The use of somatic tumor mutational profiling is growing. We envision that somatic alterations of the MMR genes can inform on the MMR-D phenotype in endometrial cancer.
We analyzed the whole-exome sequence data of 570 patients with endometrial cancer from two previously reported studies (Nature. 2013;497(7447):67–73 and Clin Cancer Res. 2018;24(23):5939–47). Another 148 patients not previously reported were included. We used the Benjamini-Hochberg procedure (q-value) for multiple hypothesis testing.
A total of 706 pts were eligible for final analysis. Pts with somatic alterations in at least one of the MMR genes (MMR alt) were 16% (112/706) of pts. MMR alt group were diagnosed at an earlier median age than the non-MMR alt group (60 vs. 64 years, p = 0.005). No significant difference among pts of different races (p=0.24). The pts with MMR alt had a superior 5-year overall survival compared to the non-MMR alt pts (93.6% vs. 72.1%, Log-rank p=0.002). Pts with MMR alt were significantly enriched with mutations in cancer-related genes, such as PTEN and PIK3CA (q<0.0001). Meanwhile, TP53 mutations were enriched in the non-MMR alt group (q<0.0001). Pts with MMR alt had significantly higher MSI-high and POLE-hypermutated phenotype tumors compared to pts with non-MMR alt (52.04% vs. 23.72% and 43.88% vs. 1.47%, p< 0.001, respectively). Pts with MMR alt showed a higher MMR-D phenotype as detected by IHC compared to non-MMR alt pts (71.43% vs. 8%, p <0.001). In pts with available transcriptomic data from non-MMR alt (419 pts) and MMR alt (98 pts) subgroups, the expression of the mRNA transcripts of MSH6 was significantly higher in the non-MMR alt compared to the MMR alt group (Log ratio =0.24, q= 0.028), suggesting decreased expression in the MMR alt group. Moreover, PD-L1 expression was negatively correlated with PMS2 expression (Spearman’s R=-0.28, p<0.001).
Somatic MMR gene alterations delineated a subgroup of pts with endometrial cancer that had better survival, younger age, and highly mutated genomic profile. There is a significant association between somatic MMR alterations and standard MSI testing, suggesting the potential use of somatic tumor testing to identify MMR-D phenotype in tissue or liquid biopsies.
K. Shohdy.
European School of Oncology (ESO).
All authors have declared no conflicts of interest.