A multi-dimensional approach to recognize genetic predisposition in children with acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with significant advances in treatment leading to high cure rates. Recent studies have highlighted the importance of genetic predisposition in ALL. Identifying contributing heritable or de novo genetic factors is crucial for potential treatment modifications, early detection of second malignant neoplasms (SMNs) and genetic counseling for surveillance of patients and family members. Multiple syndromes, such as Down syndrome (DS) or Ataxia Telangiectasia (AT), are known to give rise to increased risk for developing ALL. Most of these syndromes can be recognized by the presence of specific clinical features. However, a notable proportion of patients harboring (likely) pathogenic germline variants in cancer predisposition genes (CPGs) can easily be missed due to the absence of these characteristics. Therefore, the diagnosis of cancer predisposition syndromes (CPS) requires multiple approaches that are based on phenotypic characteristics, germline genetic analysis and genomic characterization of the leukemia samples. Despite the recognized benefits, routine screening for germline variants has not yet been implemented in large study groups due to logistical and financial challenges. This review emphasizes the importance of integrating systematic genetic testing into standard care protocols for ALL patients and summarizes current practical considerations for CPS identification in children with ALL.