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: Akihiko Yoshida, Tatsuhiro Shibata, Susumu Wakai, Tetsuo Ushiku, Koji Tsuta, Masashi Fukayama, Atsushi Makimoto, Koh Furuta, Hitoshi Tsuda
• Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (Mod Pathol) Vol. 26 Issue 6 Pg. 772-81 (Jun 2013) ISSN: 1530-0285 [Electronic] United States
• PMID: 23307059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Adolescent
• Adult
• Anaplastic Lymphoma Kinase
• Biomarkers, Tumor (analysis, genetics)
• Child
• Child, Preschool
• DNA Mutational Analysis
• Female
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics)
• Gene Amplification
• Gene Dosage
• Gene Rearrangement
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Polymerase Chain Reaction
• Prognosis
• Receptor Protein-Tyrosine Kinases (analysis, genetics)
• Rhabdomyosarcoma, Alveolar (enzymology, genetics, mortality, pathology, therapy)
• Rhabdomyosarcoma, Embryonal (enzymology, genetics, mortality, pathology, therapy)
• Young Adult