1p and/or 19q polysomy is an adverse prognostic factor in oligodendrogliomas, and easy to detect by automated FISH

Abstract

Objective: To study the feasibility of automated analysis by FISH technique in the determination of the 1p and/or 19q polysomy in oligodendrogliomas (OGs) and to explore its prognostic value.

Methods: We analyzed a retrospective monocentric series of 145 consecutive OGs with IDH mutation and 1p/19q codeletion. For all cases, automated FISH analyses were performed to determine 1p and/or 19q polysomy status and results were compared to manual analysis to verify the concordance of the two methods. Polysomic status was then compared to clinical and histological data, the CDKN2A deletion status when available, event free survival (EFS) and overall survival (OS).

Results: Our study comprised 79 grade 2 OGs (O2) and 66 grade 3 OGs (O3). Polysomy of 1p and/or 19q was observed in 58 cases (40% of whole cohort) with a significant enrichment in the high grade cohort (59% versus 24%; p < 0,0001) and recurrent cases (55%). A majority of polysomic cases were copolysomic for 1p and 19q (75% of the polysomic cohort) rather than 1p or 19q single polysomy (21% and 4% respectively). Polysomy was correlated to high grade histological criteria of high mitotic and Mib1 proliferative indices (p = 0,002 and p = 0,0005 respectively) and to vascular proliferation (p = 0,0003). Univariate and multivariate analysis showed a significant correlation betwen polysomy and a shorter EFS and OS (p = 0,02 and p = 0,016 respectively). Concordance between manual and automated analysis was almost perfect for both 1p and 19q analysis (96 and 98% respectively, κ = 0,92 and 0,95 respectively). Automated analysis revealed that the large majority of polysomic signatures are represented by a small number of R/G signals (mainly 7 signatures) allowing a very easy implementation to pre-existent FISH platforms analysis software.

Conclusion: 1p and/ or 19q polysomy status represent a prognostic factor in OGs and can be easily determined by automated analysis. Our study supports the clinical interest to determine the polysomic status in all primitive or recurrent OGs and underline the benefits of automated analysis which offers a better archive storage and facilitates multicentric comparison.

Fig 1. Representative R/G signals (Red spots/Green spots) for normal status

(A), deletion status without polysomy (B) and deletion status with polysomy (G ≥ 3) for 1p/1q and 19q/19p (C).

Fig 2. Event Free Survival (EFS) and Overall Survival (OS) according to the histological grade and to the chromosomal status. O3 anaplastic oligodendrogliomas are associated with shorter EFS and OS (raw 1). The presence of a CDKN2A gene deletion on 9p (both homozygous and heterozygous deletion) is associated with a shorter OS and a trend to a shorter EFS (raw 2).

Fig 3. Event Free Survival (EFS) and Overall Survival (OS) according to the 1p and/ or 19q polysomic status.

Polysomy is associated to a shorter EFS and OS (raw 1) regardless to 1p/19q copolsomy or single 1p or 19q polysomy status (raw 2). Polysomy is strongly associated to histological high grade (raw 3) and within the O3 cohort, presence of polysomy still corelated to shorter EFS and OS (raw 4).

Fig 4. Forest plots of Cox proportional hazard regression analysis for EFS and OS in univariate and multivariate analysis of hazard ratios (HR) and 95% confidence intervals (CI) of features in our cohort.

In the multivariate model, polysomy is independently associated with significantly shorter delay before recurrence (EFS) and worse clinical outcome (OS).

Fig 5. Repartition of R/G signals with 1p/1q and 19q/19p probes obtained by automated FISH analysis.

A,B: global R/G signal repartition with signals ≤ 0,75 corresponding to deletion status, between 0,75 and 1 to instability status, = 1 to normal status and > 1 to polysomy without deletion status. C,D: R/G signal repartition within the deletion + polysomy cohort revealed 4 distinct subgroups of signals corresponding to homozygosity for the chromosome (R/G = 0), hemizygosity (R/G < 0,5), polyploidy (R/G = 0,5 with an exception for the 1/2 signature) and instability (R/G > 0,5 and ≤ 0,75). E,F: significant R/G signatures in deletion + polysomic cohort identified 7 major signatures for both Chromosome 1 and 19 probes with a major predominance of R/G = 1/3, 2/4 and 2/3 signatures.