Intratumoral heterogeneity and clonal evolution in liver cancer

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution

Histological Grading of Hepatocellular Carcinoma—A Systematic Review of Literature

BackgroundHistological grading typically reflects the biological behavior of solid tumors, thus providing valuable prognostic information. This is also expected in hepatocellular carcinoma (HCC), although limited access to biopsy samples and a lack of standardization might hinder its full predictive value in this cancer.ObjectivesIn order to better understand the current practices of histological grading in HCC, we examined the latest publications addressing its impact on the outcome of patients following surgical treatment.MethodsWe searched the PubMed (MEDLINE) database under the headings “hepatocellular carcinoma,” “grade OR grading,” and “prognosis.” Qualitative and quantitative assessment of publications was performed according to the reference they used to grade their tumors (e.g., Edmondson–Steiner, World Health Organization).ResultsWe reviewed a total of 216 articles: 114 enclosed adequate information and were included herein. Among these, we found divergences and inaccuracies in the histological grade assessment of this cancer, which might have led to a non-standardized grade distribution, with further impact on data analysis. Nevertheless, in most of them, poor tumor differentiation correlated with worse prognosis, expressed by lower overall and/or disease-free survival.ConclusionWhile histological grading of HCC has an important prognostic role, there is an unsatisfactory heterogeneity on the microscopic assessment of this tumor, urging for a movement toward standardization

Programmed death-ligand1 is a determinant of recurrence in alveolar echinococcosis

Objectives: Alveolar echinococcosis (AE) recurrence is one of the major stakes in patients undergoing surgery, the main curative treatment. Preliminary data demonstrated an effect of programmed death-ligand1 (PD-L1) inhibitors on AE proliferation in animals. The current study aimed to analyze the prognostic value of PD-L1 expression in tissue samples of patients with AE undergoing surgery. Methods: A cross-sectional study of patients operated for AE between 2002 and 2017 was performed. Patients with recurrence were matched 1: 2 with patients without recurrence. The matching criteria were PNM staging (P = hepatic localization of the parasite, N = extra-hepatic involvement of neighboring organs, and M = absence or presence of metastasis), resection status, preoperative albendazole treatment, and lesion size. PD-L1 immunohistochemistry staining was performed in surgical liver specimens. The expression of PD-L1 was assessed in immune cells. Disease-free survival was calculated using the Kaplan-Meier method. Results: Among 68 consecutive patients, eight patients with recurrence were matched to 16 patients without recurrence. PD-L1 was overexpressed in patients with recurrence (recurrence: PD-L1 <1%: one, PD-L1 ≥1%: seven; no recurrence: PD-L1 <1%: nine, PD-L1 ≥1%: seven, P = 0.040). Moreover, patients with lower PD-L1 expression (<1%) showed better median disease-free survival (120 months, 95% confidence interval 104-135 vs 74, 95% confidence interval 44-104, P = 0.050). Conclusion: These findings highlight the proof of concept of PD-L1 in AE, but further data on its prognostic importance and the role of immune checkpoint blockade as a promising therapeutical strategy are needed

Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma.

Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to germ cells, but aberrantly reactivated in cancer tissues. Studies indicate that the expression (or re-expression) of CTAs within the MAGE-A family is common in hepatocellular carcinoma (HCC). However, no systematic characterization has yet been reported. The aim of this study is to perform a comprehensive profile of CTA de-regulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression. The transcriptomic analysis of 44 multi-regionally sampled HCCs from 12 patients identified high intra-tumor heterogeneity of CTAs. In addition, a subset of CTAs was significantly overexpressed in histologically poorly differentiated regions. Further analysis of CTAs in larger patient cohorts revealed high CTA expression related to worse overall survival and severalother markers of poor prognosis. Functional analysis of MAGEA3 was performed in human HCC cell lines by gene silencing and in a genetic mouse model by overexpression of MAGEA3 in the liver. Knockdown of MAGEA3 decreased cell proliferation, colony formation and increased apoptosis. MAGEA3 overexpression was associated with more aggressive tumors in vivo. In conclusion MAGEA3 enhances tumor progression and should be considered as a novel therapeutic target in HCC

Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic–phenotypic correlation in ovarian neoplasms

Intratumoral heterogeneity and clonal evolution in liver cancer

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCRseq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves singlebiopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolutio

Intratumoral heterogeneity and clonal evolution in liver cancer

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCRseq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves singlebiopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolutio