The characterization of ERBB family mutations in Chinese biliary tract cancers.

Abstract

e15595 Background: Next generation sequencing has been applied to identify actionable mutations in biliary tract cancers (BTCs). ERBB family genes, especially ERBB2 and ERBB3, serve as effective biomarkers for BTCs targeted therapy as shown in MyPathway and SUMMIT clinical trials. However, the distribution and major mutation types of ERBB family genes were not clear in Chinese BTC patients. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from a cohort of 716 Chinese BTC patients. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements and fusions were analyzed. Results: A total of 14% (101/716) of patients with a median age of 62 years old, including 45 males and 56 females, were identified harboring ERBB family mutations. Somatic ERBB family mutations occurred with a rate of 29% in gallbladder carcinoma (GBCA), 13% in extrahepatic cholangiocarcinoma (EHCCA), 12% in hilar cholangiocarcinoma (HCCA) and 8% in intrahepatic cholangiocarcinoma (IHCCA). No germline mutation was detected. A high rate of ERBB2 gene amplification was observed in GBCA (17%). In IHCCA and EHCCA, SNV/Indel accounted for 3% and 5%, respectively, and was the major variation in ERBB2. In HCCA, SNV/Indel was the most common mutation in ERBB3 (8%). In BTC patients, TP53 (81%) and CDK12 (36%) were the top-ranked co-mutant genes with ERBB2. The mutant frequency of CDK12 was significantly different between patients with or without an ERBB2 mutation ( p< 0.001). ERBB2 S310F/Y, ERBB3 V104L/M were hotspot mutations within the ERBB family in BTCs. Conclusions: ERBB family mutations were detected in 14% of Chinese BTC patients. Similar to Western populations (PMID: 27622582), ERBB2 gene amplification was the most common mutation in GBCA in Chinese patients. Unlike ERBB2/ ERBB3 amplification which has been reported as the major mutation in previous studies, our study of other BTC types revealed ERBB2/ ERBB3 SNV/Indel as the major mutation. BTC patients harboring ERBB family mutations have the potential to benefit from pan-HER inhibitors.