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Background  Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies.    Patients and methods  We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of  CDKN2A  alterations in histological subtypes of sarcoma.    Results  Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were  TP53  (47%),  CDKN2A  (22%),  RB1  (22%),  NF1  (11%), and  ATRX  (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only  CDKN2A  alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where  CDKN2A  altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of  CDKN2A  alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas.    Conclusion  Our clinico-genomic profiling of STS shows that  CDKN2A  deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis