Background
Chromosomal instability (CIN) and microsatellite instability (MSI) account for the major causes of colorectal cancer (CRC). As an important component of the CIN pathway, PIK3CA mutation is a negative prognostic factor in CRC. However, the relationship between PIK3CA mutation and mismatch repair (MMR) status has not been well clarified.
Conclusions
The molecular pathogenesis is different between dMMR and pMMR tumors with PIK3CA mutation in CRC. PIK3CA mutation may act as a clonally dominant truncal mutation in dMMR CRC. Thus, combination of PIK3CA mutation and MMR status might determine a specific group of CRC to select treatment or elevate prognosis.
Methods
MMR status was determined by immunohistochemical assay. KRAS, NRAS, BRAF, PIK3CA and TP53 mutations were comparatively analyzed in 424 MMR-proficient (pMMR) and 104 MMR-deficient (dMMR) CRC tumors using next-generation sequencing (NGS).
Results
PIK3CA mutation was more commonly mutated in dMMR tumors. PIK3CA mutation less commonly coexisted with KRAS/NRAS/BRAF and TP53 mutations, but more likely coexisted with HER2 and PTCH1 mutations in dMMR tumors compared with pMMR tumors. In tumors with concurrent RAS/BRAF and PIK3CA mutations, PIK3CA and RAS/BRAF mutant allele frequencies (MAFs) were highly concordant in dMMR tumors, whereas PIK3CA MAFs were significantly lower than the corresponding RAS/BRAF MAFs in pMMR tumors, implying that PIK3CA mutation may occur in the early stage of dMMR CRC. Conclusions: The molecular pathogenesis is different between dMMR and pMMR tumors with PIK3CA mutation in CRC. PIK3CA mutation may act as a clonally dominant truncal mutation in dMMR CRC. Thus, combination of PIK3CA mutation and MMR status might determine a specific group of CRC to select treatment or elevate prognosis.