Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.

Neil A J Ryan,Natalja Ter Haar,Thomas D J Walker,D Gareth Evans,Tom Van Wezel,Mark A Glaire,Emma J Crosbie,Tjalling Bosse,David N Church,James Bolton

doi:10.3390/cancers13184538

Abstract

Simple SummaryEndometrial cancers can arise due to an error in DNA mending known as mismatch repair. This can happen because of an error in the cancer itself (somatic) or due to an inherited error (Lynch syndrome). Treatment trials have considered endometrial cancers caused by either of these errors as identical. As it is easier to recruit people with Lynch syndrome, they may be overrepresented in this group despite being less numerous in clinical practice. This would not be an issue if somatic and Lynch syndrome-related endometrial cancers were similar at a molecular level. The data presented herein, however, indicates that these two routes to mismatch repair, although sharing many similarities, lead to endometrial cancers with distinct molecular and pathological features. This may explain the range of outcomes observed in clinical trials of endometrial cancers with mismatch repair errors.Background: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology. Methods: Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts. Results: After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-β signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC. Conclusions: Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study.

Highlights

The Cancer Genome Atlas (TCGA) categorises endometrial cancers (EC) into four molecular subgroups that more accurately predict clinical outcomes than histological subtype [1]
Two formalin-fixed, paraffin-embedded (FFPE) blocks were obtained from the hysterectomy specimen for next-generation sequencing alongside a representative haematoxylin and eosin (H&E) stained slide for pathology review
There were similar mutational landscapes in mismatch repair deficient (MMRd) tumours regardless of aetiology, co-occurring mutations in PTEN, PIK3CA and KRAS were more common in sporadic MMRd and perturbations of TGF-β signalling more common in Lynch syndrome (LS)-EC

Summary

Introduction

The Cancer Genome Atlas (TCGA) categorises endometrial cancers (EC) into four molecular subgroups that more accurately predict clinical outcomes than histological subtype [1]. Sporadic and hereditary causes of MMRd reflect different underlying biology that may, in turn, influence treatment response and survival outcomes [12], and failure to account for their potential differences may be an important source of confounding [12] This is important because participants of drug registration clinical trials are predominantly those with LS-associated rather than sporadic MMRd tumours, whereas, in routine clinical practice, the reverse is true [2]. Sporadic MMRd EC develops in a mostly un-primed immune microenvironment [12] It is, likely that sporadic and hereditary MMRd. Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology

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