Predisposition to Pediatric and Hematologic Cancers: A Moving Target

Abstract

Our understanding of hereditary cancer syndromes in children, adolescents, and young adults continues to grow. In addition, we now recognize the wide variation in tumor spectrum found within each specific cancer predisposition syndrome including the risk for hematologic malignancies. An increased understanding of the genetic mutations, biologic consequences, tumor risk, and clinical management of these syndromes will improve patient outcome. In this article, we illustrate the diversity of molecular mechanisms by which these disorders develop in both children and adults with a focus on Li-Fraumeni syndrome, hereditary paraganglioma syndrome, DICER1 syndrome, and multiple endocrine neoplasia syndrome. This is followed by a detailed discussion of adult-onset tumors that can occur in the pediatric population including basal cell carcinoma, colorectal cancer, medullary thyroid cancer, and adrenal cortical carcinoma, and the underlying hereditary cancer syndromes that these tumors could indicate. Finally, the topic of leukemia predisposition syndromes is explored with a specific focus on the different categories of syndromes associated with leukemia risk (genetic instability/DNA repair syndromes, cell cycle/differentiation, bone marrow failure syndromes, telomere maintenance, immunodeficiency syndromes, and transcription factors/pure familial leukemia syndromes). Throughout this article, special attention is made to clinical recognition of these syndromes, genetic testing, and management with early tumor surveillance and screening.

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…Studies addressing this infrequency focus on environmental and genetic modifiers that might promote LFS-related AML, including chemotherapy, ionizing radiation, single-nucleotide polymorphisms (SNPs) in TP53 pathway genes, increased CNAs, and telomere attrition. 3 Possible underdiagnosed LFS in t-AML should be ruled out by prospective evaluation of TP53 germ line mutations or deletion in t-AML cases. 32 AML-related TP53 mutations are mostly missense somatic mutations that embrace some of the most frequent cancer-associated TP53 hotspots, such as the contact mutations at codons 248, 273, and the structural mutation at codon 245.…”

“…Indeed, p53 LOH is frequently found in t-AML, AML postmyeloproliferative Ph1-negative neoplasms, and in LFS-related AML. 3,30,35 The most frequent TP53 mutation signature in AML is a G:C >A:T transition mutation, occurring at the hypermutable CpG dinucleotides with a frequency of 23.3%. 33 This age-correlated signature (1A/B) ensues presumably, an endogenous mutational process.…”

“…[3][4][5][6][7][8][9][10] Currently, TP53 mutations, per se, are prioritized over other p53 abnormalities with regard to AML pathogenesis, therapy response, and prognosis. However, evolvement in the field of p53 research has modified our view of p53 dysfunction by elucidating the mutant p53 (mutp53) gain-of-function (GOF) phenomenon 11 and by unveiling molecular mechanisms underlying nonmutational wtp53 inactivation.…”

“…3,4 Indeed, recent data indicate that nonmutational wtp53 dysfunction may occur in nearly all AML subsets (European Leukemia Net classification).…”

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“…However, a few well characterized disorders can be associated with a higher risk of developing leukemia [9]. For example, the most common, known genetic abnormality is Down syndrome or Trisomy 21.…”