PLoS Genetics (Dec 2020)

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes.

  • Anna Byrjalsen,
  • Thomas V O Hansen,
  • Ulrik K Stoltze,
  • Mana M Mehrjouy,
  • Nanna Moeller Barnkob,
  • Lisa L Hjalgrim,
  • René Mathiasen,
  • Charlotte K Lautrup,
  • Pernille A Gregersen,
  • Henrik Hasle,
  • Peder S Wehner,
  • Ruta Tuckuviene,
  • Peter Wad Sackett,
  • Adrian O Laspiur,
  • Maria Rossing,
  • Rasmus L Marvig,
  • Niels Tommerup,
  • Tina Elisabeth Olsen,
  • David Scheie,
  • Ramneek Gupta,
  • Anne-Marie Gerdes,
  • Kjeld Schmiegelow,
  • Karin Wadt

DOI
https://doi.org/10.1371/journal.pgen.1009231
Journal volume & issue
Vol. 16, no. 12
p. e1009231

Abstract

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PurposeHistorically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS.MethodsChildren (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries.Results198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene.ConclusionThese results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.