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Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Church, Alanna J
Author Church, Alanna J ORCID Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
Calicchio, Monica L
Author Calicchio, Monica L Department of Pathology, Boston Children's Hospital, Boston, MA, USA
Nardi, Valentina
Author Nardi, Valentina Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Skalova, Alena
Author Skalova, Alena Department of Pathology, Charles University, Faculty of Medicine in Plzen, Plzen, Czech Republic
Pinto, Andre
Author Pinto, Andre Department of Pathology, University of Miami, Miami, FL, USA
Dillon, Deborah A
Author Dillon, Deborah A Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Gomez-Fernandez, Carmen R
Author Gomez-Fernandez, Carmen R Department of Pathology, University of Miami, Miami, FL, USA
Manoj, Namitha
Author Manoj, Namitha ArcherDX, Boulder, CO, USA
Haimes, Josh D
Author Haimes, Josh D ArcherDX, Boulder, CO, USA
Stahl, Joshua A
Author Stahl, Joshua A ArcherDX, Boulder, CO, USA
Dela Cruz, Filemon S
Author Dela Cruz, Filemon S Department of Pediatrics, Memorial Sloan Kettering Cancer Institute, New York, NY, USA
Tannenbaum-Dvir, Sarah
Author Tannenbaum-Dvir, Sarah Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA
Glade-Bender, Julia L
Author Glade-Bender, Julia L Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA
Kung, Andrew L
Author Kung, Andrew L ArcherDX, Boulder, CO, USA
DuBois, Steven G
Author DuBois, Steven G Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA
Kozakewich, Harry P
Author Kozakewich, Harry P Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
Janeway, Katherine A
Author Janeway, Katherine A Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA
Perez-Atayde, Antonio R
Author Perez-Atayde, Antonio R Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
Harris, Marian H
Author Harris, Marian H Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA

Modern pathology. 2018 Mar ; 31 (3) : 463-473. [epub] 20171103

Mod Pathol
ISSN 1530-0285 | 0893-3952
Source

Language English Country United States Media print-electronic

Document type Journal Article

Persistent link https://www.medvik.cz/link/pmid29099503

Grant support
P30 CA013696 NCI NIH HHS - United States

PubMed 29099503
DOI 10.1038/modpathol.2017.127
PII: S0893-3952(22)01196-6
Knihovny.cz E-resources

MeSH
Adult MeSH
Fibrosarcoma diagnosis genetics MeSH
Oncogene Proteins, Fusion genetics MeSH
Genetic Testing MeSH
In Situ Hybridization, Fluorescence MeSH
Carcinoma genetics MeSH
Infant MeSH
Middle Aged MeSH
Humans MeSH
Neoplasm Recurrence, Local genetics MeSH
Nephroma, Mesoblastic congenital diagnosis genetics MeSH
Adolescent MeSH
Kidney Neoplasms congenital diagnosis genetics MeSH
Breast Neoplasms genetics MeSH
Infant, Newborn MeSH
Child, Preschool MeSH
ETS Translocation Variant 6 Protein MeSH
Microtubule-Associated Proteins genetics MeSH
Cell Cycle Proteins genetics MeSH
Proto-Oncogene Proteins c-ets genetics MeSH
Discoidin Domain Receptor 2 genetics MeSH
Repressor Proteins genetics MeSH
Sequence Analysis, RNA MeSH
Aged, 80 and over MeSH
Aged MeSH
Serine Endopeptidases genetics MeSH
Check Tag
Adult MeSH
Infant MeSH
Middle Aged MeSH
Humans MeSH
Adolescent MeSH
Male MeSH
Infant, Newborn MeSH
Child, Preschool MeSH
Aged, 80 and over MeSH
Aged MeSH
Female MeSH
Publication type
Journal Article MeSH
Names of Substances
DDR2 protein, human MeSH Browser
EML4 protein, human MeSH Browser
Oncogene Proteins, Fusion MeSH
Microtubule-Associated Proteins MeSH
Cell Cycle Proteins MeSH
Proto-Oncogene Proteins c-ets MeSH
Discoidin Domain Receptor 2 MeSH
Repressor Proteins MeSH
Serine Endopeptidases MeSH

Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

ArcherDX Boulder CO USA

Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA USA

Department of Pathology Boston Children's Hospital Boston MA USA

Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Department of Pathology Charles University Faculty of Medicine in Plzen Plzen Czech Republic

Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Department of Pathology University of Miami Miami FL USA

Department of Pediatric Hematology Oncology Dana Farber Boston Children's Cancer and Blood Disorders Center and Harvard Medical School Boston MA USA

Department of Pediatrics Memorial Sloan Kettering Cancer Institute New York NY USA

Division of Pediatric Hematology Oncology and Stem Cell Transplantation Columbia University Medical Center New York NY USA

See more in PubMed

J Biol Chem. 2004 Feb 20;279(8):6225-34 PubMed