title: Concurrent MET copy number gain and KRAS mutation is a poor prognostic factor in pancreatobiliary subtype ampullary cancers.
abstract: Hepatocyte growth factor (HGF) and MET are candidates of targeted therapies for cancer patients. Although MET and HGF are commonly expressed in biliary tract cancers, their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas (A-ACs), one of the aggressive periampullary cancers. MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 62 surgically resected, paraffin-embedded tumors, respectively. High MET and HGF protein expressions were detected in 24 (38.7%) and 15 (24.2%) tumors. High MET expression was associated with KRAS mutation. However, there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival. MET SISH positivity was detected in 19 tumors (30.6%), where 84.2% were due to high trisomy or polysomy and only 3 cases (15.8%) were MET gene amplification. The overall MET protein overexpression was well correlated with MET SISH positivity. The concurrent MET SISH positivity and KRAS mutation, not each alone, was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs, but not in intestinal subtype. Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs, indicating those markers could be potent candidates for a new therapeutic target in this cancer type. MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers.
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea. Electronic address: mulank99@hallym.or.kr.
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Daerim 1-Dong, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Hepato-Billiary-Pancreatic Surgery and Liver Transplantation, Department of Surgery, Hangang Sacred Heart Hospital, Hallym University College of Medicine, 12, Beodeunaru-ro 7-gil, Yeongdeungpo-gu, Seoul 150-719, Republic of Korea.
authors.forename: Jang Yong
authors.initials: JY
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 134-701, Republic of Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Nam
authors.affiliation: Department of Pathology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 134-701, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Park
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea.
authors.forename: Soo Kee
authors.initials: SK
authors.lastname: Min
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea.
authors.forename: Jinwon
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Kyoungchun-ro 153, Guri-si, Gyeonggi-do 11923, Republic of Korea.
authors.forename: Kyueng-Whan
authors.initials: KW
authors.lastname: Min
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Choe
authors.affiliation: Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 431-070, Republic of Korea.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D014670:Ampulla of Vater / Q000473:pathology*; D003138:Common Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D046888:Tissue Array Analysis
chemical_list: C117307:KRAS protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adenocarcinoma; Ampulla of Vater; HGF; Immunohistochemistry; MET; Silver in situ hybridization