BRST5:Inflammatory myofibroblastic tumour

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Yajuan Liu, PhD and Katherine Geiersbach, MD

WHO Classification of Disease

(Instructions: This table’s content from the WHO book will be autocompleted.)

Structure	Disease
Book
Category
Family
Type
Subtype(s)

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Formerly referred to as inflammatory pseudotumor, inflammatory myofibroblastic tumor of the breast relies upon morphologic, immunohistochemical, and/or molecular features shared in common with other primary tumor sites. Confirmation of rearrangements of ALK or, less commonly other receptor tyrosine kinase genes, supports the diagnosis and can identify therapeutic targets. However, molecular confirmation is not required if ALK immunohistochemistry is definitively positive. Of note, exceptional situations such as inversions or other cryptic rearrangements of ALK at 2p23 may lead to a false-negative FISH result, and other molecular testing such as RNA-Seq can be used to detect ALK fusions efficiently. In ALK-negative cases, immunohistochemistry for ROS1 and/or molecular tests for non-ALK gene fusions may be useful.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
ALK	TPM3::ALK, TPM4::ALK, EML4::ALK, RANBP2::ALK, CLTC::ALK, and others	Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion breakpoints occur in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. At the DNA level, alternative ALK breakpoints in rare cases occur upstream of exon 19, most commonly in intron 18.	Rearrangements of ALK gene locus at 2p23	Common	D, T	Yes (WHO)
ROS1	TFG::ROS1, YWHAE::ROS1, and others	Fusions result in constitutive activation of the ROS1 tyrosine kinase. Most common ROS1 breakpoints occur in intron 35; at the transcript level, various 5' partner genes are fused to exon 36 of ROS1.	Rearrangements of ROS1 gene locus at 6q22	Recurrent	D, T	Yes (WHO)
NTRK3	ETV6::NTRK3 and others	Fusions result in constitutive activation of the NTRK3 tyrosine kinase. Most commonly exon 5 of ETV6 is joined to exon 15 of NTRK3 at the transcript level.	Rearrangements of NTRK3 gene locus at 15q25. Classically, the reciprocal translocation t(12;15)(p13;q25) is associated with ETV6::NTRK3 rearrangement.	Recurrent	D, T	Yes (WHO)
PDGFRB	NAB2::PDGFRB and others	Fusions result in constitutive activation of the PDGFRB tyrosine kinase.	Rearrangements of the PDGFRB gene locus at 5q32.	Rare	D, T	Yes (WHO)
RET		Fusions result in constitutive activation of the RET tyrosine kinase.	Rearrangements of the RET gene locus at 10q11.	Rare	D, T	Yes (WHO)
NTRK1		Fusions result in constitutive activation of the NTRK1 tyrosine kinase.	Rearrangements of the NTRK1 gene locus at 1q23.	Rare	D, T
IGF1R		Fusions result in constitutive activation of the IGF1R tyrosine kinase.	Rearrangements of the IGF1R gene locus at 15q26.	Rare	D, T

Individual Region Genomic Gain/Loss/LOH

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Gene Mutations (SNV/INDEL)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Genes and Main Pathways Involved

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
ALK, ROS1, NTRK3, NTRK1, RET, PDGFRB, RET, and other tyrosine kinase genes; Activating gene fusions	JAK/STAT3, PI3K, RAS/RAF/MAPK signaling	Increased cell growth and proliferation

Genetic Diagnostic Testing Methods

Next generation sequencing and RT-PCR for fusion detection; FISH; immunohistochemistry for ALK, ROS1 (less sensitive/specific), and NTRK1/2/3 fusion detection.

Familial Forms

None

Links

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):