Abstract
BackgroundSarcomas 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 methodsWe 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.ResultsCompared 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.ConclusionOur clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.
Highlights
Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior
When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized soft tissue (STS), only cyclin-dependent kinase inhibitor 2A (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 The Cancer Genome Atlas (TCGA) dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002)
Summary
Heterogeneous group of tumors with variable tendencies for aggressive behavior. Heterogeneous mesenchymal tumors with variable tendencies for aggressive behavior. Undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, leiomyosarcoma, Cancer genomics is playing an increasingly vital role in prognostic stratification of cancer patients. Generation sequencing has entered into mainstream clinical practice with increasing adoption for metastatic cancer patients and recent FDA approval and subsequent Medicare coverage of a sequencing companion diagnostic [10]. With the proliferation of sequencing information, there is opportunity to discover new prognostic correlations from mutational data, especially for rare tumors with limited prognostic features. We examined 152 sarcoma patients treated at Stanford Cancer Institute by tumor genome sequencing and explored associations between genomic alterations and outcomes. We analyzed data from The Cancer Genome Atlas (TCGA) sarcoma project, to independently validate findings from the Stanford cohort. We explored the Foundation Medicine sequencing database to describe the landscape of CDKN2A alterations in STS
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