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To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of <jats:italic>TET2<\/jats:italic> (86%), <jats:italic>CD274<\/jats:italic> (53%), <jats:italic>TNFRSF14<\/jats:italic> (53%), and <jats:italic>TNFAIP3<\/jats:italic> (30%) in thyroid MALT lymphoma. <jats:italic>CD274<\/jats:italic> was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between <jats:italic>CD274<\/jats:italic> mutation\/deletion and <jats:italic>TNFRSF14<\/jats:italic> mutation (<jats:italic>p<\/jats:italic>\u2009=\u20090.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+\/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with <jats:italic>CD274<\/jats:italic>\/<jats:italic>TNFRSF14<\/jats:italic> genetic abnormalities than those without these changes. Both <jats:italic>CD274<\/jats:italic> and <jats:italic>TNFRSF14<\/jats:italic> genetic changes were significantly associated with Hashimoto\u2019s thyroiditis (<jats:italic>p<\/jats:italic>\u2009=\u20090.01, <jats:italic>p<\/jats:italic>\u2009=\u20090.04, respectively), and <jats:italic>CD274<\/jats:italic> mutation\/deletion additionally associated with increased erythrocyte sedimentation rate (<jats:italic>p<\/jats:italic>\u2009=\u20090.0001). In conclusion, <jats:italic>CD274<\/jats:italic>\/<jats:italic>TNFRSF14<\/jats:italic> inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.<\/jats:p>","DOI":"10.1038\/s41375-021-01289-z","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T09:03:46Z","timestamp":1621587826000},"page":"3497-3508","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Thyroid MALT lymphoma: self-harm to gain potential T-cell help"],"prefix":"10.1038","volume":"35","author":[{"given":"Fangtian","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Myrsini","family":"Tzioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0629-3927","authenticated-orcid":false,"given":"Ayse","family":"Akarca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cucco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Carmell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeduk Yoshimura","family":"Noh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Dobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-1041","authenticated-orcid":false,"given":"Sarah","family":"Moody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6021-5044","authenticated-orcid":false,"given":"Jessica","family":"Okosun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Chott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingwen","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Sung","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-5802","authenticated-orcid":false,"given":"Markus","family":"Raderer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Yong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Marafioti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1017-5045","authenticated-orcid":false,"given":"Ming-Qing","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"1289_CR1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.semcancer.2016.07.003","volume":"39","author":"MQ Du","year":"2016","unstructured":"Du MQ. 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