A Comprehensive Review of Somatic and Germline Biomarkers Associated with Childhood B-Cell Precursor Acute Lymphoblastic Leukemia: From Biological Significance to Precision Medicine Opportunities.

B-cell precursor acute lymphoblastic leukemia (B-ALL) is characterized by a constellation of somatic pathogenic variants associated with malignant transformation. These variants have implications for clinical management by providing clinical biomarkers. Most B-ALL cases have a sporadic presentation. However, some patients may present the disease as the neoplastic manifestation of cancer predisposition syndromes caused by germline pathogenic variants. In these cases, genetic counseling and personalized oncologic management is mandatory, considering the patient's sensitivity to conventional therapies. In this review, we have summarized current knowledge on the biological role and clinical relevance of somatic and germline pathogenic variants associated with B-ALL, and discuss three aspects of their application as biomarkers: (1) their usefulness to determine specific molecular subtypes, predicting prognosis and response to specific therapies, (2) their influence in genetic counseling and therapy adaptation for B-ALL in the context of underlying cancer predisposition syndromes, and (3) their detection and interpretation through methodologies. We also included a brief discussion on the need to reclassify variants of uncertain significance to clarify their clinical relevance. Finally, we discuss cases illustrating the impact of somatic and germline pathogenic variants in personalized medicine.