Stefano Caruso1, Julien Calderaro2, Eric Letouzé1, Jean-Charles Nault3, Gabrielle Couchy1, Anaïs Boulai1, Alain Luciani4, Elie-Serge Zafrani5, Paulette Bioulac-Sage6, Olivier Seror7, Sandrine Imbeaud1, Jessica Zucman-Rossi8. 1. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France. 2. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France; Université Paris-Est Créteil, 94010 Créteil, France. 3. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France; AP-HP, Hôpitaux Universitaires Paris-Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France. 4. AP-HP, Department of Medical Imaging, CHU Henri Mondor, Créteil, France. 5. AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France. 6. INSERM, UMR 1053, Bordeaux, France; Université de Bordeaux, Bordeaux, France; CHU de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France. 7. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; AP-HP, Radiology Department, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy, France. 8. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
Abstract
BACKGROUND & AIMS: Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence. METHODS: We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs). RESULTS: A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations (p=0.03). miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations. CONCLUSIONS: Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation. LAY SUMMARY: DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs.
BACKGROUND & AIMS: Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence. METHODS: We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs). RESULTS: A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations (p=0.03). miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations. CONCLUSIONS: Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation. LAY SUMMARY:DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs.
Authors: Alisa M Goldstein; Elizabeth M Gillanders; Melissa Rotunno; Rolando Barajas; Mindy Clyne; Elise Hoover; Naoko I Simonds; Tram Kim Lam; Leah E Mechanic Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-05-28 Impact factor: 4.254
Authors: Kai Zhang; Yotsawat Pomyen; Anna E Barry; Sean P Martin; Subreen Khatib; Lucy Knight; Marshonna Forgues; Dana A Dominguez; Ravinder Parhar; Ashesh P Shah; Adam S Bodzin; Xin Wei Wang; Hien Dang Journal: Mol Cancer Res Date: 2020-01-15 Impact factor: 5.852
Authors: Andreas von Deimling; Christian Koelsche; Felix K F Kommoss; Damian Stichel; Jaume Mora; Manel Esteller; David T W Jones; Stefan M Pfister; Eva Brack; Marco Wachtel; Peter Karl Bode; Hans-Peter Sinn; Dietmar Schmidt; Thomas Mentzel; Friedrich Kommoss; Felix Sahm Journal: Mod Pathol Date: 2021-04-12 Impact factor: 7.842