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Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA
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Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Isidro Cortes-Ciriano, Christopher Steele, Katherine Piculell, Alyaa Al-Ibraheemi, Vanessa Eulo, Marilyn Bui, Aikaterini Chatzipli, Brendan Dickson, Dana Borcherding, Andrew Feber, …
bioRxiv
11 May 2022
DOI: https://doi.org/10.1101/2022.05.03.490481
url
https://doi.org/10.1101/2022.05.03.490481View
SubmittedOpen Access (License Unspecified),  Open

Abstract

Chromosome 8 Copy number Cytotoxicity DNA methylation Evolutionary genetics Genomes Genomic instability Heterozygosity Infiltration Metastases Morbidity Neurofibromatosis p53 Protein Peripheral nerves Phenotypes Polycomb group proteins Recklinghausen's disease Sarcoma Transcriptomics Whole genome sequencing Tumors
Malignant peripheral nerve sheath tumour (MPNST) is an aggressive soft-tissue sarcoma that arises in peripheral nerves. MPNST occurs either sporadically or in people with neurofibromatosis type 1 (NF1), a common cancer predisposition syndrome caused by germline pathogenic variants in NF1. Although MPNST is the most common cause of death and morbidity for individuals with NF1, the molecular underpinnings of MPNST pathogenesis remain unclear. Here, we report the analysis of whole-genome sequencing, multi-regional exome sequencing, transcriptomic and methylation profiling data for 95 MPNSTs and precursor lesions (64 NF1-related; 31 sporadic) from 77 individuals. Early events in tumour evolution include biallelic inactivation of NF1 followed by inactivation of CDKN2A and in some cases also TP53 and polycomb repressive complex 2 (PRC2) genes. Subsequently, both sporadic and NF1-related MPNSTs acquire a high burden of somatic copy number alterations (SCNAs). Our analysis revealed distinct pathways of tumour evolution and immune infiltration associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumours with loss of H3K27me3 evolve through extensive chromosomal losses with retention of chromosome 8 heterozygosity followed by whole genome doubling and chromosome 8 amplification. These tumours show lower levels of immune cell infiltration with low cytotoxic activity and low expression of immune checkpoints. In contrast, tumours with retention of H3K27me3 evolve through extensive genomic instability in the absence of recurrent alterations and exhibit an immune cell-rich phenotype. Specific SCNAs detected in both tumour samples and cell-free DNA (cfDNA) act as a surrogate for loss of H3K27me3 and immune infiltration, and predict prognosis. Our results suggest that SCNA profiling of tumour or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. Competing Interest Statement A.A., A.C., I.C.C., B.C.D., V.E., A.F., A.M.F., A.G., J.H., K.B.J., R.H.K., D.L., C.M., P.J.P., K.P., N.P., P.P., J.S., M.S., C.D.S., R.T.S., J.J.S., D.V., and X.W. have no conflicting interests to declare. M.B. Advisory boards for BioAtlas, Epizyme, Bristol-Myers Squibb, ContextVision, Airforia, Caris Life Sciences, and GlaxoSmithKline, consultant for AstraZeneca Pharmaceuticals LP, Foundation Medicine Inc, Visiopharm, Roche Laboratories, Inc.; B.C.D. received lab supplies from Illumina; J.F.G. consulted for Pfizer; A.C.H. Advisory boards for AstraZeneca and Springworks Consulting, received Intellisphere Research Funding from Tango Therapeutics Licensing Agreement with Deutsches Krebsforschungszentrum; J.T.J: Navio Theragnostics consultant, Recursion member scientific advisory board and consulting, Health2047 consultant, CEC Oncology speaker at a single CME conference regarding plexiform neurofibromas; D.T.M: Advisory Board, AstraZeneca; Y.N. Chairman, Japanese Society of Recklinghausen Disease; N.U. received royalties from University of Alabama, Birmingham and UpToDate, paid lecture to the advisory board of Astra Zeneca, expert testimony for Wolf, Horowitz & Etlinger, LLC Footnotes * Removed extended and supplementary figures into separate PDF files * https://ega-archive.org/access/data-access

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