PMID- 28573357 OWN - NLM STAT- MEDLINE DCOM- 20180925 LR - 20220331 IS - 1436-3305 (Electronic) IS - 1436-3291 (Linking) VI - 21 IP - 2 DP - 2018 Mar TI - Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. PG - 225-236 LID - 10.1007/s10120-017-0732-7 [doi] AB - BACKGROUND: Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. METHODS: To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. RESULTS: NRG1 overexpression was observed in 141 (28.1%) GCs and closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) expression. NRG1 overexpression was significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040). HER3 and HER4 expressions were observed in 157 (31.3%) and 277 (55.2%), respectively. In contrast to NRG1, expression of these proteins was not associated with survival. NRG1 GCN gain (GCN >/= 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (kappa, 0.459; P < 0.001). CONCLUSIONS: Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients. FAU - Yun, Sumi AU - Yun S AD - Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea. AD - Department of Diagnostic Pathology, Samkwang Medical Laboratories, Seoul, South Korea. FAU - Koh, Jiwon AU - Koh J AD - Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea. FAU - Nam, Soo Kyung AU - Nam SK AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. FAU - Park, Jung Ok AU - Park JO AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. FAU - Lee, Sung Mi AU - Lee SM AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. FAU - Lee, Kyoungyul AU - Lee K AD - Department of Pathology, Kangwon National University Hospital, Chuncheon, Kangwon, South Korea. FAU - Lee, Kyu Sang AU - Lee KS AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. FAU - Ahn, Sang-Hoon AU - Ahn SH AD - Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea. FAU - Park, Do Joong AU - Park DJ AD - Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea. FAU - Kim, Hyung-Ho AU - Kim HH AD - Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea. FAU - Choe, Gheeyoung AU - Choe G AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. FAU - Kim, Woo Ho AU - Kim WH AD - Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea. FAU - Lee, Hye Seung AU - Lee HS AD - Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea. hye2@snu.ac.kr. LA - eng GR - HI14C1813/Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)/ PT - Journal Article DEP - 20170601 PL - Japan TA - Gastric Cancer JT - Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association JID - 100886238 RN - 0 (Biomarkers, Tumor) RN - 0 (NRG1 protein, human) RN - 0 (Neuregulin-1) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ERBB4 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.10.1 (Receptor, ErbB-4) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor/*analysis MH - Disease-Free Survival MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Neuregulin-1/analysis/*biosynthesis MH - Prognosis MH - Proportional Hazards Models MH - Receptor, ErbB-3/analysis/*biosynthesis MH - Receptor, ErbB-4/analysis/*biosynthesis MH - Stomach Neoplasms/mortality/*pathology OTO - NOTNLM OT - Copy number gain OT - Fluorescence in situ hybridization OT - Gastric cancer OT - Immunohistochemistry OT - Neuregulin 1 EDAT- 2017/06/03 06:00 MHDA- 2018/09/27 06:00 CRDT- 2017/06/03 06:00 PHST- 2017/03/07 00:00 [received] PHST- 2017/05/25 00:00 [accepted] PHST- 2017/06/03 06:00 [pubmed] PHST- 2018/09/27 06:00 [medline] PHST- 2017/06/03 06:00 [entrez] AID - 10.1007/s10120-017-0732-7 [pii] AID - 10.1007/s10120-017-0732-7 [doi] PST - ppublish SO - Gastric Cancer. 2018 Mar;21(2):225-236. doi: 10.1007/s10120-017-0732-7. Epub 2017 Jun 1.