PMID- 36464833 OWN - NLM STAT- MEDLINE DCOM- 20230405 LR - 20230409 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 12 IP - 6 DP - 2023 Mar TI - Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma. PG - 7029-7038 LID - 10.1002/cam4.5502 [doi] AB - PURPOSE: Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. EXPERIMENTAL DESIGN: Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. RESULTS: Thirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). CONCLUSIONS: This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications. CI - (c) 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Jagosky, Megan H AU - Jagosky MH AD - Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Anderson, Colin J AU - Anderson CJ AD - Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA. FAU - Symanowski, James T AU - Symanowski JT AD - Department of Biostatistics, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Steuerwald, Nury M AU - Steuerwald NM AD - The Molecular Biology and Genomics Laboratory, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Farhangfar, Carol J AU - Farhangfar CJ AD - LCI Translational Research, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Baldrige, Emily A AU - Baldrige EA AD - LCI Research Support, Clinical Trials Office, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Benbow, Jennifer H AU - Benbow JH AD - City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Livingston, Michael B AU - Livingston MB AD - Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Patt, Joshua C AU - Patt JC AD - Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA. FAU - Ahrens, Will A AU - Ahrens WA AD - Department of Pathology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA. FAU - Kneisl, Jeffrey S AU - Kneisl JS AD - Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA. FAU - Kim, Edward S AU - Kim ES AD - City of Hope Comprehensive Cancer Center, Duarte, California, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221204 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) SB - IM MH - Humans MH - In Situ Hybridization, Fluorescence MH - Retrospective Studies MH - Prognosis MH - *Liposarcoma/genetics/diagnosis/pathology MH - Genomics MH - Proto-Oncogene Proteins c-mdm2/genetics PMC - PMC10067084 OTO - NOTNLM OT - NGS OT - liposarcoma OT - next-generation sequencing OT - precision oncology OT - targeted therapy COIS- There are no financial disclosures or conflicts of interest. EDAT- 2022/12/06 06:00 MHDA- 2023/04/05 06:42 PMCR- 2022/12/04 CRDT- 2022/12/05 00:42 PHST- 2022/10/20 00:00 [revised] PHST- 2022/07/13 00:00 [received] PHST- 2022/11/19 00:00 [accepted] PHST- 2023/04/05 06:42 [medline] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/05 00:42 [entrez] PHST- 2022/12/04 00:00 [pmc-release] AID - CAM45502 [pii] AID - 10.1002/cam4.5502 [doi] PST - ppublish SO - Cancer Med. 2023 Mar;12(6):7029-7038. doi: 10.1002/cam4.5502. Epub 2022 Dec 4.