TP53 Alterations Determine Clinical Subgroups and Survival of Patients With Choroid Plexus Tumors

Abstract

PURPOSE Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. PATIENTS AND METHODS We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (+/- 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. CONCLUSION Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.

Molecular Characterization of Choroid Plexus Tumors Reveals Novel Clinically Relevant Subgroups

“…Over 50% of CPC tumors carry somatic TP53 mutations, and TP53 mutant CPCs have been associated with increased genetic tumor instability and worse prognosis (5). Germline TP53 mutations have also been observed in patients with CPC as CPC is one of the hallmark cancers of the Li-Fraumeni syndrome (LFS), a familial cancer syndrome in which affected family members harbor a mutant copy of the TP53 tumor suppressor gene.…”

“…Sequencing of the coding region of TP53 (exons 2-11) was performed in the molecular diagnostic laboratory at The Hospital for Sick Children (Toronto) by direct Sanger sequencing of whole genome DNA as previously described (5).…”

“…(3)). Conversely, CPCs exhibit a dismal prognosis, with an overall survival of about 30% (4)(5)(6). Despite aggressive treatment protocols, including surgical resection and combination of chemoand radiation therapy (6), the clinical behavior of CPCs is variable and most of the few survivors exhibit long-term cognitive and developmental deficits (6).…”

Surgical outcomes in choroid plexus papillomas: an institutional experience

“…The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway is involved in ligand-induced apoptosis and was found to be methylated in a large proportion of CPPs [31]. In choroid plexus carcinomas, extensive analysis has shown that TP53 status can predict survival; those with wild-type TP53 and low total structural variation (TSV) have a favorable prognosis and do not require radiation therapy, while those with TP53-mutated tumors should be treated more aggressively [22]. Given the rarity of these lesions and complex molecular pathways involved in tumorigenesis, large multi-institutional collaborative efforts will be needed to produce meaningful progress in the treatment of this disease.…”

“…Furthermore, we have demonstrated that these tumors can be safely removed, regardless of location, and likely do not require up-front radiation, even in cases of STR. Since some CPPs still recur despite GTR, future studies should build upon previously published genetic analysis of these tumors in order to identify markers that can refine our current grading scheme and provide improved insight towards predicting which tumors will recur [22][23][24][25][26]. Platelet-derived growth factor receptor (PDGFR) has been implicated in choroid plexus tumors, particularly carcinomas [27].…”