Differences in Molecular Genetics Between Pediatric and Adult Malignant Astrocytomas

Age Matters

Stephen W Gilheeney; Mark W Kieran

Disclosures

Future Oncol. 2012;8(5):549-558. 

In This Article

p53

The p53 tumor suppressor gene codes for a nuclear phosphoprotein involved in cell cycle arrest, apoptosis, and genetic stability and p53 mutations are among the most common mutations found in human cancers.[50,51] Previous work by multiple groups has found the presence of p53 mutations and/or overexpression in adult malignant astrocytomas, raising question as to their incidence in pediatric neoplasms. While early reports had suggested that multiple alterations of the TP53 genes were uncommon in pediatric patients, subsequent work suggests a different picture. Multiple groups have characterized pediatric WHO grade 3 and 4 tumors and found mutations or overexpression in the p53 gene in approximately 35–50% of these tumors, similar to the incidence seen in reports of adult tumors.[52,53] A specific p53 mutation (P53 Arg72Pro) in both adult and pediatric high-grade astrocytomas suggests that certain mutations are common between these two populations.[54] Pollack et al. analyzed tumor samples from the CCG-945 study, a large Children's Cancer Group study from 1985 to 1992 that treated newly diagnosed high-grade astrocytomas.[55] Their results demonstrated a frequency of TP53 mutations in pediatric tumors that was greater than that observed in previous pediatric studies, and similar to the incidence seen in young adults. The mutations that were seen in the pediatric tumors were overwhelmingly observed in patients >3 years old and further supports the differences in the biology of GBM in young children.[55] Analysis of expression (but not mutation) of p53 in 115 pediatric glioma specimens confirmed the importance of this marker as an independent outcome variable, with TP53 expression associated with poorer prognosis (5-year progression-free survival 44 ± 6% vs 17 ± 6% in low-expressing and high-expressing tumors, respectively).[56] Most recently, the role of both overexpression and mutation of p53 were confirmed in cohorts of pediatric patients with high-grade gliomas,[18] while results from pediatric pilocytic astrocytomas failed to associate with outcome,[57] which is likely related to the overall excellent prognosis in this group. These results therefore suggest an overlapping role for p53 in older pediatric and younger adult patients with high-grade astrocytomas, and are contrasted by results for infants and the elderly. P53 abnormalities in 35% of cases are also observed in pilocytic low-grade pediatric tumors with an excellent prognosis.[58] Of importance in this analysis was the significantly higher incidence of p53 abnormality compared with other publications, suggesting that as newer technologies become available, we may become more accurate at identifying expression or mutational events ([58] compared with[59]).

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