PMID- 29549897 OWN - NLM STAT- MEDLINE DCOM- 20180904 LR - 20181202 IS - 1879-3320 (Electronic) IS - 0960-7404 (Linking) VI - 27 IP - 1 DP - 2018 Mar TI - Detection of RET (rearranged during transfection) variants and their downstream signal molecules in RET rearranged lung adenocarcinoma patients. PG - 106-113 LID - S0960-7404(17)30417-6 [pii] LID - 10.1016/j.suronc.2018.01.006 [doi] AB - 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. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Kim, Jeong-Oh AU - Kim JO AD - Laboratory of Medical Oncology, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Shin, Jung-Young AU - Shin JY AD - Laboratory of Medical Oncology, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Kim, Min Young AU - Kim MY AD - Laboratory of Medical Oncology, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Son, Kyoung Hwa AU - Son KH AD - Laboratory of Medical Oncology, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Jung, Chan Kwon AU - Jung CK AD - Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Kim, Tae-Jung AU - Kim TJ AD - Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Kim, Su Young AU - Kim SY AD - Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Park, Jae Kil AU - Park JK AD - Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Sung, Sook Whan AU - Sung SW AD - Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea. FAU - Bae, Sang Ju AU - Bae SJ AD - Mirax Ltd., Seoul, Republic of Korea. FAU - Min, Hyun Jung AU - Min HJ AD - Mirax Ltd., Seoul, Republic of Korea. FAU - Kang, Jin-Hyoung AU - Kang JH AD - Department of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: oncologykang@naver.com. LA - eng PT - Journal Article DEP - 20180208 PL - Netherlands TA - Surg Oncol JT - Surgical oncology JID - 9208188 RN - 0 (Biomarkers, Tumor) RN - 0 (KIF5B-RET fusion protein, human) RN - 0 (Oncogene Proteins, Fusion) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret) RN - EC 2.7.10.1 (RET protein, human) SB - IM MH - Adenocarcinoma/*genetics/pathology MH - Adult MH - Aged MH - Aged, 80 and over MH - Animals MH - Biomarkers, Tumor/*genetics MH - ErbB Receptors/genetics MH - Female MH - Follow-Up Studies MH - *Gene Rearrangement MH - HEK293 Cells MH - Humans MH - Lung Neoplasms/*genetics/pathology MH - Male MH - Mice MH - Middle Aged MH - Mutation MH - NIH 3T3 Cells MH - Oncogene Proteins, Fusion/*genetics MH - Prognosis MH - Proto-Oncogene Proteins c-ret/*genetics MH - Translocation, Genetic MH - Xenograft Model Antitumor Assays MH - Young Adult OTO - NOTNLM OT - Fluorescence in situ hybridization OT - KIF5B-RET fusion gene OT - Lung adenocarcinoma EDAT- 2018/03/20 06:00 MHDA- 2018/09/05 06:00 CRDT- 2018/03/19 06:00 PHST- 2017/12/08 00:00 [received] PHST- 2018/01/17 00:00 [revised] PHST- 2018/01/23 00:00 [accepted] PHST- 2018/03/19 06:00 [entrez] PHST- 2018/03/20 06:00 [pubmed] PHST- 2018/09/05 06:00 [medline] AID - S0960-7404(17)30417-6 [pii] AID - 10.1016/j.suronc.2018.01.006 [doi] PST - ppublish SO - Surg Oncol. 2018 Mar;27(1):106-113. doi: 10.1016/j.suronc.2018.01.006. Epub 2018 Feb 8.