HEGEMONIC · HEpatocellular carcinoma GErmline MutatiONs ImpaCt (HEGEMONIC)
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-10-01 → 2019-09-30
- EU contribution
- €173,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
HEpatocellular carcinoma GErmline MutatiONs ImpaCt (HEGEMONIC)
- What is the problem/issue being addressed? Hepatocellular carcinoma (HCC) accounts for 80% of all primary liver cancers [1]. The risk of HCC is highly variable among individuals, but most cases (90%) develop in the context of liver cirrhosis. Advanced age, male sex, ethnicity, diabetes, obesity, alcohol consumption, and viral infection (e.g. chronic hepatitis B and C) are clinical variables linked to cirrhosis that are also independently associated with HCC occurrence [1]. However, many individuals with these environmental risk factors never develop HCC [1]. Furthermore, case–control and cancer database studies have identified a significant familial clustering of HCC [2,3]; strongly suggesting a genetic predisposition to HCC exists. However, the heritability (i.e. the proportion of phenotypic variation in a trait that is due to the underlying genetic variation [4]) of HCC is still largely unknown. Candidate gene studies have only identified a few common variants reproducibly associated with HCC and only a few genome-wide association studies (GWAS) have been performed in HCC and solely in the context of viral cirrhosis in Asian populations [5]. The aim of the HEGEMONIC project is to perform a GWAS in patients with liver disease with and without HCC in order to identity inherited genetic variants predisposing to liver carcinogenesis. - Why is it important for society? Liver cancer is the third leading and fastest growing cause of cancer death worldwide [6], and, therefore, a European societal challenge. The EU's ambitious goal is a 15% reduction of cancer incidence by 2020 (COM[2014] 584 final). Therefore, cancer research is a high priority for the EU, notably under Horizon 2020. The HEGEMONIC project is in line with this objective. More specifically, identification of HCC predisposing genes will: - Improve our comprehension of (liver) carcinogenesis. - have commercial potential (e.g. biomarkers for disease prediction, development of new therapeutic targets). Thus, this project may have a marked impact on the management of patients with liver diseases. - What are the overall objectives? The aim of the HEGEMONIC project is to identify cancer predisposing genes in cohorts of HCC patients (cases) compared to patients with liver disease and without HCC (controls). More specifically, the main objectives are to: 1) Identify common inherited genetic variants associated with HCC. 2) Test whether these variants may predict HCC occurrence and prognosis - References [1] Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019;380:1450–1462. https://doi.org/10.1056/NEJMra1713263. [2] Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000;92:1159–64. [3] Hemminki K, Li X. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden. Gut 2003;52:592–6. [4] Visscher PM, Hill WG, Wray NR. Heritability in the genomics era — concepts and misconceptions. Nat Rev Genet 2008;9:255–66. https://doi.org/10.1038/nrg2322. [5] Zucman-Rossi J, Villanueva A, Nault J-C, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology 2015;149:1226–1239.e4. https://doi.org/10.1053/j.gastro.2015.05.061.
Data: CORDIS, © European Union
Project objective
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. Although several environmental factors have been identified, many affected individuals never develop HCC, suggesting a genetic susceptibility. Candidate genes and genome-wide association studies (GWAS) have only uncovered a few variants reproducibly linked to HCC. GWAS design typically allows the detection of common variants that usually have small effect sizes. Even taken together, they explain a very limited proportion of the heritability. This could reflect the presence of rare variants that may confer very large effect sizes. These may be captured by next-generation sequencing (NGS). Whole exome sequencing (WES) of thousands of tumors has defined the somatic genetic landscape of the most common cancers. Using WES, the host group has strongly contributed to the identification of the major pathways recurrently mutated in HCC. Nevertheless, despite the large amount of NGS data generated by cancer genome projects, the analysis of rare germline variants (i.e. variation pre-existing in normal cells) is currently a neglected field, particularly in liver carcinogenesis. The HEGEMONIC project hypothesizes that rare variants in coding regions of the genome (exome) impact the risk of HCC. This project proposes an integrative approach combining (epi)genomic information generated by the host group and from publicly available sources. First, the applicant will compare WES data from a series of 350 patients with HCC to nearly 70,000 controls compiled by the Exome Aggregation and UK10K consortia. Then, validation of the top signals will be performed by conventional sequencing in three replication cohorts. Finally, the applicant will analyze genotype-phenotype associations, taking advantage of the extensive clinical data available. Ultimately, the HEGEMONIC project may generate new biological hypotheses in liver carcinogenesis and identify new biomarkers and pharmaceutical targets.
Original text from CORDIS.
Participants
- UNIVERSITE PARIS CITE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union