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Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in

Rabea Wagener1,2, Danielle Brandes1, Marie Jung1

  • 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

International Journal of Cancer
|September 30, 2023
PubMed

Insights

Optical genome mapping (OGM) reveals numerous rare structural variants (SVs) in pediatric cancer patients, identifying new potential cancer predisposition genes and improving diagnosis beyond whole exome sequencing (WES). This advanced technique offers a more comprehensive view of genetic alterations.

Area of Science:

  • Genetics
  • Oncology
  • Genomic Medicine

Background:

  • Germline alterations are key risk factors in pediatric cancers, yet current diagnostic methods like whole exome sequencing (WES) often miss crucial DNA alterations.
  • Approximately 10% of pediatric cancer patients carry known predisposing germline alterations, but many more may be undiagnosed due to limitations in current genetic analyses.

Purpose of the Study:

  • To evaluate the utility of optical genome mapping (OGM) for unbiased germline screening in pediatric cancer patients with suspected genetic predispositions.
  • To identify the frequency and impact of structural variants (SVs) in pediatric cancer patients where WES failed to detect pathogenic variants.

Main Methods:

  • Applied optical genome mapping (OGM) to a cohort of 34 pediatric cancer patients with high clinical suspicion for germline alterations.
  • Analyzed 18 patient-parent trios to identify de novo structural variants (SVs).
  • Screened for rare SVs, including deletions and duplications, in known and potential cancer predisposition genes.

Main Results:

  • OGM detected a median of 49 rare SVs per patient (range 27-149), significantly broadening the scope of detected genetic alterations.
  • Identified three de novo SVs in patient-parent trios.
  • Discovered a likely pathogenic BRCA2 deletion and a potentially novel cancer predisposition gene RPA1 duplication.

Conclusions:

  • Optical genome mapping (OGM) is effective for detecting potentially predisposing structural variants (SVs) in pediatric cancer patients.
  • OGM complements whole exome sequencing (WES) by providing a more comprehensive analysis of the genome, crucial for diagnosing rare genetic conditions.
  • This approach enhances the identification of genetic alterations contributing to pediatric cancer predisposition.

Keywords:
cancer predispositionoptical genome mappingpediatric cancerstructural variants

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