TY - JOUR
T1 - Undifferentiated sarcomas in children harbor clinically relevant oncogenic fusions and gene copy-number alterations
T2 - A report from the children's oncology group
AU - Laetsch, Theodore W.
AU - Roy, Angshumoy
AU - Xu, Lin
AU - Black, Jennifer O.
AU - Coffin, Cheryl M.
AU - Chi, Yueh Yun
AU - Tian, Jing
AU - Spunt, Sheri L.
AU - Hawkins, Douglas S.
AU - Bridge, Julia A.
AU - Williams Parsons, D.
AU - Skapek, Stephen X.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/8/15
Y1 - 2018/8/15
N2 - 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 ¼ 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q ¼ 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.
AB - 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 ¼ 0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q ¼ 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.
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U2 - 10.1158/1078-0432.CCR-18-0672
DO - 10.1158/1078-0432.CCR-18-0672
M3 - Article
C2 - 29691299
AN - SCOPUS:85051432950
SN - 1078-0432
VL - 24
SP - 3888
EP - 3897
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -