Microsatellite Instability–High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles

Abstract

Purpose: Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Design: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. Results: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). Conclusions: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

Moving into the modern era of molecular classification for endometrial cancer

“…Clinicopathologic and molecular heterogeneity within molecular subtypes has been noted (Figure 2). Our team and others have shown that the clinicopathologic features of MMR‐deficient/MSI‐H ECs differ according to the mechanism underpinning MSI instability 39–41 . MLH1 ‐hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations 39 .…”

“…37 ECs differ according to the mechanism underpinning MSI instability. [39][40][41] MLH1-hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations. 39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic).…”

“…[39][40][41] MLH1-hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations. 39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic). [39][40][41] CN-low ECs, also referred to as of NSMP, is a heterogeneous group of ECs classified by exclusion and encompassing tumors that do not display any of the other three defining molecular subtype features (i.e., POLE mutation, MSI, p53/TP53 alteration).…”

“…39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic). [39][40][41] CN-low ECs, also referred to as of NSMP, is a heterogeneous group of ECs classified by exclusion and encompassing tumors that do not display any of the other three defining molecular subtype features (i.e., POLE mutation, MSI, p53/TP53 alteration). 8,42 Several studies have focused on this NSMP group and showed that based on PTEN/PIK3CA mutation status, histology/grade, chromosome 1q gain/amplification, ER status or chromosomal instability, subgroups with distinct outcomes could be identified.…”

Update in the molecular classification of endometrial carcinoma

“…MMRd endometrial carcinomas to MLH1 promoter methylation could be associated with enrichment of JAK1 mutations, lower tumor mutational burden, and lower tumour-infiltrating lymphocytes densities, compared with MMRd endometrial carcinomas with germline mutations. 54 Furthermore, MMRd endometrial carcinomas with MLH1 promoter methylation could have shorter progressionfree survival compared with MMRd endometrial carcinomas with germline mutations, although this difference in survival was not found significant in multivariable analysis including clinicopathological features such as stage, age, or LVSI. 18 54 The need for prognostic refinement is particularly relevant in the context of NSMP endometrial carcinomas.…”