Whole genome sequencing and inheritance-based variant filtering as a tool for unraveling missing heritability in pediatric cancer

Derpoorter, Charlotte; Paemel, Ruben Van; Vandemeulebroecke, Katrien; Vanhooren, Jolien; Wilde, Bram De; Laureys, Geneviève; Lammens, Tim

doi:10.1080/08880018.2022.2101723

Cited by 1 publication

(1 citation statement)

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“…Family studies, of which trio or quad are the simplest type, in complex diseases such as autism and psychiatric disorders (Iossifov et al 2014); (Iossifov et al 2012); (McCarthy et al 2014); (Fromer et al 2014); (Lelieveld et al 2016) have shown the power of utilizing a family study design to filter shared variants with little impact on pathogenicity, while highlighting significant differences that may be causative. In fact, utilization of family structure has successfully uncovered drivers in pediatric cancers (Kuhlen et al 2019); (Derpoorter et al 2023). This may be particularly informative in early-onset cancer probands, who in addition to de novo mutations which have been found to be potentially disruptive and implicated in a variety of diseases (Acuna-Hidalgo, Veltman, and Hoischen 2016), may have inherited separate variants from each unaffected parent that act in concert to drive carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Exploring the genetic and epigenetic underpinnings of early-onset cancers: Variant prioritization for long read whole genome sequencing from family cancer pedigrees

Kramer,

Goodwin,

Wappel

et al. 2024

Preprint

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Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidatedenovoand compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses.

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