Abstract 375P
Background
BRAF p.V600E is a known prognostic factor for poor progression-free survival and overall survival in colorectal cancer (CRC), occurring in 5%-8% patients. This is a special population resistant to chemotherapies. A combined regimen of targeted drugs including MEK inhibitor, BRAF inhibitor and EGFR inhibitor is effective in BRAF V600E mutated patients, while it is only authorized as second-line treatment. BRAF V600E mutation was also considered correlated with sporadic MSI-H. However, studies on other alterations in the BRAF gene are few, and the differences of comprehensive genetic features between BRAF mutated and BRAF wild-type in microsatellite stable (MSS) CRC remain unclear.
Methods
A total of 6521 CRC with detected genomic amplifications were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions were performed using a wide panel next-generation sequencing (NGS) testing. SNV and indels in BRAF gene excluding p.V600E were defined as other BRAF mutations.
Results
316 (4.85%) patients had BRAF V600E (V600E group), 243 (3.73%) patients were detected to have other BRAF mutations (BRAF other group) and the rest was BRAF wild-type (5962, 91.43%). V600E and other BRAF mutations occurred mutually exclusively. The V600E group had significantly higher somatic mutational rate in SMAD4 (26.6% vs 17.3% vs 14.9%) and RNF43 (16.1% vs 2.9% vs 2.4%) genes and lower mutational rate in APC (15.5% vs 54.7% vs 63.9%) gene compared with the BRAF other group and BRAF wild-type group. The most recurrent amplified gene in V600E group was MYC (7% vs 3.29% vs 5%), while another gene in 8q24, PTK2 was amplified more in BRAF other group (2.5% vs 2.8% vs 3.7%). The other BRAF group had much higher TMB levels (median TMB level in the V600E group, the other BRAF group and BRAF wild-type group were 7.76 vs 59.4 vs 9.91) and significant correlated with hypermutation (>80 Muts/Mb), while no one hypermutation case was found in the V600E group.
Conclusions
The mutational rates of BRAF V600E and other BRAF mutations were approximate in MSS colorectal cancer. But the two groups had very different somatic genomic characteristics and correlations with hypermutation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Scienceand Technology Program of Guangzhou, China (Grant numbers:201904010047) Scienceand Technology Planning Project of Guangdong Province of China(Grant numbers:2020A0505100058) Guangdong Educational Committee (Key Project of Regular institutions of higher learing of Guangdong Province (Grant numbers: 2019KZDXM024).
Disclosure
X. Liu: Financial Interests, Personal, Full or part-time Employment: 3DMedicines. M. Huang: Financial Interests, Personal, Full or part-time Employment: 3DMedicines. All other authors have declared no conflicts of interest.