Genomics of Liver Tumors
We study 3 types of solid tumors using genomic approaches to better understand their molecular and clinical heterogeneity and develop new diagnostic and prognostic markers. For this we use the last advanced technologies in molecular biology associated to our expertise in bioinformatic.
The various activities of our lab and its members
The laboratory will be very well represented during this first symposium organized by SIRIC CARPEM, Paris Descartes university and the prestigious Mayo Clinic next November.
Organized by Pr Gérard Friedlander, Pr Pierre Laurent-Puig & Pr Jessica Zucman-Rossi the symposium will focused on Digestive Oncology and will be an opportunity to promote and set up new collaborations between international digestive oncology experts.
Don’t forget the 2nd HTE Workshop organized by Olivier Saut (INRIA Bordeaux) and Yannick Ladeiro from our lab. This event is organized in the field of HTE Program, coordinated by our team leader, Jessica Zucman-Rossi, and will focus on mathematical and computer modeling in order to study tumoral heterogeneity.
Didier Jean team have just published a new paper in Lung Cancer. In this work the investigated anti-tumor effect of eight major signaling pathways inhibitors involved in malignant pleural mesothelioma (MPM) carcinogenesis. They found that three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor.
Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors.
We are very proud to receive, with Pr Pascale COSSART, the 2018 René & Andrée Price from Ligue Contre le Cancer past Monday at Institut Pasteur.
Remise du Prix René et Andrée Duquesne de @LigueCancer75 hier à l' @institutpasteur au Professeur Jessica ZUCMAN -ROSSI pour ses travaux remarquables sur les #cancers hépatiques. pic.twitter.com/9bEAQwi4JM
— Ligue Cancer Paris (@LigueCancer75) 11 septembre 2018
We recently identified a novel histological subtype of hepatocellular carcinoma, designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this novel variant, we aimed to investigate its prognostic value in two large series of patients with HCC treated either by surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than 6 cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, AFP level, satellite nodules and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: OR 3.03 (1.38-6.65), p=0.006 and 2.76 (1.63-4.67), p<0.001); RFA series: 2.37 (1.36-4.13), p=0.002 and 2.19 (1.35-3.54), p=0.001, respectively). Its prognostic value was retained even after patients stratification according to common clinical, biological and pathological features of aggressiveness. No other baseline parameter was independently associated to recurrence in the RFA series. The MTM-HCC subtype, reliably observed in 12% of patients eligible for a curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies.
Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogenous cellular processes. With a diversity of risk factors, liver cancer is an ideal model to study these interactions. Here, we analyze the whole genomes of 44 new and 264 published liver cancers and we identify 10 mutational and 6 structural rearrangement signatures showing distinct relationships with environmental exposures, replication, transcription, and driver genes. The liver cancer-specific signature 16, associated with alcohol, displays a unique feature of transcription-coupled damage and is the main source of CTNNB1 mutations. Flood of insertions/deletions (indels) are identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture reveals mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin B1 signature in African migrants. Finally, chromosome duplications occur late and may represent rate-limiting events in tumorigenesis. These findings shed new light on the natural history of liver cancers.
Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively....
Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes...