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The Iceberg Map of germline mutations in childhood cancer

focus on primary immunodeficiencies

Kindler, Olivera; Quehenberger, Franzb; Benesch, Martinc; Seidel, Markus G.a,c

doi: 10.1097/MOP.0000000000000680

Purpose of review The risk of cancer is higher, and its outcome is worse in patients with primary immunodeficiency (PID) than in members of the general population. Thus, the inter-relationship of malignant diseases with PIDs requires more study.

Recent findings Large genetic screens identified a vast number of germline mutations in childhood cancer patient samples. Although TP53 was the most frequent single gene identified as mutated, many PID disorders like DNA repair defects are among the inborn causes of childhood cancer. We provide a comprehensive analysis of compiled data from seven recent studies that focused on germline genetic landscapes and preexisting conditions in pediatric oncology. As potentially causal germline variants were identified in ≈8% of malignancies in children and adolescents, we visualized this proportion as the ‘tips of the icebergs’. The results of additional network analyses showed the shared patterns of germline mutations in various malignancies and yielded a spatial distribution of the ‘icebergs’.

Summary The ‘iceberg map of germline mutations in childhood cancers’ was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed.

Video Abstract

aResearch Unit Pediatric Hematology and Immunology

bInstitute for Medical Informatics, Statistics, and Documentation

cDivision of Pediatric Hematology–Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria

Correspondence to Markus G. Seidel, MD, Division of Pediatric Hematology–Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Auenbruggerplatz 38, A-8036 Graz, Austria. Tel: +43 316 385 82621; e-mail:

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