title: Analysis of KRAS, NRAS, PIK3CA, and BRAF mutational profile in poorly differentiated clusters of KRAS-mutated colon cancer.
abstract: Recently, a grading system based on the counting of poorly differentiated clusters (PDCs) 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 PDCs 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, PDCs had the same biomolecular profile as the main tumor, but in 5, they had different biomolecular profiles. In detail, PDCs had KRAS wild type in 2 cases and additional PIK3CA mutations (E542K: 1; H1047Y: 1; E545Q: 1) in 3. All 3 cases with additional PIK3CA mutations in PDCs had nodal metastases, high pathological TNM stage, and lymphatic invasion. In 1 of 3 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 on different histologic aspects of the lesion. Because PDCs 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.
authors.affiliation: Department of Diagnostic Medicine and Public Health, , University of Modena and Reggio Emilia-Section of Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy. Electronic address: reggiani.luca@policlinico.mo.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Reggiani Bonetti
authors.affiliation: Department of Human Pathology, University of Messina, 98125 Messina, Italy. Electronic address: vbarresi@unime.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Barresi
authors.affiliation: Department of Diagnostic Medicine and Public Health, , University of Modena and Reggio Emilia-Section of Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bettelli
authors.affiliation: Department of Diagnostic Medicine and Public Health, , University of Modena and Reggio Emilia-Section of Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Caprera
authors.affiliation: Department of Diagnostic Medicine and Public Health, , University of Modena and Reggio Emilia-Section of Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Manfredini
authors.affiliation: Department of Diagnostic Medicine and Public Health, , University of Modena and Reggio Emilia-Section of Pathology, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maiorana
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Colorectal cancer; KRAS; NRAS; PIK3CA; Poorly differentiated clusters