Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma

SIMPLE SUMMARY: Genetic testing promises to provide guidance for early diagnosis and treatment of cholangiocarcinoma (CCA). Due to the different mutation landscapes across populations and the paucity of sequencing data of Chinese patients with CCA, the existing mutation landscape is insufficient to reflect the mutation characteristics of Chinese patients. We retrospectively analyzed 72 Chinese patients with CCA who had received genetic testing of targeted capture sequencing. A total of 2152 somatic mutations were detected in 56 (77.78%, 56/72) patients, of which, the frequently mutated driver genes were TP53, KMT2D, KMT2C, BCOR, APC, BAP1, ARID1A, NF1, PIK3CA, KRAS, and LRP1B. Most mutations were enriched in NRF2, TP53, and TGF-Beta oncogenic signaling pathways and cadherin repeat domain which were associated with intercellular adhesion. We identified 118 novel pathogenic or likely pathogenic somatic mutations and 77 actionable alterations, which provided potential targets for early diagnosis and treatment planning of CCA. ABSTRACT: The early diagnosis and treatment of cholangiocarcinoma (CCA) remain a challenge worldwide. Genetic testing promises to solve these problems. Due to the different mutation landscapes across populations and the paucity of sequencing data of Chinese patients with CCA, the existing mutation landscape is insufficient to reflect the mutation characteristics of Chinese patients. Thus, we retrospectively analyzed 72 Chinese patients with CCA who had received genetic testing of targeted capture sequencing. A total of 2152 somatic mutations were detected in 56 (77.78%) patients, of which, the frequently mutated driver genes were TP53 (27.78%), KMT2D (23.81%), KMT2C (20.63%), BCOR (18.06%), APC (15.28%), BAP1 (13.89%), ARID1A (12.50%), NF1 (12.50%), PIK3CA (12.50%), KRAS (11.11%), and LRP1B (11.11%). Most mutations were enriched in NRF2, TP53, and TGF-Beta oncogenic signaling pathways and cadherin repeat domains which were associated with intercellular adhesion. Based on cancer-related public databases and multiple protein function prediction algorithms, we identified 118 novel pathogenic or likely pathogenic somatic mutations and 77 actionable alterations. Molecular analysis of tumors from a precision oncology perspective can provide potential targets for early diagnosis and treatment of CCA and assist physicians in clinical decision making.