Recurrent fusion of the genes FN1 and ALK in gastrointestinal leiomyomas

Abstract

Leiomyomas of the gastrointestinal tract are mostly found in the esophagus, stomach, and colon. Genetic information about them is very limited and no fusion genes have been described. We present herein cytogenetic and molecular genetic analyses of two gastrointestinal leiomyomas found in the esophagus and small intestine. The esophageal leiomyoma had the karyotype 45,Y,der(X)t(X;6)(p22;p21),inv(2)(p23q35),add(6)(p21),-11[cp6]/46,XY[7]. The intestinal leiomyoma karyotype was 46,X,add(X)(q2?),der(2)add(2)(p23)add(2)(q33),add(4)(p14),add(14)(q22)[10]/47,XX,+12[2]/46,XX[1]. RNA-sequencing detected FN1-ALK fusion transcripts in both tumors. RT-PCR together with Sanger sequencing verified the presence of the FN1-ALK fusion transcripts. Fluorescence in situ hybridization using an ALK breakapart probe further confirmed the rearrangement of the ALK gene. Immunohistochemical investigation of ALK in the leiomyoma of the small intestine revealed positivity with strong granular cytoplasmatic staining in the tumor cells. This is the first ever ALK fusion reported in gastrointestinal leiomyomas. Our results are of potential clinical importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients whose tumors harbor ALK rearrangements. Thus, ALK emerges as a possible therapeutic target in patients whose tumors, including gastrointestinal leiomyomas, carry ALK fusions.

Malignant transformation of uterine leiomyoma to myxoid leiomyosarcoma after morcellation associated with ALK rearrangement and loss of 14q

“…Thus, the leiomyosarcoma is likely to have originated from a pre-existing leiomyoma. Its myxoid differentiation associated with a rearranged and apparently amplified allele of ALK fits with these genetic alterations seen in smooth muscle tumors in general [ 17 ] as well as in uterine myelofibroblastic tumors displaying myxoid features [ 18 , 19 ] and may offer novel options for targeted therapy [ 20 ].…”

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

“…Rearrangement of the anaplastic lymphoma kinase gene ( ALK ) located at 2p23 is a promiscuous driver event present in a wide range of human tumors including a small subset of lung adenocarcinomas and rare mesotheliomas. In mesenchymal tumors, ALK fusions were first identified in approximately half of inflammatory myofibroblastic tumors (IMTs), before more recent studies have shown their presence in epithelioid fibrous histiocytoma (EFH) and rare gastrointestinal leiomyomas . In both IMT and EFH, ALK immunohistochemistry plays an important diagnostic role.…”

“…In mesenchymal tumors, ALK fusions were first identified in approximately half of inflammatory myofibroblastic tumors (IMTs), 28 before more recent studies have shown their presence in epithelioid fibrous histiocytoma (EFH) and rare gastrointestinal leiomyomas. 29,30 In both IMT and EFH, ALK immunohistochemistry plays an important diagnostic role. IMT is typically a tumor of children and young adults that arises at visceral locations.…”

Genetic profiling of a chondroblastoma‐like osteosarcoma/malignant phosphaturic mesenchymal tumor of bone reveals a homozygous deletion of CDKN2A, intragenic deletion of DMD, and a targetable FN1‐FGFR1 gene fusion

“…In addition to FN1‐FGFR1 , there are gene fusions that involve FN1 as the 5′ or FGFR1 as the 3′ partner, albeit with other partner genes. For example, FN1 is fused to ALK in inflammatory myofibroblastic tumor, leiomyomas of the gastrointestinal tract and ovarian cancer, to EGF in calcifying aponeurotic fibroma, and to ACVR2A in one case of chondrosarcoma and one case of osteochondromatosis . FGFR1 is fused to a large number of different 5′ partners in hematological malignancies, carcinomas and sarcomas .…”