Sarcoma and the 100,000 Genomes Project: our experience and changes to practice

Area of Science:

• Oncology
• Genomics
• Bioinformatics

Background:

• The UK initiated a large-scale whole genome sequencing (WGS) project for cancer and rare diseases in 2015.
• Sarcoma, despite its rarity, was the third most frequent cancer type sequenced.
• A specialist sarcoma center recruited nearly 1000 patients for this initiative.

Purpose of the Study:

• To share lessons learned from a specialist sarcoma center's experience with WGS.
• To identify strategies for improving the yield of informative WGS data in sarcoma patients.
• To assess the utility of WGS in refining sarcoma diagnoses and identifying novel genetic alterations.

Main Methods:

• Whole genome sequencing (WGS) was performed on 597 sarcoma patient samples.
• Investigated reasons for sample unsuitability (necrosis, formalin, PCR amplification).
• Evaluated alternative methods like needle core biopsies and optimized tissue storage (4°C up to 96h).

Main Results:

• Approximately 400 samples were not sequenced due to unsuitability.
• PCR amplification reduced informative genome yield.
• Sequencing needle core biopsies and improved storage mitigated data loss.
• Diagnosis was revised for 3% of analyzed patients based on WGS findings.
• Over 50% of WGS showed domain 1 alterations, but clinical trial eligibility remained low.

Conclusions:

• Optimized sample handling and needle core biopsies can improve WGS data acquisition in sarcoma.
• WGS is valuable for refining diagnoses and discovering new alterations in diverse sarcoma subtypes.
• Further research is needed on germline mutations, hypermutation, and clinical trial design for sarcoma patients.