Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors

Abstract

Background Inflammatory myofibroblastic tumors (IMTs) are exceptionally rare neoplasms, which are often driven by rearranged tyrosine kinases. Methods This study considered 33 consecutive patients with IMT (median age, 6.6; age range, 0.6‐15.8 years). RNA and cDNA were successfully obtained in 29 cases. The molecular analysis included sequential tests for 5′/3′‐end unbalanced gene expression, variant‐specific PCR, and next‐generation sequencing (NGS). Results 5′/3′‐end unbalanced ALK expression was revealed in 15/29 (52%) IMTs. Strikingly, all these tumors demonstrated high amount of ALK protein detected by immunohistochemistry. Variant‐specific PCR was capable of identifying the type of ALK rearrangement in 11/15 IMTs with 5′/3′‐end unbalanced ALK expression. The remaining four tumors were analyzed by NGS; two known and two novel (CLTC‐ins6del84‐ALK and EEF1G‐ALK) ALK rearrangements were detected. Five IMTs demonstrated 5′/3′‐end unbalanced ROS1 expression, and all these tumors carried TFG‐ROS1 fusion. Nine tumors, which were negative for 5′/3′‐end unbalanced ALK/ROS1 expression, were subjected to further analysis. Variant‐specific PCR revealed two additional tumors with gene rearrangements (TFG‐ROS1 and ETV6‐NTRK3). The remaining seven IMTs were tested by NGS; single instances of TFG‐ROS1 and novel SRF‐PDGFRb translocations were detected. Conclusions Twenty‐four of 29 IMTs (83%) were shown to have druggable rearrangements involving tyrosine kinases, 20 of these 24 gene fusions were detectable by simple and inexpensive PCR assay, which is based on the detection 5′/3′‐end unbalanced gene expression.

Uterine inflammatory myofibroblastic tumor: First report of a ROS1 fusion

“…Akin to the association between ALK immunohistochemistry and ALK-rearrangement, 10 there is also evidence of a ROS1 immunohistochemical and molecular correlation, with only 2/18 (11%) ROS1rearranged IMTs being negative by immunohistochemistry. 2,3,14,15,18,22,23 The most common fusion partner is TFG (n = 21), while FN1 (n = 4), YWHAE (n = 3), and TIMP3 (n = 1) are less frequent; in eight tumors, the fusion partner was not detected. All patients that were treated with tyrosine kinase inhibitors for unresectable, metastatic, or recurrent disease showed either a partial or complete response.…”

“…Outside of the gynecologic tract, ROS1-rearranged IMTs account for approximately 10% 1,2,14 of tumors, with 37 cases reported to date. [1][2][3]9,[13][14][15][16][17][18][19][20][21][22][23][24] Most occur in the thoracic cavity (n = 14), gastrointestinal tract/liver (n = 10), or soft tissues (n = 10), with very rare (n = 8) are reported as being at least focally collagenized (hyalinized pattern), 3,13,15,17,19,24 which is a very rare morphologic feature in uterine IMTs, and only very focally present in the current case. Details regarding myogenic marker expression are limited in previous reports of ROS1-rearranged IMTs, but desmin, smooth muscle actin, and/or caldesmon appear to show variable expression.…”

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

“…PDGFRA D842V substitutions are particularly common; they demonstrated sensitivity towards the recently approved drug, avapritinib [62]. Inflammatory myofibroblastic tumors often carry ALK rearrangements or, less frequently, gene fusions involving other receptor tyrosine kinases [63]. NTRK1/2/3 translocations are particularly characteristic for infantile fibrosarcomas and occur at some frequency in other sarcoma types [64].…”

“…NTRK1/2/3 gene rearrangements, which are found at a reasonable frequency in pediatric tumors but are exceptionally rare in adults, are associated with the tumor's responsiveness to entrectinib or larotrectinib [105][106][107][108]. ALK, ROS1 and RET rearrangements, although not formally classified as agnostic markers, occur in multiple tumor types and render sensitivity to appropriate inhibitors [63,[109][110][111][112]. HER2 amplification accompanied by gene overexpression may also be considered as an example of a more or less agnostic druggable event [113][114][115].…”

Molecular testing for colorectal cancer: Clinical applications

“…Actionable rearrangements involving receptor tyrosine kinases are characteristic mainly for non-small cell lung carcinomas and some pediatric tumors[ 73 , 74 ]. Somewhat unexpectedly, instances of gene fusions resulting in the activation of involved kinases have been repeatedly demonstrated in microsatellite-unstable cancers arising due to somatic methylation of the MLH1 gene promoter[ 75 - 77 ].…”