Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma

Abstract

Intracranial classic (WHO grade II) and anaplastic (WHO grade III) ependymomas are among the most common tumors in pediatric patients and have due to frequent recurrences and late relapses a relatively poor outcome. The impact of histopathological grading on patient outcome is controversial and therefore, molecular prognostic and predictive markers are needed to improve patient outcome. To date, the most promising candidate marker is chromosome 1q gain, which has been associated in independent studies with adverse outcome. Furthermore, gene expression and methylation profiles revealed distinct molecular subgroups in the supratentorial and posterior fossa (PF) compartment and Laminin alpha-2 (LAMA2) and Neural Epidermal Growth Factor Like-2 (NELL2) were suggested as surrogate markers for the two PF subgroups PF-EPN-A and PF-EPN-B. PF-EPN-A tumors were also characterized by tenascin-C (TNC) expression and tenascin-C has been suggested as candidate gene on 9q, involved in tumor progression. Therefore, we have analyzed the status of chromosome 1q, TNC, LAMA2, and NELL2 expression in a series of pediatric PF ependymomas in terms of their frequency, associations among themselves, and clinical parameters, as well as their prognostic impact. We confirm the negative prognostic impact of 1q gain and TNC expression and could classify PF ependymomas by these two markers into three molecular subgroups. Tumors with combined 1q gain and TNC expression had the poorest, tumors without 1q gain and TNC expression had a favorable and TNC positive 1q non-gained cases had an intermediate outcome. We found also differences in age and tumor grade in the three subgroups and thus, provide evidence that PF pediatric ependymomas can be divided by chromosome 1q status and TNC expression in three molecular subgroups with distinct clinico-pathological features. These analyses require only few amounts of tumor tissue, are broadly available in the routine clinical neuropathological setting and thus, could be used in further therapy trials to optimize treatment of ependymoma patients.

Heterogeneity within the PF-EPN-B ependymoma subgroup

“…Therefore, patients with PFB ependymoma, particularly children are excellent candidates for radiation sparing strategies, where carefully controlled studies are being contemplated of observation alone in the setting of gross total resection. Gain of 1q has been proposed as a marker of poor prognosis in PFA ependymoma, however its role in PFB is unclear [1, 4, 7, 8, 17, 25]. We have also recently shown that PFA ependymoma are highly heterogeneous entities with two major groups with multiple subtypes[13].…”

Chromosomal gains of 12p and 1q are not associated with inferior outcome of pediatric and adolescent germ cell tumors

“…Gains of 12p have recently also been detected in prepubertal testicular teratomas, which represent Type I GCT in children . Furthermore, gain of chromosome 1q, which is known to be associated with poor prognosis in a variety of malignancies of the childhood (eg, Wilms tumor or pediatric brain tumors), was examined for its prognostic relevance in pediatric GCT …”

“…17 Furthermore, gain of chromosome 1q, which is known to be associated with poor prognosis in a variety of malignancies of the childhood (eg, Wilms tumor or pediatric brain tumors), was examined for its prognostic relevance in pediatric GCT. [18][19][20][21][22]…”

Molecular Characteristics of Pediatric Ependymomas: A Systematic Review

“…The alterations showed the following statistical values: to 1q (Tau2 = 1.53, I 2 = 45%, P = 0.02, χ 2 = 9.13), to 9p (Tau2 = 1.27, χ 2 = 6.84, I 2 = 42%, P = 0.24) to 6q (Tau2 = 0.00, χ 2 = 2.06, I 2 = 0%, P = 0.58), to 13q (Tau2 = 0.00, χ 2 = 0.08, I 2 = 0%, P = 0.14), and to 22q indicated perfect homogeneity (Tau2 = 0.00, χ 2 = 0.08, I 2 = 0%, P = 0.14). Over a wide range, our model indicated heterogeneity with the following statistical values: Tau2 = 1.72, χ 2 = 37.8, P = 0.01, [39] FISH, IHC Chromosomal alteration, protein 52 Chen et al 2016 [40] I H C P r o t e i n 1 7 4 Gojo et al 2017 [41] qRT-PCR Methylation and expression 24 a Immunochemistry, b polymerase chain reaction, c comparative genomic hybridization, d real-time polymerase chain reaction, e methylation-specific PCR, f array CGH, h fluorescence hybridization in situ I 2 = 0%. Therefore, chromosomal alterations in 1q, 6q, 9p, 13q, and 22q are features of pediatric ependymal tumors.…”