Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors

Abstract

Chromosomal alterations have recurrently been identified in Wilms tumors (WTs) and some are associated with poor prognosis. Gain of 1q (1q+) is of special interest given its high prevalence and is currently actively studied for its prognostic value. However, the underlying mutational mechanisms and functional effects remain unknown. In a national unbiased cohort of 30 primary WTs, we integrated somatic SNVs, CNs and SVs with expression data and distinguished four clusters characterized by affected biological processes: muscle differentiation, immune system, kidney development and proliferation. Combined genome-wide CN and SV profiles showed that tumors profoundly differ in both their types of 1q+ and genomic stability and can be grouped into WTs with co-occurring 1p−/1q+, multiple chromosomal gains or CN neutral tumors. We identified 1q+ in eight tumors that differ in mutational mechanisms, subsequent rearrangements and genomic contexts. Moreover, 1q+ tumors were present in all four expression clusters reflecting activation of various biological processes, and individual tumors overexpress different genes on 1q. In conclusion, by integrating CNs, SVs and gene expression, we identified subgroups of 1q+ tumors reflecting differences in the functional effect of 1q gain, indicating that expression data is likely needed for further risk stratification of 1q+ WTs.

Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics

“…Remarkable differences were an increased chromosome 1q gain (11%, n = 4) and an enhanced chromosome 10 loss (11%, n = 4) in recurrences as compared to primaries. So far, chromosome 1q gain has been associated with an inferior prognosis in different studies of ependymomas [ 1 , 12 ] and nephroblastomas [ 2 ]. Its role in AT/RT deserves further investigation.…”

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

“…To characterize complex structural variation patterns across pediatric solid tumors, we selected patients diagnosed with Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, Wilms tumor and hepatoblastoma for which primary tumor material was included in the Máxima biobank, subject to informed consent [39]. Patients were eligible when whole-genome sequencing (WGS) data of sufficient quality was available from matching tumor-normal samples taken within 150 days of diagnosis and the variant calling steps were successfully completed.…”

“…Patients were eligible when wholegenome sequencing (WGS) data of sufficient quality was available from matching tumornormal samples taken within 150 days of diagnosis and the variant calling steps were successfully completed. Sequencing library preparation and data pre-processing, including alignment and quality control, was done via the institute's standardized pipelines and guidelines as described before [39][40][41]. In summary, high quality WGS samples were selected requiring a minimum median coverage of 27x for normal samples and 81x for tumor samples.…”