Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

Abstract

Aims NTRK‐rearranged sarcomas are emerging as a distinct class of sarcomas of particular importance in the era of targeted therapy. The aim of this study was to use array comparative genomic hybridisation (aCGH) to explore the cytogenetic profile of six adult soft tissue sarcomas harbouring NTRK gene fusions. Methods and results aCGH was performed on six adult soft tissue sarcomas with proven NTRK rearrangements [NTRK1, n = 1 (TPM3–NTRK1); NTRK2, n = 1 (MTMR2–NTRK2); NTRK3, n = 4 (two ETV6–NTRK3; two with unknown partners). The morphological patterns of these cases included inflammatory myofibroblastic tumour‐like, fibrosarcoma/malignant peripheral nerve sheath tumour‐like, and Ewing sarcoma‐like. On the basis of the number of chromosomal copy number variations (CNVs), ranging from two to 15 per sample, NTRK‐associated sarcomas could be subdivided into two groups: one with a relatively simple karyotype (n = 2; median of three genomic alterations), and those with a more complex karyotype (n = 4; median of 11 genomic imbalances). Recurrent chromosomal CNVs included gains at chromosomes 6p, 1q, 7 (whole chromosome), and 12p, and losses at chromosomes 10q, 13q, 19q, and 9p. Conclusions NTRK‐rearranged sarcomas constitute a heterogeneous group of tumours that can show a relatively simple or a complex karyotype. Although there were some, but inconsistent, associations between karyotype complexity and morphology, our study showed that a more complex karyotype in this group of tumours appeared to correlate with more aggressive clinical behaviour. Gains at chromosome 6p and 1q were the most common recurrent genomic alterations, being present in 67% of the samples (4/6), followed by gains at chromosome 7, which were present in 50% of the samples (3/6).

The novel finding of an FGFR1::TACC1 fusion in an undifferentiated spindle cell sarcoma of soft tissue with aggressive clinical course

“…[25][26][27][28][29] For those tumors that morphologically resemble a fibrosarcoma or malignant peripheral nerve sheath tumor, NTRK and RET fusions have been reported. 8,10,13 Our reported case showed markedly increased tumor cellularity with intersecting fascicles of spindle cells exhibiting moderate atypia, brisk mitosis, and necrosis. The tumor is hence clearly at the high-grade end of morphologic spectrum.…”

“…Tyrosine kinase gene fusions are increasingly recognized in soft tissue tumors of diverse morphology. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In some cases, the identification of fusion genes provides a hint for the diagnosis; in others, their recognition is directly relevant to clinical management due to the availability of tyrosine kinase inhibitors for treatment. This is of particular importance for those with clinically advanced or refractory disease.…”

“…The gene fusions have involved ALK, NTRK, RET, BRAF, ROS1, RAF1, MET, and FGFR genes. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] They are attaining increasing significance as target therapy is available for some of these tumors. The tumor types may include inflammatory myofibroblastic tumors, 1 epithelioid fibrous histiocytoma, 2,3 infantile fibrosarcoma, 4,5 lipofibromatosis-like neural tumors, 6,7 and a large heterogeneous group of tumors that show predominant spindle cell morphology and uncertain histogenesis.…”

“…The latter group may show variable collagen production or hyalinization, staghorn-like vessels, and expression of CD34 or S100. [8][9][10][11][12][13][14][15][16][17] While many of these are benign to low-grade in morphology and behavior, occasional cases have morphologically resembled a fibrosarcoma or malignant peripheral nerve sheath tumor and may show dismal prognosis. 8,10,13 Specifically, gene fusions involving tyrosine kinase of the fibroblast growth factor receptor family (mostly FGFR1 and FGFR2) have also been described.…”

“…[8][9][10][11][12][13][14][15][16][17] While many of these are benign to low-grade in morphology and behavior, occasional cases have morphologically resembled a fibrosarcoma or malignant peripheral nerve sheath tumor and may show dismal prognosis. 8,10,13 Specifically, gene fusions involving tyrosine kinase of the fibroblast growth factor receptor family (mostly FGFR1 and FGFR2) have also been described. The partner genes that fuse with FGFR members appear to correlate closely with tumor morphology in the context of soft tissue tumors.…”