH1 or MSH2 expression, had a worse 5-year disease-free survival (81% v 92%; P = .035) compared to tumors with normal MLH1 and MSH2 expression. In contrast to these results, in the same year, Black et al,12 in a cohort of 473 patients with endometrial cancer characterized for MMR defects by MSI testing, reported that MSI-H endometrial cancers had markedly improved disease-free survival (hazard ratio [HR], 0.3; 95% CI, 0.2 to 0.7; P = .01) and disease-specific survival (HR, 0.3; 95% CI, 0.1 to 0.9; P = .02) compared to MSS endometrial tumors.12 Most recently, in 2007, Zighelboim et al13 evaluated survival in a cohort of 446 endometrioid endometrial cancers that were characterized for defective MMR by MSI testing, and saw no difference between MSI-H and MSS endometrial tumors in either disease-free survival (HR, 0.95; 95% CI, 0.55 to 1.64; P = .86) or overall survival (HR, 1.01; 95% CI, 0.69 to 1.48; P = .96). In this issue of Journal of Clinical Oncology, Zighelboim et al14 build on their previous work, and provide valuable insights that may have substantial impact on both our understanding of MSI-H endometrial cancer and possible therapeutic targets in this disease. In this report, Zighelboim et al examine a series of 141 MSI-H endometrioid endometrial cancers for mutations in a 10-base mononucleotide repeat in exon 10 of the ATR gene.14 This gene is a logical one to explore, given its importance in the activation of cell cycle checkpoints in response to DNA damage and its potential increased susceptibility to somatic mutations in the setting of defective mismatch repair, due to the presence of the long mononucleotide repeat in a protein coding exon. Zighelboim et al14 identified protein truncating mutations in 12 (8.5%) of 141 MSI-H endometrial cancers. The authors also confirmed the work of prior groups and demonstrated no mutations in this A10 mononucleotide repeat in an additional 107 MSS endometrioid endometrial tumors. On multivariate analysis, presence of an ATR mutation was strongly associated with poorer overall survival when compared to the 129 MSI-H endometrial cancers without an ATR mutation (HR, 3.52; 95% CI, 1.45 to 8.57; P = .005) as well as when compared to the entire cohort of 236 endometrial cancers without an ATR mutation unselected for MSI status (HR, 3.88; 95% CI, 1.64 to 9.81; P = .002). Building on recent data suggesting that tumors with defective ATR may demonstrate enhanced sensitivity to drugs that inhibit DNA synthesis,15 the authors suggest that knowledge of ATR mutation status may provide a therapeutic opportunity in MSI-H endometrial cancers. There are many strengths of this intriguing study. Zighelboim et al14 have analyzed one of the largest single institution cohorts of endometrioid endometrial cancers characterized for MSI status. The methods are robust, and the results make a compelling argument that mutations in ATR are strongly associated with prognosis in MSI-H endometrial cancer. As Zighelboim et al14 also confirm prior reports that mutations in the ATR A10 mononucleotide repeat occur exclusively in MSI-H unstable endometrial tumors,16 it appears that the authors have identified an issue that affects only a small fraction of the patients with endometrial cancer. This does not, however, decrease the translational relevance of this study. Previously, Zighelboim et al,13 in a cohort largely overlapping with that in the current report, found that there was no difference in prognosis between MSI-H and MSS endometrial cancer. Given the current results that MSI-H tumors with ATR mutations have markedly worse survival compared to MSI-H tumors that are ATR wild-type, this would suggest that MSI-H tumors that are ATR wild-type might also have an improved prognosis compared to MSS endometrial tumors. While Zighelboim et al14 did not see such an effect, it was likely underpowered to do so. In addition, the study inclusion criteria potentially excluded patients with MSI-H endometrial tumors most likely to demonstrate an improved outcome. Of the 195 endometrioid tumors available for analysis, the authors excluded patients with synchronous or metachronous cancers. This group, however, includes many patients likely to have a germline defect in MMR associated with Lynch syndrome. In the 2007 report from Zighelboim et al,13 there was a suggestion that MSI-H tumors without methylation of the MLH1 promoter (which are likely associated with germline mutations causative of Lynch syndrome) had improved survival compared to both MSS tumors and MSI-H tumors with MLH1 promoter methylation. In Lynch syndrome, MMR is lost as an early event in tumorigenesis. In patients with defective MMR due to methylation of the MLH1 promoter, it occurs much later in the process. Whether the etiology or timing of loss of MMR function impacts biologic behavior is not clear in either endometrial or colorectal cancer. There is, however, a suggestion that this etiology may play a role in the likelihood of loss of ATR function. Miquel et al17 have previously reported that mutations in the A10 mononucleotide repeat of exon 10 were present in six (75%) of eight sporadic MSI-H colorectal cancers as compared to only seven (23%) of 31 familial MSI-H colorectal cancers. This apparent difference in frequency of mutations suggests that the etiology of the MMR defect may have an important role in the types of subsequent oncogenic mutations that develop. Since its identification in 1993, it has become clear that defects in MMR are important in the development of a large fraction of endometrial cancers. Despite studying this phenomenon for the past 16 years, we are only beginning to understand the role defects in this DNA repair pathway have on tumorigenesis in endometrial cancer. The current report from Zighelboim et al14 substantially moves our understanding forward. Further progress, however, likely will require a comprehensive approach addressing both the etiology for the defective MMR as well as its impact of the development of subsequent carcinogenic changes. Studies such as these will likely allow us to elucidate the true importance of MMR in endometrial and related cancers and open a window for the development of targeted therapeutics that exploit defects in this pathway. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Aaltonen LA, Peltomäki P, Leach FS, et al: Clues to the pathogenesis of familial colorectal cancer. Science 260:751–752, 1993. 2. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260:816–819, 1993. 3. Ionov Y, Peinado MA, Malkhosyan S, et al: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561, 1993.[CrossRef][Medline] 4. Risinger JI, Berchuck A, Kohler MF, et al: Genetic instability of microsatellites in endometrial carcinoma. Cancer Res 53:5100–5103, 1993. 5. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268, 2004. 6. Soliman PT, Lu K: Endometrial cancer associated with defective DNA mismatch repair. Obstet Gynecol Clin North Am 34:701–715, 2007.[CrossRef][Medline] 7. Gryfe R, Kim H, Hsieh ET, et al: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342:69–77, 2000. 8. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618, 2005. 9. Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257, 2003. 10. Carethers JM, Smith EJ, Behling CA, et al: Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 126:394–401, 2004.[CrossRef][Medline] 11. Cohn DE, Frankel WL, Resnick KE, et al: Improved survival with an intact DNA mismatch repair system in endometrial cancer. Obstet Gynecol 108:1208–1215, 2006.[CrossRef][Medline] 12. Black D, Soslow RA, Levine DA, et al: Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol 24:1745–1753, 2006. 13. Zighelboim I, Goodfellow PJ, Gao F, et al: Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol 25:2042–2048, 2007. 14. Zighelboim I, Schmidt AP, Gao F, et al: ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J Clin Oncol 27:3091–3096, 2009. 15. Wilsker D, Bunz F: Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival. Mol Cancer Ther 6:1406–1413, 2007. 16. Vassileva V, Millar A, Briollais L, et al: Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability. Cancer Res 62:4095–4099, 2002. 17. Miquel C, Jacob S, Grandjouan S, et al: Frequent alteration of DNA damage signaling and repair pathways in human colorectal cancers with microsatellite instability. Oncogene 26:5919–5926, 2007.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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