TP53 – Choroid Plexus Carcinoma

Choroid plexus carcinoma (CPC) is a rare, aggressive pediatric brain tumor predominantly linked to germline TP53 variants. Clinical studies and case series have consistently identified TP53 mutations in CPC patients, implicating TP53 as a key predisposition gene.

TP53 variants have been reported in over 20 unrelated CPC probands, including five families with germline mutations (n = 5 families) (PMID:15925506), nine R337H founder carriers in a Brazilian cohort (PMID:21192060), and six individual cases comprising de novo germline (PMID:11800650), Li-Fraumeni syndrome (PMID:15654279), somatic (PMID:22534715), constitutional mosaicism (PMID:29025599), and a sibling pair (PMID:36128143). This abundance of independent observations supports a definitive gene–disease relationship.

Inheritance is autosomal dominant with high penetrance. Segregation of heterozygous TP53 variants in two affected siblings confirms familial transmission (PMID:36128143). No unaffected carriers have been reported among obligate carriers in these families, underscoring the variant pathogenicity.

The variant spectrum in CPC includes missense hotspots (e.g., c.455C>T (p.Pro152Leu) (PMID:15654279), c.742C>T (p.Arg248Trp) (PMID:29025599), c.1010G>A (p.Arg337His) (PMID:21192060)), frameshifts (e.g., c.72dup (p.Leu25ThrfsTer4) (PMID:36128143)), splicing defects, and large deletions.

Mechanistically, CPC-associated TP53 mutants exhibit loss of transcriptional activation, dominant-negative inhibition of wild-type p53, and gain-of-function oncogenic properties. In vitro transcriptional assays demonstrate abrogation of p53-mediated reporter activation by hotspot mutants (PMID:2144364, PMID:2218501). These functional data are concordant with human phenotypes and support haploinsufficiency and dominant-negative pathogenic mechanisms.

Integrating genetic and experimental evidence yields a definitive association between TP53 and CPC, justifying TP53 testing in all pediatric CPC cases for diagnosis, familial counseling, and surveillance planning. TP53 variant detection directly informs personalized management and cancer prevention strategies.

References

• Archives of pathology & laboratory medicine • 2002 • Coincident choroid plexus carcinoma and adrenocortical carcinoma with elevated p53 expression: a case report of an 18-month-old boy with no family history of cancer. PMID:11800650
• Journal of pediatric hematology/oncology • 2005 • Successful treatment of an unresectable choroid plexus carcinoma in a patient with Li-Fraumeni syndrome. PMID:15654279
• Medical science monitor • 2012 • A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma. PMID:22534715
• Cancer genetics • 2017 • Constitutional mosaicism of a de novo TP53 mutation in a patient with bilateral choroid plexus carcinoma. PMID:29025599
• Surgical neurology international • 2022 • Choroid plexus carcinoma in two siblings, with a novel genetic mutation in TP53 - A case report and review of literature. PMID:36128143
• European journal of cancer • 2005 • Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. PMID:15925506
• Cancer • 2011 • Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. PMID:21192060
• Science • 1990 • Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. PMID:2144364
• Science • 1990 • Different tumor-derived p53 mutants exhibit distinct biological activities. PMID:2218501

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