title: Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.
abstract: Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs.
authors.affiliation: Department of Pathology, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hee Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Bundang Hospital, Seoul National University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Kyung Han
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jiwoon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea woohokim@snu.ac.kr.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics*; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; DAXX; TERC; Telomere shortening; altered lengthening of telomeres; hybridization; immunohistochemistry; in situ; telomerase