Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma

Michele Simbolo,Simone Conci,Andrea Mafficini,Claudio Bassi,Matteo Fassan,Aldo Scarpa,Andrea Ruzzenente,Matteo Brunelli,Vincenzo Corbo,Emilio Bria,Giona Turri,Borislav Rusev,Paola Capelli,Serena Pedron,Rita T Lawlor,Giampaolo Tortora,Alfredo Guglielmi,Caterina Vicentini

doi:10.1038/s41598-018-25669-1

Abstract

The incidence and mortality rates of intrahepatic cholangiocarcinoma have been rising worldwide. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. To identify new independent marker related to aggressive behaviour, two prognostic groups of patient were selected and divided according to prognostic performance. All patients alive at 36 months were included in good prognostic performers, while all patients died due to disease within 36 months in poor prognostic performers. Using high-coverage target sequencing we analysed principal genetic alterations in two groups and compared results to clinical data. In the 33 cases included in poor prognosis group, TP53 was most mutated gene (p = 0.011) and exclusively present in these cases. Similarly, ARID1A was exclusive of this group (p = 0.024). TP53 and ARID1A are mutually exclusive in this study. Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis (TP53, p = 0.0031, ARID1A, p = 0.0007, MET, p = 0.0003 in Cox analysis). LOH in PTEN was also identified as marker of disease recurrence (p = 0.04) in univariate analysis. This work improves our understanding of aggressiveness related to this tumour type and has identified novel prognostic markers of clinical outcome.

Highlights

Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma
Only 10–20% of patients present with early-stage disease that is amenable to curative surgery[4,5] and after resection, a high recurrence rate of 50–60% makes for a dismal five-year overall survival (OS) of only 30%5–8
Molecular analyses suggested that the observed heterogeneity in prognosis and response to treatments could be attributed to the underlying differential alteration of the molecular mechanisms that drive crucial differences in cancer aggressiveness and treatment outcomes[10,11]

Summary

Introduction

Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. Only 10–20% of patients present with early-stage disease that is amenable to curative surgery[4,5] and after resection, a high recurrence rate of 50–60% makes for a dismal five-year overall survival (OS) of only 30%5–8. Using high-coverage targeted sequencing (HCTS), we investigated somatic mutations and copy number status of a large number of genes that have been identified as frequently altered by previous studies[12,13,14,15] to uncover the molecular features characterizing the more aggressive subpopulation of this tumour type

Methods

Results

Conclusion