{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:38:21Z","timestamp":1774330701530,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T00:00:00Z","timestamp":1594080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (<jats:italic>FH<\/jats:italic>) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome\u2010associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome\u2010associated RCC exhibited an unusual morphology with accumulation of \u201ccolloid\u2010like\u201d cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next\u2010generation sequencing analyses of HLRCC syndrome\u2010associated RCC and leiomyomas in our patients revealed divergent genetic changes in the <jats:italic>FH<\/jats:italic> gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a <jats:italic>FH<\/jats:italic> loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC\u2010RCC showed a second, undescribed NM_000143.3; c.947C&gt;T; p.Ala316Val <jats:italic>FH<\/jats:italic> mutation accompanying the preexisting splice site mutation c.378+2T&gt;C. In the other HLRCC syndrome\u2010associated RCC, the <jats:italic>FH<\/jats:italic> mutation (NM_000143.3; c.462T&gt;G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC \u2010 and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome\u2010associated RCC, both cases were treated in first line with bevacizumab\/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the \u201csecond hit\u201d hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.<\/jats:p>","DOI":"10.1002\/gcc.22878","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T05:15:29Z","timestamp":1592198129000},"page":"611-619","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in <scp>HLRCC<\/scp> syndrome patients with a tailored therapeutic approach"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8702-7091","authenticated-orcid":false,"given":"Nicolas","family":"Wyvekens","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadejda","family":"Valtcheva","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel","family":"Mischo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Helmchen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hermanns","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Choschzick","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas M.","family":"H\u00f6tker","sequence":"additional","affiliation":[{"name":"Institute of Diagnostic and Interventional Radiology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Rauch","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics (IMG), University of Zurich  Schlieren\u2010Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beda","family":"M\u00fchleisen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dilara","family":"Akhoundova","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achim","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"},{"name":"Institute of Molecular Cancer Research (IMCR) University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Moch","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7043-3456","authenticated-orcid":false,"given":"Niels J.","family":"Rupp","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,7,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.051633798"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61757-9"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.02.029"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2019-205924"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","unstructured":"LauHD ChanE FanAC et al.A Clinicopathologic and molecular analysis of fumarate 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