Desmoid tumors arise through pathogenic alterations in the APC gene, which encodes a protein involved in the regulation of cell proliferation via the Wnt signaling pathway. APC is located on chromosome 5, as documented in this packet's gene location data. Tumors may arise in the context of germline APC pathogenic variants associated with APC-related familial adenomatous polyposis, or through somatic APC mutations in individuals without constitutional APC alterations, as documented in the disease subtype 'desmoid tumor caused by somatic mutation.' GeneReviews characterization of APC-associated polyposis conditions describes genotype-phenotype correlations indicating that desmoid tumor risk is associated with pathogenic variants in specific APC codon regions (codons 1395-1493), as well as female sex and a family history of desmoid tumors. GeneReviews notes that there is evidence that the risk of developing desmoid tumors is increased following abdominal surgery, and that this risk may be higher following two-stage procedures. Prevalence of APC-associated polyposis conditions is estimated at 1 in 6,850 to 1 in 31,250 live births in the GeneReviews entry; desmoid-specific prevalence data are not available in this packet.

Diagnosis of desmoid tumor combines clinical assessment, imaging, and pathologic confirmation. Molecular evaluation for APC pathogenic variants is relevant when an APC-associated familial syndrome is suspected, particularly when colorectal polyposis or other FAP-related features co-occur. APC is identified in this packet as a gene with known clinical validity in relation to desmoid tumor. GeneReviews for APC-associated polyposis conditions indicates that diagnosis is prompted by colorectal adenomatous polyps and extracolonic manifestations including desmoid tumors. Histopathological examination of tissue is used to characterize the neoplasm. Imaging studies including CT and MRI characterize disease extent and involvement of adjacent structures. Differential diagnoses in the hereditary polyposis context, as enumerated in GeneReviews, include other polyposis and colorectal cancer syndromes distinguished by molecular genetic testing, histopathological findings, and phenotypic characteristics. Phenotypic variability — with inter- and intrafamilial variation common in FAP — is noted in the GeneReviews entry.

No pharmacologic agents are listed in this packet's approved treatments or foundational therapies fields for desmoid tumor. Clinical trials documented in this packet include a Phase II investigation of nirogacestat in Japanese adults with desmoid tumors/aggressive fibromatosis (NCT07170644, SpringWorks Therapeutics, active not recruiting). Additional active and recruiting trials across multiple phases and sites are listed in the clinical trial data. GeneReviews documentation for APC-associated polyposis conditions notes that abdominal surgery carries an elevated risk of desmoid tumor development in individuals at high genetic risk; surgical planning in this population takes this risk into account. GeneReviews also documents investigational therapeutic approaches studied in APC-associated polyposis conditions, including omega-3 polyunsaturated fatty acids (eicosapentaenoic acid), obeticholic acid, lorpucitinib (a pan-Janus kinase inhibitor), encapsulated sirolimus, and guselkumab (an IL-23 inhibitor), as investigated in clinical trials focused on polyposis burden rather than desmoid tumor specifically.

Natural history data specific to desmoid tumor are not available in this packet. In the context of APC-associated polyposis conditions, GeneReviews documents that penetrance is 100% in classic familial adenomatous polyposis, meaning colorectal polyposis expression is essentially universal, with extracolonic manifestations including desmoid tumors occurring variably. GeneReviews reports wide phenotypic variability in individuals with APC-associated polyposis, with inter- and intrafamilial differences observed even among individuals carrying identical APC pathogenic variants. This variability applies to desmoid tumor occurrence and behavior as well. GeneReviews notes that fecundity implications may arise in women following certain colectomy procedures, a consideration relevant to the surgical management context of APC-associated desmoid tumor cases. Long-term clinical management of desmoid tumors involves monitoring of tumor behavior and management of co-occurring conditions associated with APC pathogenic variants.

Active clinical research in desmoid tumor is documented across multiple trials in this packet. Phase II investigation of nirogacestat in desmoid tumors/aggressive fibromatosis in Japan is actively enrolling (NCT07170644). Additional trials across multiple phases, including studies of targeted agents, are listed as recruiting or active not recruiting. GeneReviews documents multiple ongoing multicenter trials in APC-associated polyposis conditions investigating obeticholic acid, lorpucitinib, encapsulated sirolimus, and guselkumab, as well as a Phase III study of eicosapentaenoic acid for rectal polyposis. Research in desmoid tumors increasingly includes evaluation of signaling pathway-targeted agents in advanced disease settings, as reflected in the clinical trial portfolio in this packet.