12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors

Abstract

Background: Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs.

Methods: Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH).

Results: A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs.

Conclusions: 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

Keywords: 12p gain; DNA methylation; FISH; central nervous system germ cell tumor; copy number alteration.

Fig. 1

Profile of copy number alterations in central nervous system germ cell tumors (CNS GCTs). 12p gain is the most frequently altered chromosome arm, particularly in non-germinomatous germ cell tumors (NGGCTs) (A). In the conumee plot of a representative case with 12p gain, the copy number level of 12p is higher than what would be expected for a single copy gain, suggesting the presence of polyploidy. There was no sign of 12q loss (B).

Fig. 2

The frequency of copy number alteration in each chromosomal arm in CNS GCT. 12p gain is the most frequently altered chromosome arms (A). 12p gain is significantly overrepresented in non-germinomatous germ cell tumors (NGGCT) (P = 0.0002). Among the NGGCTs, tumors with malignant histological components (immature teratoma, yolk sac tumor, choriocarcinoma, or embryonal carcinoma) harbored significantly more frequent 12p gain (B).

Fig. 3

Copy number analysis in a microdissected mixed germ cell tumor, GCT51. The case consists of approximately 50% of germinoma, 30% of YST, and 20% of immature teratoma on formalin-fixed, paraffin-embedded section. The histology is shown in the top row. 12p gain was shared in germinoma and NGGCT components by 450K (middle row, arrowhead). Fluorescence in situ hybridization (FISH) analysis also showed 12p gain in germinoma and NGGCT (yolk sac tumor; YST) components (bottom row). In FISH analysis, green and orange signals correspond to 12p and centromere of chromosome 12 (CEP12) signals, respectively. Scale bar = 5 mm, 100 μm, or 25 μm, as indicated in the figures.

Fig. 4

Survival analysis in 80 central nervous system germ cell tumors (CNS GCTs). Among all CNS GCTs, 12p-gained cases showed significantly shorter progression-free survival (PFS) (A) and overall survival (OS) (B) as compared to 12p-intact cases. There was no statistically significant difference in survival in germinomas with 12p-gained cases and without (C, D), although 12p gain cases showed a trend of shorter OS (D). Among non-germinomatous germ cell tumors, 12p-gained cases showed significantly shorter PFS (E) and OS (F) as compared to 12p-intact cases.