{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T02:58:30Z","timestamp":1767927510117,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The single\u2010arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed\/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4\u00a0months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer\u2010related genes was examined. Responder\u2010 versus nonresponder\u2010associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing \u201cpredicted nonresponders\u201d set and were evaluated with 10\u2010fold cross\u2010validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to &gt;500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in &gt;10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder\u2010associated genes <jats:italic>FANCA<\/jats:italic>, <jats:italic>HISTH1B<\/jats:italic>, <jats:italic>ANXA6<\/jats:italic>, <jats:italic>BTG1<\/jats:italic>, and <jats:italic>PARP10<\/jats:italic>, highlighting the importance of functions outside of B\u2010cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle\/proliferation, and cell motility\/invasiveness. While nonresponder\u2010associated genes included well\u2010known <jats:italic>TP53<\/jats:italic> and <jats:italic>CARD11<\/jats:italic>, genetic classifiers developed using nonresponder\u2010associated genes included <jats:italic>ATP6AP1<\/jats:italic>, <jats:italic>EP400<\/jats:italic>, <jats:italic>ARID1A<\/jats:italic>, <jats:italic>SOCS1<\/jats:italic>, and <jats:italic>TBL1XR1<\/jats:italic>, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer\u2010associated signaling pathways (mTOR, JAK\/STAT, NF\u2010\u03baB).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder\u2010associated genes, which warrants further investigation.<\/jats:p><jats:p><jats:bold>Trial registration<\/jats:bold>: NCT01779791.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.4422","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T06:15:48Z","timestamp":1637216148000},"page":"61-73","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of a genetic signature enriching for response to ibrutinib in relapsed\/refractory follicular lymphoma in the DAWN phase 2 trial"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2018-2094","authenticated-orcid":false,"given":"Sriram","family":"Balasubramanian","sequence":"first","affiliation":[{"name":"Janssen Research &amp; 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Development Spring House Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Sun","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilles","family":"Salles","sequence":"additional","affiliation":[{"name":"Hospices Civils de Lyon Universit\u00e9 de Lyon Pierre\u2010B\u00e9nite Cedex, Lyon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajay K.","family":"Gopal","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Department of Medicine The University of Washington Seattle Washington USA"},{"name":"Clinical Research Division Fred Hutchinson Cancer Research Center Lymphoma Program Seattle Cancer Care Alliance Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx020"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21357"},{"key":"e_1_2_9_4_1","unstructured":"National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology. 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