Germline cancer predisposition variants and pediatric glioma: a population-based study in California

Abstract

Background Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level. Methods DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes. Results We identified 33 putatively pathogenic germline variants among 31 patients (11.1%) which were located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N = 9/63). Five variants were located in tumor protein 53 (TP53), of which 4 were identified among patients with glioblastoma (6.3%, N = 4/63). The next most frequently mutated gene was neurofibromatosis 1 (NF1), in which putatively pathogenic variants were identified in 4 patients with astrocytoma not otherwise specified. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (odds ratio, 32.8, P = 8.04 × 10−7). Conclusion A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.

Increased Cancer Risk in Families with Pediatric Cancer Is Associated with Gender, Age, Diagnosis, and Degree of Relation to the Child

“…The relatively low number of children with CNS tumors in the current cohort could explain the lack of overall increased breast cancer risk among first-degree relatives. Specific pathogenic germline variants are associated with increased risk for both pediatric CNS tumors and breast cancer, such as variants in TP53, BRCA2, BRCA1, and APC (31,32). However, in the present cohort, these variants were identified in a minority of the patients with childhood cancer (n ¼ 12).…”

Population-based whole-genome sequencing with constrained gene analysis identifies predisposing germline variants in children with central nervous system tumors

“…These studies, however, include partly overlapping cohorts with overrepresentation of cancers with poor clinical outcome potentially resulting in misleading variant estimates compared to population-based approaches. Similar studies on pediatric CNS tumors have found pathogenic germline alterations in up to 35%, with estimates varying greatly depending on tumor type focus, sample selection and study methodology [4][5][6][7] . Although some have employed population-based approaches, most studies suffer from either small sample sizes, selection bias towards recurrent/high-grade tumors, restricted tumor type focus or from lack of detailed clinical data and relevant family history.…”

Die Rolle von genetischer Prädisposition bei Krebserkrankungen im Kindesalter

“…Obwohl Leukämien die häufigste bösartige Erkrankung im Kindesalter darstellen, ist die Wahrscheinlichkeit auf das Vorliegen eines KPS bei den soliden Tumoren 22 und den Tumoren des Zentralnervensystems 23 – 25 insgesamt höher.…”