{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:38:20Z","timestamp":1780616300187,"version":"3.54.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Med Case Reports"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (<jats:italic>ARID1A<\/jats:italic>) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand\u00a01 (PD-L1) expression. This is the first case report in lung adenocarcinoma of <jats:italic>ARID1A<\/jats:italic> gene alterations leading to sporadic MSI, through somatic mutL homolog\u00a01 (<jats:italic>MLH1<\/jats:italic>) promoter methylation, with an <jats:italic>MLH1<\/jats:italic> gene mutation as the second somatic hit.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in <jats:italic>ARID1A<\/jats:italic> gene, rearranged during transfection (<jats:italic>RET<\/jats:italic>) gene fusions, epidermal growth factor receptor (<jats:italic>EGFR<\/jats:italic>) gene R776H mutation, breast cancer (<jats:italic>BRCA<\/jats:italic>) genes 1\/2, and cyclin-dependent kinase inhibitor 2A (<jats:italic>CDKN2A<\/jats:italic>) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19\u00a0months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8<jats:sup>+<\/jats:sup> T\u00a0cells expression and showed MSI with a deleterious c.298C&gt;T (p.R100*) <jats:italic>MLH1<\/jats:italic> gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled <jats:italic>MLH1<\/jats:italic> gene promoter methylation. The <jats:italic>MLH1<\/jats:italic> gene mutation and the <jats:italic>MLH1<\/jats:italic> gene methylation were not present at the germline setting.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In this particular case, we show that <jats:italic>ARID1A<\/jats:italic> gene mutations with sporadic MSI due to somatic <jats:italic>MLH1<\/jats:italic> gene promoter methylation and <jats:italic>MLH1<\/jats:italic> gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against <jats:italic>ARID1A<\/jats:italic> mutations and epigenomic methylation when involved in MSI neoplasms.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13256-020-02589-1","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T23:22:42Z","timestamp":1613863362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report"],"prefix":"10.1186","volume":"15","author":[{"given":"Mercedes","family":"Dur\u00e1n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Faull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Lastra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Francois","family":"Laes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Bel\u00e9n","family":"Rodrigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"S\u00e1nchez-Escribano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"2589_CR1","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1056\/NEJMoa1507643","volume":"373","author":"H Borghaei","year":"2015","unstructured":"Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627\u201339.","journal-title":"N Engl J Med"},{"key":"2589_CR2","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/s41591-018-0012-z","volume":"24","author":"J Shen","year":"2018","unstructured":"Shen J, Ju Z, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24:556\u201362.","journal-title":"Nat Med"},{"key":"2589_CR3","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1016\/j.cell.2012.08.029","volume":"150","author":"M Imielinski","year":"2012","unstructured":"Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107\u201320.","journal-title":"Cell"},{"key":"2589_CR4","doi-asserted-by":"publisher","first-page":"e255","DOI":"10.1016\/j.jtho.2018.07.099","volume":"13","author":"N Karachaliou","year":"2018","unstructured":"Karachaliou N, Paulina Bracht JW, Rosell R. ARID1A gene driver mutations in lung adenocarcinomas. J Thorac Oncol. 2018;13:e255\u20137.","journal-title":"J Thorac Oncol"},{"key":"2589_CR5","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.aan6733","volume":"357","author":"DT Le","year":"2017","unstructured":"Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409\u201313.","journal-title":"Science"},{"key":"2589_CR6","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1200\/JCO.19.00818","volume":"38","author":"NS Azad","year":"2020","unstructured":"Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: results from arm Z1D-A subprotocol of the NCI-MATCH (EAY131) study. J Clin Oncol. 2020;38:214\u201322.","journal-title":"J Clin Oncol"},{"issue":"15_Suppl","key":"2589_CR7","doi-asserted-by":"publisher","first-page":"e14624","DOI":"10.1200\/JCO.2019.37.15_suppl.e14624","volume":"37","author":"J Wei","year":"2019","unstructured":"Wei J, Zhang J, Wen Q, et al. The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients. J Clin Oncol. 2019;37(15_Suppl):e14624.","journal-title":"J Clin Oncol"},{"issue":"11","key":"2589_CR8","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1038\/modpathol.2013.96","volume":"26","author":"T Bosse","year":"2013","unstructured":"Bosse T, ter Haar NT, Seeber LM, et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod Pathol. 2013;26(11):1525\u201335.","journal-title":"Mod Pathol"},{"key":"2589_CR9","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1158\/1078-0432.CCR-1118-3","volume":"10","author":"G Deng","year":"2004","unstructured":"Deng G, Bell I, Crawley S, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10:191\u20135.","journal-title":"Clin Cancer Res"},{"key":"2589_CR10","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1056\/NEJMoa064522","volume":"356","author":"MP Hitchins","year":"2007","unstructured":"Hitchins MP, Wong JJ, Suthers G, et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med. 2007;356:697\u2013705.","journal-title":"N Engl J Med"},{"key":"2589_CR11","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1002\/gcc.20678","volume":"48","author":"RC Niessen","year":"2009","unstructured":"Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009;48:737\u201344.","journal-title":"Genes Chromosomes Cancer"},{"key":"2589_CR12","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.1200\/JCO.18.00328","volume":"36","author":"TP Slavin","year":"2018","unstructured":"Slavin TP, Banks KC, Chudova D, et al. Identification of incidental germline mutations in patients with advanced solid tumors who underwent cell-free circulating cell-free DNA sequencing. J Clin Oncol. 2018;36:3459\u201365.","journal-title":"J Clin Oncol"},{"key":"2589_CR13","first-page":"1","volume":"3","author":"RS Nelson","year":"2019","unstructured":"Nelson RS, Mehta RJ, McLeod HL, et al. Prioritization of therapy options for a patient with high tumor mutation burden and microsatellite instability but no clinical benefit from immunotherapy. JCO Precision Oncol. 2019;3:1\u20137.","journal-title":"JCO Precision Oncol"},{"issue":"6","key":"2589_CR14","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1158\/0008-5472.CAN-18-3126","volume":"79","author":"E Cocco","year":"2019","unstructured":"Cocco E, Benhamida J, Midda S, et al. Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF\/KRAS are enriched for targetable kinase fusions. Can Res. 2019;79(6):1047\u201353.","journal-title":"Can Res"},{"key":"2589_CR15","doi-asserted-by":"publisher","first-page":"39945","DOI":"10.18632\/oncotarget.18098","volume":"8","author":"S Deihimi","year":"2017","unstructured":"Deihimi S, Lev A, Slifker M, et al. BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations. Oncotarget. 2017;8:39945\u201362.","journal-title":"Oncotarget"},{"key":"2589_CR16","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1158\/2159-8290.CD-14-0849","volume":"5","author":"J Shen","year":"2015","unstructured":"Shen J, Peng Y, Wei L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 2015;5:752\u201367.","journal-title":"Cancer Discov"},{"key":"2589_CR17","doi-asserted-by":"publisher","first-page":"698","DOI":"10.3892\/ijmm.2015.2269","volume":"36","author":"W Wang","year":"2015","unstructured":"Wang W, Wang J, Li M, et al. 5-Azacitidine induces demethylation of PTPL1 and inhibits growth in non-Hodgkin lymphoma. Int J Mol Med. 2015;36:698\u2013704.","journal-title":"Int J Mol Med"},{"issue":"7","key":"2589_CR18","doi-asserted-by":"publisher","first-page":"678","DOI":"10.3390\/cells8070678","volume":"8","author":"L Li","year":"2019","unstructured":"Li L, Li M, Jiang Z, et al. ARID1a mutations are associated with increased immune activity in gastrointestinal cancer. Cells. 2019;8(7):678.","journal-title":"Cells"}],"container-title":["Journal of Medical Case Reports"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-020-02589-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13256-020-02589-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-020-02589-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T23:24:01Z","timestamp":1613863441000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmedicalcasereports.biomedcentral.com\/articles\/10.1186\/s13256-020-02589-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":18,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2589"],"URL":"https:\/\/doi.org\/10.1186\/s13256-020-02589-1","relation":{},"ISSN":["1752-1947"],"issn-type":[{"value":"1752-1947","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,19]]},"assertion":[{"value":"21 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki. The case report is part of the project \u201cOncoDeep Immune RNA-seq panel for predicting response to immunotherapy in recurrent locally advanced or metastatasic, NSCLC: a pilot study\u201d approved by the ethical committee of Complejo Asistencial Universitario de Burgos.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"89"}}