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

Anna Byrjalsen,Henrik Hasle,Tina Elisabeth Olsen,David Scheie,Karin Wadt,Nanna Moeller Barnkob,Niels Tommerup,René Mathiasen,Kjeld Schmiegelow,Mana M Mehrjouy,Peter Wad Sackett,Maria Rossing,Ramneek Gupta,Ruta Tuckuviene,Adrian Otamendi Laspiur ,Ulrik Kristoffer Stoltze ,Pernille A Gregersen ,Charlotte Kvist Lautrup ,Anne Gerdes ,Peder Skov Wehner ,Rasmus Lykke Marvig ,Lisa Lyngsie Hjalgrim ,Thomas V.o Hansen

doi:10.1371/journal.pgen.1009231

Abstract

Historically, 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. Children (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. 198 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. These 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.

Highlights

In Europe, 15,000 children (1 in 300) are diagnosed with cancer each year.[1]
Pediatric cancer have been thought to be–mostly–caused by pure bad luck. This notion has been challenged by novel findings as both maternal environmental exposure and genetic causes have been proven to increase the risk of certain pediatric cancers
With this study we have investigated a national cohort of pediatric cancer patients in Denmark

Summary

Introduction

In Europe, 15,000 children (1 in 300) are diagnosed with cancer each year.[1] Cancer can be attributed to genetic predisposition, exposure to carcinogens, and/or random mutations during cell division. Children are exposed to fewer carcinogens than adults.[2,3] genetic predisposition and randomly acquired mutations are the major causes of most childhood cancers. Cancer predisposition syndromes (CPSs) were previously considered rare among pediatric cancer patients, but increasing use of whole-exome sequencing (WES) and whole-genome sequencing (WGS) have identified up to 10% CPS among children, including several cases of CPS for adult-onset cancers not previously associated with childhood CPS. Most studies have focused on single nucleotide variants (SNVs) and few have included the effects of copy number variants (CNVs).[12]

Results

Discussion

Conclusion