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

Abstract

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.

Keywords: CDKN2A; Genomics; Prognostic markers; Soft tissue sarcoma.

Fig. 1

Genomic landscape of bone and soft tissue sarcoma. a Average frequency per patient of SNVs, amplifications, deletions, and fusions per cancer type for 1291 Stanford patients with tumor sequencing. When ordered by average number of SNVs, bone and soft tissue have the lowest amount of SNVs while having the highest relative proportion of copy number and structural rearrangements. b Oncoprint [30] plot of genomic alterations in soft tissue sarcoma clustered by frequency. The genes are ordered from most frequent (top) to least frequent (bottom). Tumor histology is shown on the topmost colored bar

Fig. 2

Clinical outcomes for localized soft tissue sarcomas with genomic sequencing treated at Stanford (n = 96). a Forest plot of most commonly altered 8 genes with prognosis reveals only CDKN2A to be significantly associated with worse prognosis. b Kaplan–Meier plot of overall survival for CDKN2A altered vs. non-CDKN2A altered patients (p = 0.017). c Histologic distribution of all patients (d) and CDKN2A altered patients (C2) reveals increases in representation of MPNST, MFS, and UPS with decreases in LMS and LPS. e Kaplan–Meier plot of time to recurrence for CDKN2A altered vs. non-CDKN2A altered patients (p = 0.09). f Kaplan–Meier plot of time to treatment failure for first line systemic chemotherapy for CDKN2A altered vs. non-CDKN2A altered patients (p = 0.29)

Fig. 3

Clinical outcomes for TCGA soft tissue sarcoma patients (n = 206). a Kaplan–Meier curve of overall survival for CDKN2A altered versus non-CDKN2A altered patients (Cox Proportional Hazards adjusted for age, stage, and tumor size, p = 0.002). b Kaplan–Meier curve of survival by sarcoma histologies shows no significant difference in survival overall (p = 0.392). c Histologic distribution of patients who are CDKN2A wild type c versus CDKN2A altered d shows increase in proportion of MPNST, MFS, and UPS with decrease in LMS and DDLPS

Fig. 4

Frequency of CDKN2A mutations per histologic sarcoma type in Foundation Medicine dataset (n = 7733). Copy number changes (orange) dominate the mutational landscape with infrequent occurrences of SNVs (green) and rearrangements (purple). The overall prevalence of CDKN2A mutations in sarcoma (left most bar) is 16.7% (n = 7733), with the highest mutated tumor being MPNST (60.7%, n = 262) followed by myxofibrosarcoma (29.3%, n = 140), and undifferentiated pleomorphic sarcoma (26.8%, n = 372)