The largest whole genome sequencing (WGS) endeavour involving cancer and rare 
diseases was initiated in the UK in 2015 and ran for 5 years. Despite its 
rarity, sarcoma ranked third overall among the number of patients' samples sent 
for sequencing. Herein, we recount the lessons learned by a specialist sarcoma 
centre that recruited close to 1000 patients to the project, so that we and 
others may learn from our experience. WGS data was generated from 597 patients, 
but samples from the remaining approximately 400 patients were not sequenced. 
This was largely accounted for by unsuitability due to extensive necrosis, 
secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in 
formalin. The number of informative genomes produced was reduced further by a 
PCR amplification step. We showed that this loss of genomic data could be 
mitigated by sequencing whole genomes from needle core biopsies. Storage of 
resection specimens at 4 °C for up to 96 h overcame the challenge of freezing 
tissue out of hours including weekends. Removing access to formalin increased 
compliance to these storage arrangements. With over 70 different sarcoma 
subtypes described, WGS was a useful tool for refining diagnoses and identifying 
novel alterations. Genomes from 350 of the cohort of 597 patients were analysed 
in this study. Overall, diagnoses were modified for 3% of patients following 
review of the WGS findings. Continued refinement of the variant-calling 
bioinformatic pipelines is required as not all alterations were identified when 
validated against histology and standard of care diagnostic tests. Further 
research is necessary to evaluate the impact of germline mutations in patients 
with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the 
WGS exhibiting domain 1 alterations, the number of patients with sarcoma who 
were eligible for clinical trials remains small, highlighting the need to 
revaluate clinical trial design.