Undifferentiated Sarcomas in Children Harbor Clinically Relevant Oncogenic Fusions and Gene Copy-Number Alterations: A Report from the Children's Oncology Group

Abstract

Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy-number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332.Experimental Design: Copy-number alterations were assessed by OncoScan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from eight tumors with sufficient archived material were sequenced on HiSeq (2 × 100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases.Results: Five-year overall survival for patients with UDS was 83% (95% CI, 69%-97%) with risk-adapted therapy (surgery, chemotherapy, and radiotherapy). Both focal and arm-level copy-number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high-risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a 5-year event-free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q = 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q = 0.07). Known oncogenic fusions were identified in eight of 10 cases analyzed by next-generation sequencing.Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy-number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS, and next-generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers. Clin Cancer Res; 24(16); 3888-97. ©2018 AACR.

Figure 1:

Consort flow diagram. The 32 patients with undifferentiated sarcoma enrolled on ARST0332 with slides available for copy number analysis were analyzed here.

Figure 2:

Event free and overall survival for all 32 patients with undifferentiated sarcoma (A), event free survival by risk group (B), overall survival by risk group (C). Event free (D) and overall survival (E) by morphologic subtype. Int = Intermediate

Figure 3:

Recurrent copy number gains and losses in all tumors, and in tumors classified as primarily round cell or spindle cell variants.

Figure 4:

Event free survival (top) and overall survival (bottom) of patients with and without loss of 1p (A), gain of 1q (B), gain of chromosome 2 (C), gain of chromosome 8 (D), and both loss of 1p and gain of 1q (E).