title: CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.
abstract: Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology.
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Noriaki
authors: http://orcid.org/0000-0001-7001-0106
authors: N
authors: Yoshida
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Hiroaki
authors: H
authors: Miyoshi
authors: Department of Pathology, Kurume University School of Medicine, Japan.|Department of Haematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Japan.
authors: Takeharu
authors: T
authors: Kato
authors: Department of Haematology, Faculty of Medicine, University of Tsukuba, Japan.
authors: Mamiko
authors: M
authors: Sakata-Yanagimoto
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Daisuke
authors: D
authors: Niino
authors: Department of Haematology, Sasebo City General Hospital, Japan.
authors: Hiroaki
authors: H
authors: Taniguchi
authors: Department of Haematology, Sasebo City General Hospital, Japan.
authors: Yukiyoshi
authors: Y
authors: Moriuchi
authors: Department of Internal Medicine, Karatsu Red Cross Hospital, Japan.
authors: Masaharu
authors: M
authors: Miyahara
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Daisuke
authors: D
authors: Kurita
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Yuya
authors: Y
authors: Sasaki
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Joji
authors: J
authors: Shimono
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Keisuke
authors: K
authors: Kawamoto
authors: Department of Haematology, Imamura Bun-in Hospital, Kagoshima, Japan.
authors: Atae
authors: A
authors: Utsunomiya
authors: Department of Haematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Japan.
authors: Yoshitaka
authors: Y
authors: Imaizumi
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Masao
authors: M
authors: Seto
authors: Department of Pathology, Kurume University School of Medicine, Japan.
authors: Koichi
authors: K
authors: Ohshima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D054398:Receptors, CCR4 / Q000032:analysis / Q000235:genetics*; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C515354:CCR4 protein, human; D054398:Receptors, CCR4
keywords: CCR4 mutation; adult T cell leukaemia/lymphoma; clinicopathological analyses; prognostic impact; tissue array