FoundationOne CDx testing accurately determines whole arm 1p19q codeletion status in gliomas

Abstract

Background: Molecular profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify clinical trial options for primary and recurrent tumors. This study aimed to determine the accuracy of reporting the whole arm 1p19q codeletion status from the FoundationOne platform.

Methods: Testing was performed on glioma samples as part of clinical care and analyzed up to 395 cancer-associated genes (including IDH1/2). The whole arm 1p19q codeletion status was predicted from the same assay using a custom research-use only algorithm, which was validated using 463 glioma samples with available fluorescence in-situ hybridization (FISH) data. For 519 patients with available outcomes data, progression-free and overall survival were assessed based on whole arm 1p19q codeletion status derived from sequencing data.

Results: Concordance between 1p19q status based on FISH and our algorithm was 96.7% (449/463) with a positive predictive value (PPV) of 100% and a positive percent agreement (PPA) of 91.0%. All discordant samples were positive for codeletion by FISH and harbored genomic alterations inconsistent with oligodendrogliomas. Median overall survival was 168 months for the IDH1/2 mutant, codeleted group, and 122 months for IDH1/2 mutant-only (hazard ratio (HR): 0.42; P < .05).

Conclusions: 1p19q codeletion status derived from FoundationOne testing is highly concordant with FISH results. Genomic profiling may be a reliable substitute for traditional FISH testing while also providing IDH1/2 status.

Keywords: 1p19q; CGP; F1CDx; FoundationOne; comprehensive genomic profiling; glioma.

Figure 1.

Pie chart depicting the distribution of IDH1/2 mutations across samples. Results are summarized in the table.

Figure 2.

(A) Top plot shows the normalized coverage data for a sample with 1p19q codeletion, normalized to a process-matched control. Blue dots represent target baits and cyan dots represent SNP baits. The bottom plot shows the minor allele frequency for SNPs found within this patient. (B) Fraction of chr1p (x-axis) and chr19q (y-axis) under LOH across all 463 samples. Samples that were categorized as positive for codeletion by FISH are shown in orange and those categorized as negative are shown in dark blue. The cutoff of 0.5 used for our computational 1p19q codeletion algorithm is shown as a dotted line. All samples called as positive by our testing were FISH positive, depicted in orange. Discordant samples are depicted in orange (FISH positive) but lie outside of our dotted cut-off line for the fraction of chr1p and chr19q that is under LOH.

Figure 3.

(A) Table showing the concordance results for all samples regardless of their IDH1/2 mutation status. (B) Table showing the concordance results for IDH1/2-mutated samples. (C) Tile plot showing the distribution of alterations, 1p19q codeletion, age, TMB, and mutational signatures across samples used for validation. (D) Tile plot showing the distribution of alterations and 1p19q codeletion among discordant samples. F1, FoundationOne testing; F1CDx, FoundationOne CDx testing; LOH, loss of heterozygosity; TMB, tumor mutational burden; FISH, fluorescence in-situ hybridization.

Figure 4.

(A) Matrix showing the number of samples classified under each group by pathology (rows) vs. by molecular classification (columns). (B) An alluvial plot showing how samples are distributed across the different pathological groups vs. molecular classification.

Figure 5.

Kaplan Meier plot showing the overall survival (A) and progression-free survival (B) of IDH1/2 WT vs. mutated samples. The overall survival and progression-free survival of IDH1/2 WT vs. IDH1/2 mutated 1p19q codeleted vs. IDH1/2 mutated 1p19q intact are shown in (C) and (D). The overall survival and progression-free survival of IDH1/2 mutated hypermutated vs. IDH1/2 mutated non-hypermutated are shown in (E) and (F).