TP53 – Sarcoma

Germline and somatic alterations of the tumor suppressor gene TP53 (HGNC:11998) are established drivers of sarcoma (MONDO:0005089). Sarcomas represent 25% of tumors in TP53 mutation carriers and occur predominantly before age 50, underscoring the gene’s critical role in mesenchymal neoplasia (PMID:21837677).

Sarcoma predisposition follows an autosomal dominant inheritance pattern, with both de novo and familial germline TP53 mutations documented. In a cohort of 196 sarcoma patients, eight unrelated individuals harbored germline TP53 mutations, three of which occurred in apparently sporadic cases (PMID:1565143). De novo synonymous splice‐site and missense mutations further highlight mutational diversity in adolescents and adults (PMID:28475293).

Segregation analysis in Li‐Fraumeni‐like families reveals multiple affected relatives. A three‐generation kindred exhibited malignant fibrous histiocytoma in a mother and liposarcoma in two offspring, consistent with autosomal dominant transmission despite negative blood sequencing in the proband (PMID:9167603). Another pedigree included 16 sarcoma-affected relatives, demonstrating high penetrance and familial clustering (PMID:14584079).

The variant spectrum encompasses missense substitutions, truncating alleles, splice-site changes, and founder mutations. Notably, the Brazilian founder mutation c.1010G>A (p.Arg337His) is present in 8% of unselected sarcoma patients, predominantly leiomyosarcoma, reflecting population-specific recurrence (PMID:31978118).

Functional studies confirm that most TP53 mutations disrupt DNA binding and transcriptional activation, exert dominant‐negative effects, or impair apoptotic signaling. Oncogenic p53 mutants fail to activate p53-responsive promoters and can abrogate wild‐type function in cotranslation assays, consistent with loss-of-function and dominant‐negative mechanisms (PMID:1589764).

Taken together, extensive genetic and experimental data establish a definitive association between TP53 mutations and sarcoma risk, supporting the utility of TP53 testing in patients with early-onset or familial sarcomas. Early identification enables tailored surveillance and informs therapeutic decisions.

Key Take-home: TP53 germline and somatic mutations confer high sarcoma susceptibility via dominant‐negative and loss‐of-function mechanisms, warranting genetic screening in at‐risk individuals for improved clinical management.

References

• The New England Journal of Medicine • 1992 • Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. PMID:1565143
• Cancer • 2012 • Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. PMID:21837677
• Archives of pathology & laboratory medicine • 1997 • Familial aggregation of soft tissue sarcomas: a report of three cases from a Li-Fraumeni-like family. PMID:9167603
• Pediatric and developmental pathology • 2010 • p53+/mdm2- atypical lipomatous tumor/well-differentiated liposarcoma in young children: an early expression of Li-Fraumeni syndrome. PMID:20028212
• PLoS One • 2020 • The Brazilian TP53 mutation (R337H) and sarcomas. PMID:31978118
• Science • 1992 • Oncogenic forms of p53 inhibit p53-regulated gene expression. PMID:1589764

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