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Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement.
Am J Surg Pathol 2015; 39(7):957-67AJ

Abstract

Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.

Authors+Show Affiliations

*Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, Brigham and Women's Hospital, Boston, MA †Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands §Department of Pathology, University of Padova, Padova, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25723109

Citation

Antonescu, Cristina R., et al. "Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement." The American Journal of Surgical Pathology, vol. 39, no. 7, 2015, pp. 957-67.
Antonescu CR, Suurmeijer AJ, Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. 2015;39(7):957-67.
Antonescu, C. R., Suurmeijer, A. J., Zhang, L., Sung, Y. S., Jungbluth, A. A., Travis, W. D., ... Alaggio, R. (2015). Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. The American Journal of Surgical Pathology, 39(7), pp. 957-67. doi:10.1097/PAS.0000000000000404.
Antonescu CR, et al. Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement. Am J Surg Pathol. 2015;39(7):957-67. PubMed PMID: 25723109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. AU - Antonescu,Cristina R, AU - Suurmeijer,Albert J H, AU - Zhang,Lei, AU - Sung,Yun-Shao, AU - Jungbluth,Achim A, AU - Travis,William D, AU - Al-Ahmadie,Hikmat, AU - Fletcher,Christopher D M, AU - Alaggio,Rita, PY - 2015/2/28/entrez PY - 2015/2/28/pubmed PY - 2015/8/21/medline SP - 957 EP - 67 JF - The American journal of surgical pathology JO - Am. J. Surg. Pathol. VL - 39 IS - 7 N2 - Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/25723109/Molecular_characterization_of_inflammatory_myofibroblastic_tumors_with_frequent_ALK_and_ROS1_gene_fusions_and_rare_novel_RET_rearrangement_ L2 - http://dx.doi.org/10.1097/PAS.0000000000000404 DB - PRIME DP - Unbound Medicine ER -