APC – Desmoid Tumor

Germline variants in the adenomatous polyposis coli (APC) gene underlie autosomal dominant predisposition to desmoid tumors, a fibroblastic proliferation associated with familial adenomatous polyposis (FAP) and sporadic aggressive fibromatosis. Desmoid tumors display local invasiveness and high recurrence rates but lack metastatic potential. The mode of inheritance is autosomal dominant, with germline truncating APC mutations clustering at the 3′ end of the gene conferring near‐complete penetrance of the desmoid phenotype in multiple kindreds.

Clinical Validity

Strong evidence supports the APC–desmoid tumor association: at least 9 unrelated probands with germline APC truncating variants have been reported across 7 families, all showing autosomal dominant transmission with penetrance approaching 100% and multi‐family segregation (6 affected relatives) ([PMID:29998021]). Somatic second hits of the wild‐type APC allele are consistently identified in desmoid lesions, demonstrating biallelic inactivation and fulfilling Knudson’s two‐hit model ([PMID:8221638]; [PMID:10782927]). Experimental concordance across human tumors and animal models further substantiates causality.

Genetic Evidence

Inheritance is autosomal dominant. Segregation analysis in a large Uruguayan kindred identified the recurrent frameshift variant c.4393_4394del (p.Ser1465fs) in 6 family members with desmoid tumors ([PMID:29998021]). Case series describe at least 9 probands with truncating APC variants—insertions (e.g., Alu I insertion at codon 1526), small deletions (e.g., c.4393_4394del), and nonsense changes—predominantly in exon 15. Founder and recurrent alleles cluster between codons 1399–1578, the region associated with heightened desmoid risk. Polyposis is often attenuated or absent in these families, with desmoids as the sentinel manifestation.

Functional Evidence

Desmoid tumors from APC‐mutant FAP patients consistently show loss of the wild‐type allele or large genomic deletions at 5q22.5 including the APC locus, and immunohistochemistry reveals nuclear β-catenin accumulation in tumor cells, linking APC loss to constitutive Wnt pathway activation ([PMID:10782927]; [PMID:8221638]). In Apc^Min/+ mouse models, loss of PKCα exacerbates tumor multiplicity, further tying APC dysfunction to desmoid‐like lesion development ([PMID:16849539]). Pharmacologic studies demonstrate elevated COX-2 and PDGFR signaling in desmoid tissues, consistent with APC‐driven Wnt dysregulation.

Conflicting Evidence

Somatic APC mutations are rare in truly sporadic desmoids lacking CTNNB1 alterations, suggesting distinct pathogenetic subsets and the predominant role of CTNNB1 in non‐FAP cases ([PMID:9744495]). However, germline APC variants remain the primary driver in familial desmoid disease.

Integration & Clinical Utility

Germline APC truncating variants—particularly in the 3′ region—are definitively associated with autosomal dominant desmoid tumors via haploinsufficiency and biallelic inactivation in tumors leading to Wnt/β-catenin overactivation. Genetic testing for APC mutations is recommended in individuals and families presenting with desmoid tumors, even in the absence of significant colonic polyposis. Early identification enables tailored surveillance, prophylactic interventions, and family counseling.

Key Take-home: Germline truncating APC mutations, especially between codons 1399–1578, confer a high risk of desmoid tumors through Wnt pathway dysregulation, warranting genetic testing in familial and select sporadic cases.

References

• Human heredity • 1999 • Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene. PMID:10077730
• Clinical genetics • 2000 • A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. PMID:10782927
• Journal of gastrointestinal oncology • 2018 • Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance. PMID:29998021
• Cancer research • 1993 • Coexistence of somatic and germ-line mutations of APC gene in desmoid tumors from patients with familial adenomatous polyposis. PMID:8221638
• British journal of cancer • 1998 • Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours. PMID:9744495
• Gut • 2004 • Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation. PMID:15542524
• Cancer research • 2006 • Protein kinase C alpha but not PKCζ suppresses intestinal tumor formation in ApcMin/+ mice. PMID:16849539

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