دورية أكاديمية
Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma.
العنوان: | Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma. |
---|---|
المؤلفون: | Jagosky MH; Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Anderson CJ; Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA., Symanowski JT; Department of Biostatistics, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Steuerwald NM; The Molecular Biology and Genomics Laboratory, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Farhangfar CJ; LCI Translational Research, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Baldrige EA; LCI Research Support, Clinical Trials Office, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Benbow JH; City of Hope Comprehensive Cancer Center, Duarte, California, USA., Livingston MB; Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Patt JC; Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA., Ahrens WA; Department of Pathology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health, Charlotte, North Carolina, USA., Kneisl JS; Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health, Charlotte, North Carolina, USA., Kim ES; City of Hope Comprehensive Cancer Center, Duarte, California, USA. |
المصدر: | Cancer medicine [Cancer Med] 2023 Mar; Vol. 12 (6), pp. 7029-7038. Date of Electronic Publication: 2022 Dec 04. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: John Wiley & Sons Ltd Country of Publication: United States NLM ID: 101595310 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2045-7634 (Electronic) Linking ISSN: 20457634 NLM ISO Abbreviation: Cancer Med Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Malden, MA] : John Wiley & Sons Ltd., c2012- |
مواضيع طبية MeSH: | Liposarcoma*/genetics , Liposarcoma*/diagnosis , Liposarcoma*/pathology, Humans ; In Situ Hybridization, Fluorescence ; Retrospective Studies ; Prognosis ; Genomics ; Proto-Oncogene Proteins c-mdm2/genetics |
مستخلص: | 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. (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.) |
References: | Fletcher CDM, Hogendoorn P, Mertens F. WHO Classification of Tumors of Soft Tissue and Bone. IARC Press; 2013:321-324. Singer S, Antonescu CR, Riedel E, Brennan MF. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg. 2003;238(3):358-370. discussion 370-1. Patt A, Demoret B, Stets C, et al. MDM2-dependent rewiring of metabolomic and lipidomic profiles in dedifferentiated liposarcoma models. Cancers (Basel). 2020;12(8):2157. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41(18):2853-2860. Bramwell VH, Anderson D, Charette ML; Sarcoma Disease Site Group. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev. 2003;2003(3):CD003293. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-423. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793. Schoffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12(11):1045-1052. Call JW, Wang Y, Montoya D, Scherzer NJ, Heinrich MC. Survival in advanced GIST has improved over time and correlates with increased access to post-imatinib tyrosine kinase inhibitors: results from life raft group registry. Clin Sarcoma Res. 2019;9:4. Keung EZ, Somaiah N. Overview of liposarcomas and their genomic landscape. J Transl Genet Genom. 2019;3:8. Dei Tos AP, Doglioni C, Piccinin S, et al. Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. J Pathol. 2000;190(5):531-536. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1. Agarwal P, Sandey M, DeInnocentes P, Bird RC. Tumor suppressor gene p16/INK4A/CDKN2A-dependent regulation into and out of the cell cycle in a spontaneous canine model of breast cancer. J Cell Biochem. 2013;114(6):1355-1363. Kim YJ, Kim M, Park HK, et al. Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology. Lab Invest. 2019;99(9):1309-1320. Gahvari Z, Parkes A. Dedifferentiated liposarcoma: systemic therapy options. Curr Treat Options Oncol. 2020;21(2):15. MedlinePlus. CDKN2A gene. 2020. Xiao YF, Yong X, Tang B, et al. Notch and Wnt signaling pathway in cancer: crucial role and potential therapeutic targets (review). Int J Oncol. 2016;48(2):437-449. Morishita A, Zaidi MR, Mitoro A, et al. HMGA2 is a driver of tumor metastasis. Cancer Res. 2013;73(14):4289-4299. Mo D, Zhao Y, Balajee AS. Human RecQL4 helicase plays multifaceted roles in the genomic stability of normal and cancer cells. Cancer Lett. 2018;413:1-10. Lao VV, Welcsh P, Luo Y, et al. Altered RECQ helicase expression in sporadic primary colorectal cancers. Transl Oncol. 2013;6(4):458-469. Maire G, Yoshimoto M, Chilton-MacNeill S, Thorner PS, Zielenska M, Squire JA. Recurrent RECQL4 imbalance and increased gene expression levels are associated with structural chromosomal instability in sporadic osteosarcoma. Neoplasia. 2009;11(3):260-268. 3p following 268. Ragel BT, Jensen RL. Molecular genetics of meningiomas. Neurosurg Focus. 2005;19(5):E9. Pei J, Zhao X, Patchefsky AS, et al. Clinical application of RNA sequencing in sarcoma diagnosis: an institutional experience. Medicine (Baltimore). 2019;98(25):e16031. Gromley A, Jurczyk A, Sillibourne J, et al. A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase. J Cell Biol. 2003;161(3):535-545. Ren M, Qin H, Kitamura E, Cowell JK. Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models. Blood. 2013;122(6):1007-1016. Yadav RK, Chauhan AS, Zhuang L, Gan B. FoxO transcription factors in cancer metabolism. Semin Cancer Biol. 2018;50:65-76. Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene. 2008;27(16):2312-2319. Liu Y, Ao X, Ding W, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104. Hornsveld M, Dansen TB, Derksen PW, Burgering BMT. Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol. 2018;50:90-100. Song SS, Ying JF, Zhang YN, et al. High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma. Oncol Lett. 2020;19(4):3181-3188. NCBI. MAML2 mastermind like transcriptional coactivator 2 [Homo sapiens (human)] [updated 06/06/2021]. Boddu S, Walko CM, Bienasz S, et al. Clinical utility of genomic profiling in the treatment of advanced sarcomas: a single-center experience. JCO Precis Oncol. 2018;2:1-8. Groisberg R, Hong DS, Holla V, et al. Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas. Oncotarget. 2017;8(24):39254-39267. Asano N, Yoshida A, Mitani S, et al. Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/dedifferentiated liposarcoma. Oncotarget. 2017;8(8):12941-12952. Bauer T, Gounder M, Weise A, et al. A phase 1 study of MDM2 inhibitor DS-3032b in patients with well/de-differentiated liposarcoma (WD/DD LPS), solid tumors (ST) and lymphomas (L). J Clin Oncol. 2018;36:11514. Fang DD, Tang Q, Kong Y, et al. MDM2 inhibitor APG-115 synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment. J Immunother Cancer. 2019;7(1):327. Laroche-Clary A, Chaire V, Algeo MP, Derieppe MA, Loarer FL, Italiano A. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. J Hematol Oncol. 2017;10(1):123. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor Palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937-940. Phase II Trial of Ribociclib and Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS): ClinicalTrials.gov; [updated 07/29/2020]. Available from: https://clinicaltrials.gov/ct2/show/NCT03114527. Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery: ClinicalTrials.gov; [updated 12/22/2020]. Available from: https://clinicaltrials.gov/ct2/show/NCT03009201. Stojadinovic A, Yeh A, Brennan MF. Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcomes. J Am Coll Surg. 2002;194(4):436-447. |
فهرسة مساهمة: | Keywords: NGS; liposarcoma; next-generation sequencing; precision oncology; targeted therapy |
المشرفين على المادة: | EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) |
تواريخ الأحداث: | Date Created: 20221205 Date Completed: 20230405 Latest Revision: 20230409 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC10067084 |
DOI: | 10.1002/cam4.5502 |
PMID: | 36464833 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2045-7634 |
---|---|
DOI: | 10.1002/cam4.5502 |