Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas.

Alicia León‐Castillo,David N Church,Remi Nout,Robert A Soslow,Stefan Kommoss,Joseph W Carlson,Tjalling Bosse,Esther Oliva,Melissa Mcconechy,Tilman T Rau,Raji Ganesan,Ester Gilvazquez,Beth T Harrison,C Blake Gilks,Elisabeth Epstein,Vincent Thbm Smit,Sara Y Brucker,Xavier Matias‐Guiu,Jessica N Mcalpine

doi:10.1002/path.5373

Abstract

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as ‘multiple‐classifier’ ECs. We aimed to describe the clinicopathological and molecular features of multiple‐classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single‐classifier MMRd tumours (20/23) rather than single‐classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single‐classifier POLEmut tumours (12/13) and seldom with single‐classifier p53abn tumours (1/13) (both p ≤ 0.001, chi‐squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5‐year recurrence‐free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single‐classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Highlights

Of the many advances in the field of endometrial cancer (EC) during the last decade, perhaps the one with most impact is the molecular classification proposed by The Cancer Genome Atlas (TCGA) [1], which has gained prominence in recent years [2]
This classifies ECs into four molecular subtypes – POLE/ultramutated (POLE), microsatellite instability-high/hypermutated (MSI), somatic copy-number alteration high/serous-like (SCNA-high), and somatic copy-number alteration low (SCNA-low) – with significantly different prognoses [3], and of potential clinical relevance
Of the remaining 167 tumours, 30 were classified as mismatch repair deficiency (MMRd)–POLEmut ECs and will be reported separately (León-Castillo et al [18]), leaving 138 tumours (3.9%) that were assigned a provisional status of multiple-classifier with abnormal p53

Summary

Introduction

Of the many advances in the field of endometrial cancer (EC) during the last decade, perhaps the one with most impact is the molecular classification proposed by The Cancer Genome Atlas (TCGA) [1], which has gained prominence in recent years [2]. This classifies ECs into four molecular subtypes – POLE/ultramutated (POLE), microsatellite instability-high/hypermutated (MSI), somatic copy-number alteration high/serous-like (SCNA-high), and somatic copy-number alteration low (SCNA-low) – with significantly different prognoses [3], and of potential clinical relevance. A randomised controlled clinical trial (PORTEC4a [8]) is currently testing the added value of integrating this molecular approach into risk assessment, to individualise adjuvant treatment and reduce over- and under-treatment in patients [9]

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Conclusion