TY - JOUR
T1 - Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer prone syndromes
AU - Byrjalsen, Anna
AU - Hansen, Thomas V.O.
AU - Stoltze, Ulrik K.
AU - Mehrjouy, Mana M.
AU - Barnkob, Nanna Moeller
AU - Hjalgrim, Lisa L.
AU - Mathiasen, René
AU - Lautrup, Charlotte K.
AU - Gregersen, Pernille A.
AU - Hasle, Henrik
AU - Wehner, Peder S.
AU - Tuckuviene, Ruta
AU - Sackett, Peter Wad
AU - Laspiur, Adrian O.
AU - Rossing, Maria
AU - Marvig, Rasmus L.
AU - Tommerup, Niels
AU - Olsen, Tina Elisabeth
AU - Scheie, David
AU - Gupta, Ramneek
AU - Gerdes, Anne Marie
AU - Schmiegelow, Kjeld
AU - Wadt, Karin
PY - 2020/12/17
Y1 - 2020/12/17
N2 - PURPOSE: 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.METHODS: 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. RESULTS: 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. CONCLUSION: 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.
AB - PURPOSE: 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.METHODS: 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. RESULTS: 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. CONCLUSION: 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.
UR - http://www.scopus.com/inward/record.url?scp=85098964008&partnerID=8YFLogxK
U2 - 10.1371/JOURNAL.PGEN.1009231
DO - 10.1371/JOURNAL.PGEN.1009231
M3 - Journal article
C2 - 33332384
AN - SCOPUS:85098964008
SN - 1553-7390
VL - 16
JO - PLOS Genetics
JF - PLOS Genetics
IS - 12
M1 - e1009231
ER -