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

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.

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma

“…Nonetheless, only BAP1 expression loss was correlated to prolonged DFS and OS in the large duct type of ICCs. Most previous studies [4,25,28] showed that these factors did not have any prognostic meaning in ICCs, but Sarcognato S et al [8] found that the retained expression of BAP1 were related to a poor prognosis, and two studies [8,9] drew conflicting conclusions about predictive value of ARID1A in ICCs. Anyhow, our study can explain the inconsistency about the prognostic value of BAP1: loss of BAP1 expression was related to improved survival in large duct type ICCs, and was not associated with prognosis in small duct type ICCs; After combining two subtypes into one group, BAP1 would be considered as a favorable or irrelevant predictor in ICCs according to the ratio of large duct and small duct type ICCs.…”

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma

“…Nonetheless, only BAP1 expression loss was correlated to prolonged DFS and OS in the large duct type of ICCs. Many studies [4,25,28] showed that these factors have no prognostic value in ICCs, but Sarcognato S et al [8] found that the retained expression of BAP1 was correlated to poor prognosis, while another two studies [8,9] got to conflicting conclusions about predictive value of ARID1A in ICCs. Accordingly, our study may explain the inconsistency in the prognostic value of BAP1: loss of BAP1 expression was correlated to improved survival in large duct type ICCs rather than in small duct type ICCs.…”

“…Here we investigated the mutational status of IDH1/2, BAP1, ARID1A and PBRM1, and for the first time, determined whether these mutations are correlated to clinicopathological characteristics and prognoses in each histological subtype of ICCs. Due to the heterogeneity of ICC, by analyzing their relationships in the subtypes, rather than the total cohort of ICCs, we could obtain more reasonable and accurate results to explain the inconsistencies reported previously [4,[6][7][8][9]25].…”

“…With the application of next-generation sequencing technology, many frequent genetic mutations have been discovered in ICCs, such as isocitrate dehydrogenase 1/2 (IDH1/2), KRAS, BAP1, ARID1A, PBRM1 and FGFR2-fusion [4,5]. Almost all literatures reported that the incidences of their mutations are more than 10% in cases with ICCs [4][5][6][7][8][9].…”

“…Alternatively, immunohistochemistry (IHC) staining is effective to detect the above mutations, because the presence of mutations correlates strongly with loss of the corresponding protein expressions [22,24]. Some studies have estimated the association of these inactive mutations with clinical features and prognosis, but there are still many discrepancies [4,8,9,25].…”