title: Comparison of neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status in primary and metastatic colorectal cancer.
abstract: Neuroendocrine differentiation of tumor tissue has been recognized as an important prerequisite for new targeted therapies. To evaluate the suitability of colorectal cancer (CRC) tissue for these treatment approaches and to find a possible link to pretherapeutic conditions of other targeted strategies, we compared neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary and metastatic CRC. Immunohistochemical expression analysis of neuroendocrine markers chromogranin A and synaptophysin was performed on archival CRC tissue, comprising 116 primary tumors, 258 lymph node metastases and 72 distant metastases from 115 patients. All CRC samples but 30 distant metastases were subjected to mutation analysis of KRAS, NRAS, BRAF, PIK3CA, and TP53. Neuroendocrine marker expression was found significantly less frequently in lymph node metastases compared to primary tumors and distant metastases (20%, 31%, 28%, respectively, P = 0.044). KRAS mutation rates increased significantly from primary tumors to lymph node metastases and distant metastases within the neuroendocrine negative CRC group (44%, 53%, 64%, respectively, P = 0.042). Neuroendocrine differentiation was significantly less concordant than KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary tumor/lymph node metastases pairs (65% versus 88%-99%; P < 0.0001) and primary tumor/distant metastases pairs (64% versus 83%-100%; P = 0.027 and P < 0.0001, respectively). According to these data, therapeutic targeting of neuroendocrine tumor cells can be considered only for a subset of CRC patients and biopsies from the metastatic site should be used to guide therapy. A possible importance of lacking neuroendocrine differentiation for progression of KRAS mutant CRC should be further investigated.
authors.affiliation: Department of Pathology, Southern Hospital Trust Kristiansand, Norway.
authors.forename: Britta
authors.initials: B
authors.lastname: Kleist
authors.affiliation: Institute of Legal Medicine, University Hospital Essen Essen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kempa
authors.affiliation: ViennaLab Diagnostics GmbH Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Novy
authors.affiliation: ViennaLab Diagnostics GmbH Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Oberkanins
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center Houston, Texas, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center Houston, Texas, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, Southern Hospital Trust Kristiansand, Norway.
authors.forename: Christiane
authors.initials: C
authors.lastname: Loland
authors.affiliation: Institute of Legal Medicine, University Hospital Essen Essen, Germany.
authors.forename: Micaela
authors.initials: M
authors.lastname: Poetsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000201:enzymology / Q000235:genetics* / Q000556:secondary*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; 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); D018631:ras Proteins
keywords: KRAS mutations; Neuroendocrine differentiation; colorectal cancer