Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours

Abstract

Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

Figure 1. TGCT somatic SNV spectrum exome wide.

Proportions are displayed for all 12 possible SNV alterations, collapsed by strand complementarity. Each line represents one of the 42 tumours.

Figure 2. Mutated genes in testicular germ cell tumour by histological subtype.

The top bars represent somatic mutation rate per sample for the 42 samples (synonymous and non-synonymous (including small-scale indels)). The genes listed on the right are mutated genes as prioritized by MutSigCV, ranked by −log₁₀(P value) (far right), with the dotted red line denoting a significance threshold of P=0.05 and the solid red line a genome-wide significance threshold of 5 × 10⁻⁶ (see Methods). Below the top ranked genes in a separate box are other notable but non-significant mutations. Mutations by sample are depicted in the central box, with colour indicating mutation type as per the legend. The far left bars represent the absolute number of mutations observed per gene across all samples and adjacent to this is the % of samples this represents.

Figure 3. Circos Plot showing the count of SNV variants and copy number changes in the 42 tumours.

Outer ring marks the count of SNV variants across all 42 samples with proposed driver SNVs as blue dots and other SNVs as black lines; inner ring marks large-scale copy number gains (red) and losses (green).