Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

Abstract

Objective We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer Methods After pathology review, only endometrioid tumors with high neoplastic cellularity (≥70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. Results A total of 475 eligible cases were identified. Of 368 MSI+ cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI+) (12.9%, p<0.001) and were associated with higher tumor grade (p=0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58–2.32; p=0.68) or DFS (HR 0.61; 95%CI, 0.25–1.50; p=0.28). Conclusion Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer.

ATR and p-ATR are Emerging Prognostic Biomarkers and DNA Damage Response Targets in Ovarian Cancer

“…When we conducted additional analysis, p-ATR was an independent predictive biomarker of poor prognosis in ovarian cancer patients. These results are in line with previous works in breast cancer, endometrial cancer, and esophageal carcinoma [17,29,33].…”

Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type

“…B, Overall survival (OS) according to the cluster model was analyzed and plotted, and cluster 2 showed relatively shorter survival with marginal statistical significance RNF43 and the MSI status in GCs as well. In addition, ATR mutations are known to be exclusively present in MSI-H endometrial adenocarcinomas, 41 and enriched ATR mutations in MSI-H GCs in this study also suggests the important role of ATR in microsatellite instability.…”

“…The finding that three out of seven RNF43 mutated cases were MSI‐H GCs in this study implies the potential association between RNF43 and the MSI status in GCs as well. In addition, ATR mutations are known to be exclusively present in MSI‐H endometrial adenocarcinomas, and enriched ATR mutations in MSI‐H GCs in this study also suggests the important role of ATR in microsatellite instability.…”

ATM and ATR signaling at a glance

“…In pre-cancerous lesions, both the ATM and ATR pathways are activated, thereby helping the cell to mount a resistance to tumor development (Gorgoulis et al, 2005;Negrini et al, 2010). In addition, loss-of-function mutations or deletions of ATM or ATR, as well as their reduced kinase activity or expression levels, or deletions of components of their downstream pathways, all promote cell survival and result in a multi-fold increase in the propensity of a cell to become cancerous, and in an acceleration of tumor progression (Nevanlinna and Bartek, 2006;Spring et al, 2002;Vahteristo et al, 2002;Bertoni et al, 1999;Greenman et al, 2007;Guarini et al, 2012;Hollestelle et al, 2010;Menoyo et al, 2001;Reiman et al, 2011;Renwick et al, 2006;Roberts et al, 2012;Squatrito et al, 2010;Tanaka et al, 2012;Zighelboim et al, 2015Zighelboim et al, , 2009) (see poster). In particular, in ATM, distinct mutations have been found that cause different human malignancies, including lung cancer, breast cancer, colon cancer, lymphocytic leukemia, pancreatic cancer, and head and neck cancer, among others (Ding et al, 2008;Goldgar et al, 2011;Guarini et al, 2012;Roberts et al, 2012;Seshagiri et al, 2012) (see poster).…”