Molecular and Clinical Studies of Bone and Soft Tissue Tumors

Molekylära Och Kliniska Studier av Ben Och mjukdelstumörer

The goal of this observational study is to learn whether tumors of bone and soft tissue can be sorted into groups by their genes. Today these tumors are named mainly by how they look under a microscope. There are more than 150 names in use. The same tumor can be given different names by different doctors.

The study includes people of any age with a bone or soft tissue tumor. All of them had tissue sampled at Karolinska University Hospital in Stockholm, Sweden.

The main questions it aims to answer are:

Can tests of a tumor's genes sort these tumors into clearer groups than the names used today? How often does a tumor's gene group differ from the name it was given at diagnosis? Can a computer program tell these groups apart from scanned pictures of the tissue?

Researchers will compare the groups found by the gene tests with the diagnoses given at the time. They will also look at how each group did over the years that followed. This shows which way of sorting tumors better matches what happened to participants.

Participants will not have extra visits, tests, or treatment for this study. The study does not change anyone's care.

Researchers will:

Use tumor tissue that was already taken as part of regular care Read the DNA and RNA in the tumor, which carry its genetic instructions Read the chemical marks on the tumor's DNA that switch genes on and off Scan the glass slides of the tissue into digital pictures Collect facts about treatment and health from medical records

Participants who are newly diagnosed will also be asked for a blood sample. Blood shows which gene changes a person was born with and which ones started in the tumor.

If the study finds a gene change that matters for a participant's care, the study team tells the treating doctors through normal hospital routines.

Study Overview

• Status: Recruiting
• Conditions: Bone and Soft Tissue Tumors

• Study Type: Observational
• Enrollment (Estimated): 50000

Contacts and Locations

• Study Contact: Name: Felix Haglund de Flon, MD PhD, Associate Professor; Phone Number: +46-8-524 800 00; Email: felix.haglund@ki.se

Study Locations

• Sweden
  • Stockholm, Sweden, 17176
    • Recruiting
    • Karolinska University Hospital
    • Contact: Felix Haglund de Flon, MD PhD, Associate Professor; Phone Number: 08-524 800 00; Email: felix.haglund@ki.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

People of any age with a tumor or tumor-like lesion of bone or soft tissue, benign, intermediate or malignant, diagnosed or reviewed at the Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden. The retrospective cohort is identified from the pathology archive by a predefined SNOMED-based search covering bone and soft tissue tumor codes, with an addendum capturing non- mesenchymal tumors that enter the differential diagnosis, such as melanoma, sarcomatoid carcinoma and lymphoma. The prospective cohort comprises people evaluated at the center during the study period. The center is a national referral center for sarcoma, so the population includes both locally diagnosed and referred cases.

Description

Inclusion Criteria:

• Histopathologically diagnosed tumor or tumor-like lesion of bone or soft tissue, including benign, intermediate and malignant lesions
• Tissue sampled, resected or reviewed at the study center
• Archived diagnostic material available and adequate for the analyses of the relevant cohort: formalin-fixed paraffin-embedded tissue, fresh-frozen tissue, or diagnostic glass slides
• For the prospective cohort, documented informed consent

Exclusion Criteria:

• No retrievable diagnostic material or diagnostic report
• Documented objection by the participant to the research use of their material or data

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Group/Cohort 1 - Retrospective archival cohort; People of any age with a bone or soft tissue tumor sampled or resected at the study center before the start of the study, identified from the pathology archive using a predefined SNOMED-based search. Diagnostic glass slides are scanned for the full archival cohort. A nested subset with tissue of sufficient quality also undergoes whole genome sequencing, RNA sequencing and DNA methylation profiling. Clinical and outcome data are taken from pathology reports and medical records. No study procedure is performed on participants. Assigned Interventions: Diagnostic Test: Digital pathology and computational image analysis Genetic: Whole genome and whole transcriptome sequencing (nested subset) Genetic: Genome-wide DNA methylation profiling (nested subset)
Group/Cohort 2 - Prospective cohort; People of any age newly diagnosed with, or referred for evaluation of, a bone or soft tissue tumor at the study center during the study period, who consent to the use of their tissue and data. Diagnostic tissue undergoes whole genome and transcriptome sequencing with a matched germline reference sample, DNA methylation profiling and slide digitization. Diagnosis and treatment follow routine practice and are not altered by the study. Assigned Interventions: Diagnostic Test: Digital pathology and computational image analysis Genetic: Whole genome and whole transcriptome sequencing Genetic: Genome-wide DNA methylation profiling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discordance between molecularly defined class and the original histopathological diagnosis	Proportion of tumors in the molecularly profiled cohort whose class assignment from integrated genomic, transcriptomic and methylation data, made without reference to the diagnostic label, differs from the WHO-based diagnosis in the original pathology report. Reported with a 95 percent confidence interval and accompanied by the adjusted Rand index for the full cross-classification. Only assignments above a pre-specified confidence threshold are counted as discordant; low-confidence assignments are reported separately. Discordant cases undergo blinded review by two sarcoma pathologists to separate reclassification from diagnostic error.	Through completion of the primary analysis of the molecular cohort, up to [5] years after study start.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of stable molecular classes identified	Number of classes recovered by consensus clustering of the integrated data that meet pre-specified stability criteria, reported with the stability metrics used (consensus matrix concordance, proportion of ambiguous clustering, cophenetic correlation) across the tested range of cluster numbers.	Through completion of the primary analysis, up to [5] years.
Proportion of tumors in residual diagnostic categories that receive a defined molecular class	Among tumors originally reported as undifferentiated pleomorphic sarcoma, spindle cell sarcoma not otherwise specified, or an equivalent unclassified bone lesion, the proportion assigned above the confidence threshold to a molecular class that has a defined biological identity.	Through completion of the primary analysis, up to [5] years.
Accuracy of molecular class prediction from digitized slides	Performance of machine learning models predicting molecular class membership from whole slide images, evaluated in held-out data split at the level of individual participants. Reported as balanced accuracy and macro-averaged area under the receiver operating characteristic curve, with 95 percent confidence intervals, plus per-class sensitivity and specificity.	Through completion of model development and evaluation, up to [5] years.
Frequency of clinically actionable somatic alterations	Proportion of tumors carrying at least one somatic alteration classified as clinically actionable according to a pre-specified evidence framework, reported by molecular class and by original WHO diagnosis.	Through completion of the primary analysis, up to [5] years.
Frequency of pathogenic germline variants in cancer predisposition genes	Proportion of participants with a matched germline sample carrying a pathogenic or likely pathogenic variant in a pre-specified panel of cancer predisposition genes, classified according to current guidelines.	Through completion of the primary analysis, up to [5] years.
Overall survival by molecular class	Time from date of diagnosis to death from any cause, with participants alive at last contact censored at that date. Estimated by the Kaplan-Meier method for each molecular class with a sufficient number of participants, and reported with the number of participants per class.	From date of diagnosis to death from any cause, assessed up to [30] years.
Prognostic information added by molecular class beyond current diagnosis and grade	Comparison of Cox proportional hazards models for overall survival that include molecular class against models that include the original diagnosis and grade, using the concordance index and likelihood-based comparison, adjusted for age, anatomical site, tumor size and treatment.	From date of diagnosis to death from any cause, assessed up to [30] years.

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Lund University; Uppsala University; Region Stockholm; KTH Royal Institute of Technology

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Estimated): March 1, 2046
• Study Completion (Estimated): March 1, 2046

Study Registration Dates

• First Submitted: September 10, 2026
• First Submitted That Met QC Criteria: September 10, 2026
• First Posted (Actual): September 16, 2026

Study Record Updates

• Last Update Posted (Actual): September 16, 2026
• Last Update Submitted That Met QC Criteria: September 10, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Sarcoma; Whole genome sequencing; Methylation; WGS; Bone and Soft Tissue Tumors; WTS
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Sarcoma; Soft Tissue Neoplasms
• Other Study ID Numbers: 2025-06780-01; 2025 (U.S. NIH Grant/Contract: Faculty of Social Sciences Scientific Grant at the University of Gdańsk); 2025-03129 (Other Grant/Funding Number: Vetenskapsrådet); 25 4631 (Other Grant/Funding Number: Cancerfonden)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Individual participant data will not be shared publicly. The data are whole genome sequences, transcriptomes, methylation profiles and whole slide images derived from clinical material, which are personal data under the General Data Protection Regulation and are not de-identifiable to a standard that permits open release. The ethics approval (Etikprövningsmyndigheten dnr 2025-06780-01) does not cover open publication of individual participant data. Derived and aggregated data supporting the published results, including class assignments, summary variant tables and model performance data, will be published with the primary reports. Requests for access to pseudonymized individual-level data for scientific purposes will be considered by the study's principal investigator and the responsible organizations, and may be granted where the request is compatible with the ethics approval and applicable law, and where a data transfer or processing agreement is in place. Analytic code developed in

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No