Abstract 1540P
Background
Characterization of the recurrent and oncogenic alterations in PDACs can provide important insights to molecular biology of this disease, also lay the foundation for developing approaches of early detection, effective treatment and improved prognosis. However, little is known about the comprehensive genomic alterations of PDACs in Chinese population.
Methods
Comprehensive genomic profiling (CGP) was performed with a 500-gene next generation sequencing (NGS) panel on tumor tissues from a cohort of 339 Chinese PDAC patients. A thorough investigation of mutations, copy number alterations and gene fusion events was performed.
Results
Deep panel sequencing revealed significant recurrent mutations in KRAS, TP53, SMAD4, CDKN2A, ARID1A, ATM, KMT2D, LRP1B, FAT3 and RNF43. KRAS mutations accounted for 86% (292/339) of the samples. Multiple oncogenic KRAS alleles were identified, most prominently G12D (n =125), G12V (n =99), and G12R (n =31). We discovered a non-reported new in-frame duplication of the switch 2 domain, leading to a tandem repeat of amino acids D57_E62dup of K-Ras. Evidence of multiple distinct KRAS mutations was identified in three PDACs, two patients carried multiple known oncogenic hotspot mutations, one each with a G12D and a G12V as the dominant clone. Another case harbored G12A and a rare mutation V8I, which were both inferred subclonal and with complemented cancer cell fractions. This is the first time of KRAS V8I spotted in pancreas. For investigation of other possible molecular drivers in 47 KRAS wild-type patients, a GNAS mutation (R201H), a NRAS mutation (Q61R), a BRAF mutation (V600E) and a SND1-BRAF fusion was found in two, two, one and one patients, respectively. There were three KRAS wild-type tumors carried a known oncogenic missense mutation in CTNNB1. High TMB (>10 muts/Mb) was only observed in three cases, and except for one MSI-L, all patients showed stable microsatellite, which were consistent with previous studies.
Conclusions
This is the largest data set of PDAC cases providing comprehensive characterisation on genetic alterations of Chinese population, which exhibit distinct features from published data. We also discover a new class of oncogenic KRAS D57_E62dup mutation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Li, H. Yuan, T. Ma: Full/Part-time employment: Genetron Health (Beijing) Technology, Co. Ltd. All authors have declared no conflicts of interest.