Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

C Mircea S Tesileanu,Roberta Rudà,Alba Ariela Brandes,Matthew Griffin,Martin Van Den Bent,Ken Aldape,Paul J Mulholland,Sara Erridge,Youri Hoogstrate,Lorenzo Boggiani,Catherine Mcbain,Wies Vallentgoed ,Paul M Clément ,Brigitta G Baumert ,Johan M Kros,Sanne Venneker,Filip De Vos,J Baurain ,Roelien H Enting,Vassilis Golfinopoulos,Warren Mason ,Hendrikus J Dubbink,Olivier Chinot ,Maurice De Wit,Francesca Caparrotti,Sanjeev Gill,Marc Sanson,Elizabeth Lim,Thierry Gorlia,Leland Rogers,Wolfgang Wick,Thierry Lesimple,Walter Taal,Michael Weller,Judith V.m.g Bovée ,Anja Gijtenbeek,Martin J.b Taphoorn ,Helen Wheeler,Robert B Jenkins,Iris De Heer,Jaap C Reijneveld ,Susan Clenton,Anna K Nowak,Michael A Vogelbaum,Jan Oosting,Pieter Wesseling,Pim J French

doi:10.1007/s00401-021-02291-6

Abstract

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Highlights

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in various tumour types including gliomas, intrahepatic cholangiocarcinomas, enchondromas and chondrosarcomas, sinonasal undifferentiated carcinomas and leukemias [12, 33]
We report that tumours harbouring IDH1R132H mutations, regardless of tumour type, have lower genome-wide DNA methylation levels compared to those harbouring other IDH1/2 hotspot mutations (‘nonIDH1-R132H IDH1/2-mutated tumours’)
We screened the catalogue of somatic mutations in the cancer (COSMIC) database [16], extracted IDH1/2 hotspot mutation data (IDH1R132, IDH2R172 and IDH2R140) and stratified them by tumour organ site

Summary

Introduction

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in various tumour types including gliomas (primary malignant central nervous system tumours), intrahepatic cholangiocarcinomas (bileExtended author information available on the last page of the article duct tumours), enchondromas and chondrosarcomas (bone tumours), sinonasal undifferentiated carcinomas and leukemias [12, 33]. Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in various tumour types including gliomas (primary malignant central nervous system tumours), intrahepatic cholangiocarcinomas IDH1/2 mutations are causal for the disease and tumours often remain dependent on the mutation for growth [22, 42]. The importance of the mutation is confirmed by the activity of IDH-inhibitors: inhibiting the mutant activity of either IDH1 or IDH2 shows anti-tumour activity in relapsed/refractory IDH1/2 mutated acute myeloid leukemia [14, 45] and cholangiocarcinoma. The objective response rates in these trials are in the order of 40%, though patients eventually relapse. Mutant IDH1/2 inhibitors have far not shown a survival benefit, but further studies on early-stage tumours are ongoing [32]

Methods

Results

Conclusion