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. 2022 Nov 5;12(1):18775.
doi: 10.1038/s41598-022-22543-z.

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma

Margherita Rimini  1 , Carles Fabregat-Franco  2 , Valentina Burgio  3 , Sara Lonardi  4 , Monica Niger  5 , Mario Scartozzi  6 , Ilario Giovanni Rapposelli  7 , Giuseppe Aprile  8 , Francesca Ratti  9 , Federica Pedica  10 , Helena Verdaguer  2 , Mario Rizzato  11 , Federico Nichetti  5 , Eleonora Lai  6 , Alessandro Cappetta  8 , Teresa Macarulla  2 , Matteo Fassan  12   13 , Filippo De Braud  5   6   7   8   9   10   11   12   13   14 , Andrea Pretta  6 , Francesca Simionato  8 , Francesco De Cobelli  15 , Luca Aldrighetti  9 , Lorenzo Fornaro  15 , Stefano Cascinu  16 , Andrea Casadei-Gardini  16
Affiliations

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma

Margherita Rimini et al. Sci Rep. .

Abstract

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients.

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Conflict of interest statement

MN: Travel expenses from Celgene, speaker honorarium from Accademia della Medicina. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte and MSD Italia. FdB: Honoraria from Roche, Pfizer, BMS, Merck, MSD, SERVIER, Sanofi, Amgen Astellas BioPharma, Incyte. Consulting or Advisory Role for Roche, Incyte, EMD Serono, BMS, Nerviano Medical Sciences, Sanofi, Novartis Italy, Menarini, research funding (institution): Novartis, Roche, Merck Serono, Pfizer, Servier, Philogen, Loxo, Tesaro, Nerviano Medical Sciences, Kymab. Research funding: BMS/Medarex, Merck KGaA, Ignyta, MedImmune, Exelis, Bayer health, Daiichi Sangyo Europe GmbH, Incyte, Basilea Pharmaceutical, jassen Oncology. TM: (SOBI) Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Got It Consulting SL, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience , Inc, Janssen, Lilly. Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, and Zymeworks. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Most common altered genes in the whole sample, in IDH1m patients and in IDH1wt patients.
Figure 2
Figure 2
Mutations’ incidence in IDH1m patients and in IDH1wt patients.
Figure 3
Figure 3
Kaplan Meyer curves of DFS and OS from surgery according to the altered genes with prognostic impact.
Figure 4
Figure 4
Kaplan Meyer curves of PFS and OS from first line therapy according to the altered genes with prognostic impact.
See this image and copyright information in PMC

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