{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:52:40Z","timestamp":1791424360366,"version":"4.3.3"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T00:00:00Z","timestamp":1694044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005302","name":"Alexander S. Onassis Public Benefit Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005302","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Although <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> inactivating mutations that lead to mTORC1 hyperactivation have been reported in hepatic angiomyolipomas (hAML), the role of other somatic genetic events that may contribute to hAML development is unknown. There are also limited data regarding the tumour microenvironment (TME) of hAML. The aim of the present study was to identify other somatic events in genomic level and changes in TME that contribute to tumorigenesis in hAML.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>In this study, we performed exome sequencing in nine sporadic hAML tumours and deep\u2010coverage targeted sequencing for <jats:italic>TSC2<\/jats:italic> in three additional hAML. Immunohistochemistry and multiplex immunofluorescence were carried out for\u00a015 proteins to characterise the tumour microenvironment and assess immune cell infiltration. Inactivating somatic variants in <jats:italic>TSC2<\/jats:italic> were identified in 10 of 12 (83%) cases, with a median allele frequency of 13.6%. Five to 18 somatic variants (median number: nine, median allele frequency 21%) not in <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> were also identified, mostly of uncertain clinical significance. Copy number changes were rare, but detection was\u00a0impaired by low tumour purity. Immunohistochemistry demonstrated numerous CD68+ macrophages of distinct appearance from K\u00fcpffer cells. Multiplex immunofluorescence revealed low numbers of exhausted PD\u20101+\/PD\u2010L1+, FOXP3+ and CD8+ T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>hAML tumours have consistent inactivating mutations in <jats:italic>TSC2<\/jats:italic> and have a low somatic mutation rate, similar to other TSC\u2010associated tumours. Careful histological review, standard IHC and multiplex immunofluorescence demonstrated marked infiltration by non\u2010neoplastic inflammatory cells, mostly macrophages.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.15005","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T01:36:48Z","timestamp":1694137008000},"page":"569-581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp><i>TSC2<\/i><\/scp> inactivation, low mutation burden and high macrophage infiltration characterise hepatic angiomyolipomas"],"prefix":"10.1111","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9633-3541","authenticated-orcid":false,"given":"Krinio","family":"Giannikou","sequence":"first","affiliation":[{"name":"Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"},{"name":"Cancer Genome Program 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