{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T03:38:50Z","timestamp":1764733130074,"version":"3.41.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The role of FAT1 mutations in acute myeloid leukemia (AML) remains unclear, particularly regarding their impact on the chemosensitivity of AML patients. To elucidate the effect of FAT1 mutations on the therapeutic outcomes and prognosis of AML patients, we conducted this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To analyze the impact of FAT1 mutations, we obtained data from the LAML-KR cohort of the International Cancer Genome Consortium (ICGC), consisting of 205 patients. Additionally, we retrospectively collected data from 108 primary AML patients who received initial induction chemotherapy with a venetoclax combination regimen between January 2019 and December 2023 at Qingdao Medical College Affiliated Hospital and Shengli Oilfield Central Hospital (referred to as the Venetoclax-AML cohort). We analyzed the characteristics, clinical features, and molecular genetic features of FAT1 mutations, and assessed the impact of FAT1 mutations on therapeutic outcomes and prognosis in both cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the public LAML-KR cohort (n = 205), the mutation rate of the FAT1 gene was approximately 15% (31\/205), with a nonsynonymous mutation rate of about 6%. Patients with FAT1 mutations (including synonymous mutations) exhibited a higher tumor mutation burden (TMB) compared to wild-type patients (p &amp;lt; 0.001). Further analysis of the 83 patients in the LAML-KR cohort with complete clinical data showed that the mutation rates of P53, DNMT3A, FLT3, and NPM1 genes (including synonymous mutations) were higher in the FAT1 mutant group than in the wild-type group (p &amp;lt; 0.05). In our retrospective Venetoclax-AML cohort (n = 108), the nonsynonymous mutation rate of the FAT1 gene was approximately 13% (14\/108), which was higher than the mutation rate in the public LAML-KR cohort. Moreover, only the P53 mutation rate was higher in FAT1 mutant patients (p &amp;lt; 0.01), while the mutation rates of DNMT3A, FLT3, and NPM1 genes showed no significant difference between FAT1 mutant and wild-type patients (p &amp;gt; 0.05). In both the LAML-KR and Venetoclax-AML cohorts, FAT1 mutant patients showed better initial induction chemotherapy outcomes compared to wild-type patients. However, in the LAML-KR cohort, there was no improvement in overall survival (OS) for FAT1 mutant patients (median survival time: 34.6 months vs. 41.7 months, p = 0.6757), whereas there was a trend toward improved progression-free survival (PFS) in the Venetoclax-AML cohort (p = 0.103).Interestingly, further analysis of P53 mutant patients (n = 17) in the Venetoclax-AML cohort revealed that FAT1 mutant patients had better initial induction chemotherapy outcomes and a trend toward improved PFS compared to wild-type patients (p = 0.1381).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>AML patients with FAT1 mutations have better initial induction chemotherapy efficacy with venetoclax-based regimens compared to wild-type patients, and there is a trend toward improved PFS. This may be related to the improved efficacy and prognosis in P53 mutation-positive patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1456832","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T06:06:37Z","timestamp":1743401197000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The association of FAT1 mutations with therapeutic outcomes in AML, especially in receiving venetoclax combination"],"prefix":"10.3389","volume":"15","author":[{"given":"Tao","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junxia","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqian","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junting","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiwei","family":"Mou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.03.005","article-title":"AML treatment: conventional chemotherapy and emerging novel agents","volume":"45","author":"Forsberg","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.v127.12","article-title":"De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017","volume":"127","author":"Sasaki","year":"2021","journal-title":"Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31694-5","article-title":"Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016\u201340 for 195 countries and territories","volume":"392","author":"Foreman","year":"2018","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13045-023-01424-6","article-title":"Recent advances in targeted therapies in acute myeloid leukemia","volume":"16","author":"Bhansali","year":"2023","journal-title":"J Hematol Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41408-023-00911-w","article-title":"Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors","volume":"13","author":"Short","year":"2023","journal-title":"Blood Cancer J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00509-w","article-title":"Towards precision medicine for AML","volume":"18","author":"D\u00f6hner","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"102549","DOI":"10.1016\/j.eclinm.2024.102549","article-title":"Survival of adult AML patients treated with chemotherapy in the U.S. population by age, race and ethnicity, sex, calendar-year period, and AML subgroup, 2001\u20132019","volume":"71","author":"Linet","year":"2024","journal-title":"eClinicalMedicine"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020004856","article-title":"Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial","volume":"135","author":"Wei","year":"2020","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3390\/cancers14010022","article-title":"Venetoclax in relapsed\/refractory acute myeloid leukemia: are supporting evidences enough","volume":"14","author":"Brancati","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(20)30210-6","article-title":"10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial","volume":"7","author":"DiNardo","year":"2020","journal-title":"Lancet Haematol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(24)00241-2","article-title":"Venetoclax plus decitabine as a bridge to allogeneic haematopoietic stem-cell transplantation in older patients with acute myeloid leukaemia (VEN-DEC GITMO): final report of a multicentre, single-arm, phase 2 trial","volume":"11","author":"Russo","year":"2024","journal-title":"Lancet Haematol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08137-x","article-title":"RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax","volume":"636","author":"Sango","year":"2024","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200508121","article-title":"The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals","volume":"173","author":"Hou","year":"2006","journal-title":"J Cell Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.905717","article-title":"The atypical cadherin FAT1 limits mitochondrial respiration and proliferation of vascular smooth muscle cells","volume":"9","author":"Riascos-Bernal","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200403006","article-title":"Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact","volume":"165","author":"Tanoue","year":"2004","journal-title":"J Cell Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1242\/dev.077461","article-title":"Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity","volume":"139","author":"Saburi","year":"2012","journal-title":"Development"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03046-1","article-title":"Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis","volume":"589","author":"Pastushenko","year":"2021","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S111176","article-title":"History and progression of Fat cadherins in health and disease","volume":"9","author":"Zhang","year":"2016","journal-title":"Onco Targets Ther"},{"key":"B20","doi-asserted-by":"publisher","first-page":"21598","DOI":"10.1038\/s41598-022-26008-1","article-title":"A pan-cancer analysis of the FAT1 in human tumors","volume":"12","author":"Wang","year":"2022","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"130519","DOI":"10.1016\/j.bbagen.2023.130519","article-title":"FAT1 inhibits AML autophagy and proliferation via downregulating ATG4B expression","volume":"1868","author":"Zhang","year":"2024","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-2727.2023.09.001","article-title":"Chinese guidelines for diagnosis and treatment of adult acute myeloid leukemia (not APL) (2023)","volume":"44","year":"2023","journal-title":"Zhonghua Xue Ye Xue Za Zhi"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"D\u00f6hner","year":"2022","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-05-646240","article-title":"Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse","volume":"126","author":"Garg","year":"2015","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.bbmt.2015.07.030","article-title":"DNMT3A R882 mutation with FLT3-ITD positivity is an extremely poor prognostic factor in patients with normal-karyotype acute myeloid leukemia after allogeneic hematopoietic cell transplantation","volume":"22","author":"Ahn","year":"2016","journal-title":"Biol Blood Marrow Transplant"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-3659","article-title":"The proteomic landscape of growth factor signaling networks associated with FAT1 mutations in head and neck cancers","volume":"81","author":"Chen","year":"2021","journal-title":"Cancer Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1090838","article-title":"Identification of tumor mutation burden-associated molecular and clinical features in cancer by analyzing multi-omics data","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"10732748221076682","DOI":"10.1177\/10732748221076682","article-title":"Prognostic and immunological role of FAT family genes in non-small cell lung cancer","volume":"29","author":"Feng","year":"2022","journal-title":"Cancer Control"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.155218","article-title":"Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer","volume":"7","author":"Mai","year":"2022","journal-title":"JCI Insight"},{"key":"B31","doi-asserted-by":"publisher","first-page":"110970","DOI":"10.1016\/j.celrep.2022.110970","article-title":"YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4","volume":"39","author":"Chen","year":"2022","journal-title":"Cell Rep"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1273798","article-title":"Tislelizumab plus nimotuzumab is effective against recurrent or metastatic oral squamous cell carcinoma among patients with a performance status score \u2265 2: a retrospective study","volume":"13","author":"Wu","year":"2024","journal-title":"Front Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007732","article-title":"Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia","volume":"137","author":"Uy","year":"2021","journal-title":"Blood"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009759","article-title":"Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-TCD123 in relapsed\/refractory AML","volume":"137","author":"Wermke","year":"2021","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(24)00033-4","article-title":"Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study","volume":"11","author":"Bazinet","year":"2024","journal-title":"Lancet Haematol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2020.07.038","article-title":"FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK\/ERK signaling pathway in esophageal squamous cell cancer","volume":"494","author":"Hu","year":"2020","journal-title":"Cancer Lett"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.061002","article-title":"Gain of oncogenic function of p53 mutants regulates E-cadherin expression uncoupled from cell invasion in colon cancer cells","volume":"123","author":"Roger","year":"2010","journal-title":"J Cell Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.870055","article-title":"FAT1 upregulates in oral squamous cell carcinoma and promotes cell proliferation via cell cycle and DNA repair","volume":"12","author":"Lan","year":"2022","journal-title":"Front Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13171","article-title":"Clinical significance of FAT1 gene mutation and mRNA expression in patients with head and neck squamous cell carcinoma","volume":"16","author":"Kim","year":"2022","journal-title":"Mol Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1456832\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T08:46:19Z","timestamp":1743583579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1456832\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":39,"alternative-id":["10.3389\/fonc.2025.1456832"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1456832","relation":{},"ISSN":["2234-943X"],"issn-type":[{"type":"electronic","value":"2234-943X"}],"subject":[],"published":{"date-parts":[[2025,3,31]]},"article-number":"1456832"}}