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Master Thesis

Circulating tumor DNA as prognostic marker of tumor recurrence/progression during the follow-up of patients on the waiting list of liver transplantation for hepatocellular carcinoma: a multicenter prospective study

Abstract : Background: Hepatocellular carcinoma, is the first primary malignant tumor of the liver. It represents a real public health problem at the global level as it is the second leading cause of cancer-related mortality worldwide. The ideal theoretical treatment is liver transplantation. In this study, we assessed the prognostic power of circulating tumor DNA (ctDNA) in a prospective cohort of patients listed for liver transplantation for hepatocellular carcinoma. Methods: Prospective cohort of 371 patients listed for liver transplantation for hepatocellular carcinoma. Plasma samples were collected prospectively for all patients at the time of listing. We analyzed plasma samples from a cohort of 194 patients chosen on a case-control study basis. We extracted cell free DNA from the plasma and then analyzed ctDNA by "next generation” sequencing. We used a panel targeting hotspot mutations in TP53, TERT promoter, CTNNB1, PIK3CA and NFE2L2 genes, which are the most frequently mutated genes in HCC. The detectability of ctDNA and its quantification were analyzed to predict the risk of post-transplant recurrence or drop-out for tumor progression. Results: 42 patients dropped out from the waiting list for tumor progression were matched to 90 transplant patients. In parallel, 38 patients experienced tumor recurrence within a 5-year follow-up period, and were matched to 81 transplanted patients who did not have recurrence. Patients who recurred had a higher but not significant mutation rate in plasma DNA for TP53, TERTp and CTNNB1 than controls (p=0.49; p=0.93; p=0.09 respectively). No PIK3CA or NFE2L2 mutations were found in this group. The variant allele frequency (VAF) of TP53, TERTp, and CTNNB1 mutations was not different between recurrence and control patients (p=0.13; p=0.74; p=0.61 respectively). In patients dropped out from the list for tumor progression, there was no significant difference in the mutation rate of TP53, TERTp (p=0.92; p=0.92 respectively) or in the frequency of TP53 and TERTp mutations (p=0.13; p=0.72 respectively). No mutation in CTNNB1, PIK3CA or NFE2L2 were found in the drop-out patients. Finally, in the overall cohort of patients we found a significant association between the TERTp mutations VAF and the number of nodules (p=0.035), and between the CTNNB1 mutations VAF and age (p=0.014). Finally, there was a trend between the TERTp mutations VAF and alpha-fœtoprotein level (p=0.098) and the existence of NASH (p=0.061). Similarly, the CTNNB1 mutation VAF was associated with the diameter of the largest tumor (p=0.168) and alpha-fœtoprotein level (p=0.127) but is not significant. Conclusion: ctDNA is an interesting biological marker but failed to help the refinement of tumor progression during the waiting time or tumor recurrence after liver transplantation in a large cohort of patient listed for LT for HCC. The absence of prognostic factor is probably due to strict selection of these patients.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-03332405
Contributor : Jean-Hugues Morneau Connect in order to contact the contributor
Submitted on : Tuesday, September 28, 2021 - 9:41:09 AM
Last modification on : Thursday, September 30, 2021 - 3:24:06 AM

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Olivier Msika. Circulating tumor DNA as prognostic marker of tumor recurrence/progression during the follow-up of patients on the waiting list of liver transplantation for hepatocellular carcinoma: a multicenter prospective study. Human health and pathology. 2020. ⟨dumas-03332405⟩

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