title: Anaplastic lymphoma kinase status in rhabdomyosarcomas.
abstract: Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (≥4 ALK copies in ≥40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma.
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan. akyoshid@ncc.go.jp
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Susumu
authors.initials: S
authors.lastname: Wakai
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Makimoto
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D000293:Adolescent; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018233:Rhabdomyosarcoma, Embryonal / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases