Detection of RET (rearranged during transfection) variants and their downstream signal molecules in RET rearranged lung adenocarcinoma patients

Autor: Sang Ju Bae, Jung Young Shin, Jeong Oh Kim, Kyoung Hwa Son, Hyun Jung Min, Chan Kwon Jung, Tae-Jung Kim, Sook Whan Sung, Jin Hyoung Kang, Su Young Kim, Min Young Kim, Jae Kil Park
Rok vydání: 2018
Předmět:
Adult
Male
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
endocrine system
Lung Neoplasms
Oncogene Proteins
Fusion
endocrine system diseases
Microarray
Adenocarcinoma
Translocation
Genetic
Fusion gene
Mice
Young Adult
03 medical and health sciences
0302 clinical medicine
Biomarkers
Tumor
medicine
Animals
Humans
neoplasms
Gene
Aged
Aged
80 and over
Gene Rearrangement
Tissue microarray
medicine.diagnostic_test
business.industry
Proto-Oncogene Proteins c-ret
Middle Aged
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Molecular biology
ErbB Receptors
Reverse transcription polymerase chain reaction
HEK293 Cells
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Mutation
NIH 3T3 Cells
Immunohistochemistry
Female
Surgery
business
Follow-Up Studies
Fluorescence in situ hybridization
Zdroj: Surgical Oncology. 27:106-113
ISSN: 0960-7404
DOI: 10.1016/j.suronc.2018.01.006
Popis: Background We screened resected tumor tissues from patients with lung cancer for EGFR mutations, ALK rearrangements, and rearranged during transfection (RET) gene variants (including RET rearrangements and the Kinesin Family Member 5B (KIF5B)-RET fusion gene) using various methods including reverse transcription polymerase chain reaction (RT-PCR), transcript assays, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). We also examined the protein expression of associated downstream signaling molecules to assess the effect of these variants on patient outcome. Method We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from patients with lung adenocarcinoma and analyzed the microarray by both FISH (using RET break-apart and KIF5B-RET SY translocation probes) and a commercial RET transcript assay. We evaluated the expression of RET and RET-related signaling molecules, including p-AKT and p-ERK, by TMA -based IHC staining. Results Among the 581 specimens, 51 (8.8%) specimens harbored RET rearrangements, including 12 cases (2.1%) carrying a KIF5B-RET fusion gene. Surprisingly, RET expression was lower in KIF5B-RET fusion gene-positive than in RET wild-type specimens. We detected activating EGFR mutations in 11 (21.6%) of the 51 RET variant-positive specimens. Among the KIF5B-RET fusion gene-positive specimens, p-ERK expression was significantly lower in the EGFR mutation subgroup showing RET expression than in the EGFR mutation subgroup that did not express RET. Similarly, the RET rearrangement group showed significant variation in the expression level of p-AKT (P = 0.028) and p-ERK, whose expression remarkably increased in specimens not expressing RET. The expression of p-ERK markedly increased in the RET rearrangement group regardless of RET expression. Conclusion This result suggests that a combination of RET and ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring RET variants.
Databáze: OpenAIRE
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