64. A rare finding of triple KRAS mutations with OmniSeq® INSIGHT in a patient with colorectal adenocarcinoma

Background

Colorectal cancer (CRC) ranks third in terms of new tumor cases and the second leading cause of cancer-related death worldwide (PMID: 30207593). KRAS is one of the most frequently mutated oncogenes in CRC, with approximately 40% of patients harboring activating missense mutations in KRAS (PMID: 31972237). Patients with KRAS-mutant CRC have a worse prognosis than those with KRAS wild-type CRC [PMID: 20008640; PMID: 28453697). Here we report a rare finding of three clinically significant KRAS mutations co-occurring in a patient with microsatellite stable colorectal adenocarcinoma.

Methods

Comprehensive genomic and immune profiling (CGIP) was performed on a hemicolectomy specimen from a >80 year old patient with advanced colorectal adenocarcinoma with 60% tumor nuclei and more than 1000 neoplastic cells per slide at a CAP/CLIA and NYS CLEP certified reference laboratory with the OmniSeq® INSIGHT test (PMID: 34855780). OmniSeq INSIGHT is a next generation sequencing-based laboratory developed test for both DNA and RNA for the detection of genomic and transcriptomic variants, in formalin-fixed paraffin-embedded (FFPE) tumor tissue.

Results

We identified three co-occurring KRAS mutations (c.35G>A p.G12D, c.38G>A p.G13D and c.351A>T p.K117N) with VAF 10.1%, 9.5% and 4.1% respectively in the same colorectal adenocarcinoma patient specimen. All three mutations are associated with resistance to targeted therapies with cetuximab and panitumumab. In addition, the sequencing utilized was able to reveal that G12D and G13D mutations occurred in different cell clones/populations.

Conclusions

CGIP revealed three distinct KRAS co-mutations at known KRAS hot-spots. In addition, CGIP can distinguish allele-specific KRAS mutations and tumoral sub-clonal populations.