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Basic Science and Translational Research

(P 06) RAPID, POINT-OF-CARE DNA METHYLATION & MOLECULAR LANDSCAPE BASED SARCOMA CLASSIFICATION

    Co-Author(s)

  • MM

    Myriam Maoz, Ms.

    Oncology Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • BB

    Boaz Ben-Kuzari, Mr.

    Oncology Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • Omer Or, MD

    Director of Orthopedic Oncology unit
    Orthopedic Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • NO

    Noam Olshinkaa, M.D.

    Orthopedic Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • JD

    Jonathan Abraham Demma, M.D.

    Surgical Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • MB

    Meni Brakha, M.D.

    Surgical Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • GV

    Gilad W Vainer, M.D.\Ph.D.

    Pathology Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

  • GF

    Galina Feinberg, Ph.D.

    Hemato-Oncology Laboratory, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
    Petach Tikva, HaMerkaz, Israel

  • YB

    Yehudit Birger, Ph.D.

    Hemato-Oncology Laboratory, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Israel. Felsenstein Medical Research Center, Tel Aviv University, Israel
    Petach Tikva, HaMerkaz, Israel

  • AG

    Assaf Grunwald, Ph.D.

    Felsenstein Medical Research Center, Tel Aviv University, Israel. Department of Physical Chemistry, School of Chemistry, Tel Aviv University, Tel Aviv, Israel
    Petach Tikva, HaMerkaz, Israel

  • OM

    Orly Michaeli, M.D.

    Hemato-Oncology Laboratory, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
    Petach Tikva, HaMerkaz, Israel

  • AD

    Alaa Darwish, Ph.D.

    Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
    Jerusalem, Yerushalayim, Israel

  • AE

    Amir Eden, Ph.D.

    Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
    Jerusalem, Yerushalayim, Israel

    • Author(s)

  • Aviad Zick, MD\PhD (he/him/his)

    Senior oncologist/Senior lecturer
    Oncology Department, Sharett Institute for Oncology, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Jerusalem, Yerushalayim, Israel

Objective: Sarcomas are a group of >200 types of cancer with mesenchymal differentiation. In up to 20% of patients, sarcoma cannot be conclusively classified. Identifying translocations and DNA methylation patterns can classify specific sarcoma sub-types. Oxford Nanopore DNA sequencing is a rapid, point-of-care method. Nanopore DNA sequencing detects DNA methylation, translocations, copy number alterations and point mutations. In this work we characterize which sarcoma sub-types are correctly classified using whole genome nanopore sequencing?

Methods: All patients signed an informed consent to participate in the study. Fresh tissue was flash frozen, and DNA extracted using Qiagen DNeasy blood and Tissue Kit; Whole genome sequencing was performed at low coverage of ≈0.1X using the Minion or at ≈10X high coverage using Promethion2 solo. We use NanoDx Methylation based classification to classify sarcomas. Using the NanoSV and Clair3 analysis tools single nucleotide and structural variant are identified.

Results: Using Nanopore low coverage whole genome DNA sequencing we examined 59 sarcoma samples from different subtypes. The NanoDx methylation classifier correctly diagnoses sarcomas such as all 8 Ewing's sarcoma and 3 desmoplastic small round blue cell sarcoma samples. In liposarcoma samples 3 of 10 samples are correctly classified using NanoDx and MDM2 amplification is found in all samples. Using Nanopore high coverage whole genome DNA sequencing we examined five sarcoma and matched blood samples of synovial, Ewing's and desmoplastic small round blue cell sarcoma, the SYT and EWS translocations are identified correctly. A patient initially diagnosed with undifferentiated spindle cell sarcoma was reclassified. The NanoDx classified the sample as an Ewing’s sarcoma and a FUS-ERG translocation verified the diagnosis. The tumor's DNA Methylation patterns and translocations can accurately identify certain types of sarcomas. A classifier incorporating clinical data, methylation data & molecular features could improve sarcoma classification. Additional testing of different sarcoma sub-types is needed to further evaluate the clinical utility of whole genome nanopore sequencing.

Conclusion: Whole genome nanopore sequencing can classify some sarcoma subtypes using low coverage sequencing and identify rare translocations using high coverage sequencing.