19 MOLECULAR PATHOGENESIS OF LIVER TUMOURS IN PATIENTS WITH CONGENITAL PORTO-SYSTEMIC SHUNTS
Athanasios Tyraskis,1, Claudio De Vitto,2, Nigel Heaton2, Alberto Quaglia2, Richard Thompson2, Mark Davenport1
1Kings College Hospital, London, United Kingdom. 2Institute of Liver Studies, London, United Kingdom

Abstract

Aims Hepatic tumours are recognised complications of congenital porto-systemic shunts (CPS). CTNNB1 is commonly implicated in the pathogenesis of hepatocellular carcinomas and mutations in exon three are particularly pathogenic.

In patients with CPS we compared the subgroup of patients with hepatic tumours to those without tumours, and investigated for the presence of genetic mutations.

Methods Single-centre retrospective cohort study of patients with CPS from 1990 to 2016 (ethical approval REC: 16/EM/0342). Next generation sequencing was performed on DNA extracted from tumour and background liver specimens using HaloPlex™ library preparation and a MiSeq™ sequencer for a panel of 52 genes. Data are quoted as median (IQR). Categorical data were compared using a two-tailed Chi-squared test. A P value of 0.05 was considered significant.

Results 46 patients were investigated for CPS at 8 months (1mth– 14yrs) of which 21/46 (46%) had liver tumours. The group with tumours presented significantly older and a higher proportion had type 1 (end-to-side-like) CPS (Table 1).

26 individual tumours were sequenced with corresponding background liver . Heterozygous somatic mutations in CTNNB1 were identified in 21/26 (81%) tumours, of which 19/21 (90%) were missense mutations in exon 3. Eight distinct pathogenic amino acid changes were observed. Somatic missense mutations were also observed in TERT promoter in two tumours; and APCAXIN1, HNF1AATMand WRN each on one occasion. 

Conclusions

Tumours are associated with greater portal venous deprevation (type 1 shunt) and older presentation. Pathogenic somatic CTNNB1 mutations occur at high frequency in CPS patients with a predisposition for exon 3. 

 

 

Tumour

(n=21)

No Tumour

(n=25)

P value

Age at presentation

    IQR (years)

12(0.7-17)

0.1(0-2.3)

<0.001

Sex (M:F)

13:8

14:11

 

0.77

Perinatal presentation

5(24%)

16(64%)

0.009

Classification

    Type 1

    Type 2

 

11

10

 

1

24

 

<0.001


Website
Yes