Localization of active, dually phosphorylated extracellular signal-regulated kinase 1 and 2 in colorectal cancer with or without activating BRAF and KRAS mutations

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• 作者：Susanne Holck ; MD ; DMSc^a ; Jesper Bonde ; PhD^a ; ^b ; Helle Pedersen ; BA^a ; Anja Alex Petersen ; BA^a ; ^b ; Amita Chaube ; PhD^a ; Hans Jø ; rgen Nielsen ; MD ; DMSc^c ; Lars-Inge Larsson ; MD ; DSc^a ; ^b ; ^{lars.inge.larsson@regionh.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ERK ; KRAS ; BRAF ; Mutations ; Colorectal carcinoma ; Immunohistochemistry
• 刊名：Human Pathology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：54
• 期：Complete
• 页码：37-46
• 全文大小：1964 K

文摘

Colorectal cancers (CRC) often show activating mutations of the KRAS or BRAF genes, which stimulate the extracellular signal-regulated kinase (ERK) pathway, thus increasing cell proliferation and inhibiting apoptosis. However, immunohistochemical results on ERK activation in such tumors differ greatly. Recently, using a highly optimized immunohistochemical method, we obtained evidence that high levels of ERK activation in rectal adenocarcinomas were associated with resistance to radiochemotherapy. In order to determine whether KRAS and/or BRAF mutations correlate to immunohistochemically detectable increases in phosphorylation of ERK (pERK), we stained biopsies from 36 CRC patients with activating mutations in the BRAF gene (BRAFV600E: BRAF^m), the KRAS gene (KRAS^m) or in neither (BRAF/KRASⁿ) with this optimized method. Staining was scored in blind-coded specimens by two observers. Staining of stromal cells was used as a positive control. BRAF^m or KRAS^m tumors did not show higher staining scores than BRAF/KRASⁿ tumors. Although BRAFV600E staining occurred in over 90% of cancer cells in all 9 BRAF^m tumors, 3 only showed staining for pERK in less than 10% of cancer cell nuclei. The same applied to 4 of the 14 KRAS^m tumors. A phophorylation-insensitive antibody demonstrated that lack of pERK staining did not reflect defect expression of ERK1/2 protein. Thus, increased staining for pERK does not correlate to BRAF or KRAS mutations even with a highly optimized procedure. Further studies are required to determine whether this reflects differences in expression of counterregulatory molecules, including ERK phosphatases.