Analysis of KRAS, NRAS, PIK3CA and BRAF mutational profile in poorly differentiated clusters (PDC) of KRAS mutated colon cancer

Reggiani Bonetti L1, Barresi V2, Bettelli S1, Caprera C1, Manfredini S1, Maionara A1.
Authors information:
1.Department of Diagnostic Medicine and Public Health , University of Modena and Reggio Emilia – Section of Pathology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100, Modena, Italy
2.Department of Human Pathology, University of Messina, Via Consolare Valeria, 98125, Messina, Italy

Recently, a grading system based on the counting of poorly differentiated clusters (PDC) of neoplastic cells was shown to be a strong predictor of nodal metastases and negative prognosis in colon cancer (CC). In this study, we assessed and compared the mutational status of KRAS, NRAS and PIK3CA in PDC and corresponding main tumor tissue of 25 CCs with KRAS mutations. For each tumor, PDC and main tumor tissue were distinctly analyzed by using laser microdissection and mass spectrometry. In 3 CCs the main tumor tissue had also PIK3CA mutations (C420R: 1; E545K: 1; H1047R: 1) and in 1 it showed  NRAS mutation (codon 12). In 20 cases PDC had the same biomolecular profile as the main tumor, but in 5 they had different biomolecular profile. In detail, PDC had KRAS wild type in 2 cases and additional PIK3CA mutations (E542K: 1; H1047Y: 1; E545Q: 1) in 3. All three cases with additional PIK3CA mutations in PDC had nodal metastases, high pTNM stage, high pTNM stage and lymphatic invasion. In one out of the three cases, additional PIK3CA mutation detected in PDC, but not in the main tumor, was also found in the corresponding nodal metastases.
Our findings show for the first time that heterogeneous biomolecular profile previously observed in CC may depend upon different histological aspects of the lesion. As PDC may represent the tumor cells with the highest potential to metastatize, their molecular status may be relevant for the prediction of response to targeted therapies.