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HEpatocellular carcinoma GErmline MutatiONs ImpaCt (HEGEMONIC)

Periodic Reporting for period 1 - HEGEMONIC (HEpatocellular carcinoma GErmline MutatiONs ImpaCt (HEGEMONIC))

Reporting period: 2017-10-01 to 2019-09-30

- 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.
We performed a genome-wide association study (GWAS) in a discovery cohort of patients with chronic liver disease (e.g. alcoholic liver disease, hepatitis C...). The discovery cohort included 4,012 patients from 3 European center cohorts (1. Centre de Recherche des Cordeliers Université de Paris, Paris France, 2. CRB GHPSSD cohort, Hôpital Jean Verdier, Bondy, France and 3. CUB Hôpital Erasme, Brussels, Belgium). Inclusion and exclusion criteria are shown in Table 1. DNA was extracted from whole-blood or non-tumor liver tissue.


Our analyses performed with and without adjustment for clinical factors (e.g. age, gender) allowed us to identify several genomic regions associated with HCC (Figure 1).

Preliminary results of the projects have currently been presented as oral communications to the American association for the study of liver diseases annual congress (San Francisco, United States November 2018) and the European Association for the Study of the liver (Vienna, April 2019). Depending on the validation of our observations in an independent cohort (see below), research results will be widely disseminated and openly accessible to other academic researchers, pharmaceutical/biotech companies, physicians, and Europarliamentarians involved in actions against cancer. Results will be disseminated using:
- The group’s website (http://zucmanlab.com) and the Centre de Recherche des Cordeliers (@CRCordeliers) and Université de Paris (@Univ_Paris) Twitter accounts.
- Publications in peer-reviewed international journals. HEGEMONIC publications will follow the « green model » of open access. All publications will be made available through the host group website, and submitted to OpenAIRE.
- Other presentations at international scientific conferences for liver diseases and cancer genomics.
- Workshops involving academic and private sector interactions.
Cancer genetic consortia have largely neglected the analysis of inherited genetic variants. Therefore, the identification of new predisposing genes in liver cancer (Figure 1) is an innovative and timely research project that goes beyond the current state of the art. Moreover, the originality of the HEGEMONIC ptoject relies on a unique population including the largest European cohort of HCC patients developed on various liver disease.

Currently, we aim to validate the top 5 genetic regions (Figure 1) corresponding to the analysis performed in the discovery cohort. We are currently analysing the results of a multicenter French cohort of more than 4,000 patients. Inclusion and exclusion criteria are similar to those used at the discovery stage.

Thanks to the well-phenotyped replication cohort, we will assess the association between validated variants and various clinical outcomes (e.g. patient survival). The detailed clinical data available will also allow for adjustment for confounding clinical factors.

Overall, the HEGEMONIC project explores a field that has been largely overlooked by international cancer consortia. Ultimately, if variants identified at the discovery stage are validated identification of new liver cancer predisposing genes may:
1) foster our comprehension of liver cancer development
2) Have a clinical impact on patients with liver disease. Indeed, these genes could serve as biomarkers and therefore provide a window of opportunity to implement surveillance and/or risk-reducing measures that mitigate or prevent HCC. They may also serve as potential therapeutic targets that could be further evaluated in randomised controlled trials. This may therefore benefit EU research excellence and competitiveness.