Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov 26;26(1):404.
doi: 10.1186/s13059-025-03812-2.

Loss of IDH1 and IDH2 mutations during the evolution of metastatic chondrosarcoma

William Cross  1 , Iben Lyskjær  2 , Christopher Davies  3   4 , Abigail Bunkum  5   6   7 , Ana Maia Rocha  3   4 , Tom Lesluyes  8 , Fernanda Amary  3 , Roberto Tirabosco  3 , Cristina Naceur-Lombardelli  6   7   9 ; PEACE consortium; Mariam Jamal-Hanjani  6   7   9 , Charles Swanton  7   9   10 , Nischalan Pillay  3   4 , Simone Zaccaria  5   7 , Adrienne M Flanagan #  11   12 , Peter Van Loo #  8   13   14
Collaborators, Affiliations

Loss of IDH1 and IDH2 mutations during the evolution of metastatic chondrosarcoma

William Cross et al. Genome Biol. .

Abstract

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Keywords: IDH1; IDH2; Bone tumor; Cancer evolution; Chondrosarcoma; Metastasis.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: Use of the samples for this research project (project no: EC17.14) was granted by the UCL/UCLH Biobank Ethics Committee, a committee that is approved by the National Research Ethics Committee (Integrated Research Application System (IRAS) project identifier: 272816). The samples included in the project were held at the Royal National Orthopaedic Hospital (RNOH), a UCL satellite licensed Human Tissue Authority-approved premises (Licensing no. 12055). Competing interests: M.J-H. has consulted for, and is a member of, the Achilles Therapeutics Scientific Advisory Board and Steering Committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, and holds a patent PCT/US2017/028013 relating to methods for lung cancer detection. C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc—collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical. He is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Centre – Shanghai, Metabomed (until July 2022), and the Sarah Cannon Research Institute C.S has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina, and Roche-Ventana. C.S. had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), US patent relating to detecting tumour mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892).

Figures

Fig. 1
Fig. 1
The evolution of IDH1 mutant loss in a case of metastatic chondrosarcoma. A Mutational burden summary for index case CS1. B Driver mutation summary. The IDH1 mutation is clonal in primary tumor samples, but absent or near absent in three metastatic sites. All metastatic sites are genome doubled. C Copy number states of the IDH1 locus across sites with IDH1 mutation loss. D The presence of eight clones detected are indicated in the body map. Multiple parallel losses of IDH1 (red branches) were observed. E The evolutionary history of the tumor inferred via HATCHet and MEDICC2. F Seeding pattern determined via MACHINA suggests the liver was the first metastatic site
Fig. 2
Fig. 2
Exploration of IDH1 and IDH2 loss in ddPCR and immunohistochemistry. A Driver mutation summary of four cases subjected to exome sequencing, identified as harboring mutant IDH1 loss. B Copy neutral LOH of the IDH1 loci in CS2. C ddPCR frequency of IDH1/2 mutant droplets for 19 cases of metastatic chondrosarcoma. Partial loss defined as frequencies > 1% and < 10%. Near-complete loss frequencies are defined as < 1% but higher than the background (Methods). Samples assayed for IDH1 R132H immunostaining included in panel D are marked. D Tumor content distribution, as measured by sequencing and histological estimation. E Immunostaining for IDH1 R132H. Loss of immunoreactivity confirmed the genetic findings in CS6_Met and CS7_Pri_1 (which had a low droplet count)
See this image and copyright information in PMC

References

    1. Pirozzi CJ, Yan H. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol. 2021;18:645–61. - DOI - PubMed
    1. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224:334–43. - DOI - PubMed
    1. Zhu GG, Nafa K, Agaram N, Zehir A, Benayed R, Sadowska J, et al. Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma. Clin Cancer Res. 2020;26:419–27. - DOI - PMC - PubMed
    1. Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 2011;43:1262–5. - DOI - PubMed
    1. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011;43:1256–61. - DOI - PMC - PubMed

LinkOut - more resources