Genetic Predisposition to Solid Pediatric Cancers

Abstract

Progresses over the past years have extensively improved our capacity to use genome-scale analyses-including high-density genotyping and exome and genome sequencing-to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.

Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

“…Several genes related to predisposition to different childhood malignancies have been described since then (myeloid leukemia [ 8 ] and lymphoblastic leukemia [ 9 ], neuroblastoma [ 10 ], medulloblastoma [ 11 , 12 , 13 ], osteosarcoma [ 14 ] and soft tissue and bone sarcomas [ 15 , 16 ]). Meanwhile, knowledge on several disorders remains scarce, but current next generation sequencing technologies have expanded the frontiers of genetic predisposition research and, hence, the possibility of discovering new genotype–phenotype relationships [ 17 ].…”

Unraveling the genetic architecture of hepatoblastoma risk: birth defects and increased burden of germline damaging variants in gastrointestinal/renal cancer predisposition and DNA repair genes

“…Germline mutations have been detected in 8-18% of children and adolescents with cancer [3,[8][9][10], and the most prevalent CPGs reported to be mutated are TP53, APC, BRCA2, NF1, PMS2, RB1, andRUNX1 [3]. In a very recent work about the spectrum of germline mutations in childhood cancer, the majority of the mutations (55%) were mapped to genes not previously associated with the patient's tumor type [10]; this work included a small number of HB patients (3 patients) with no pathogenic or likely pathogenic variants.…”

“…Most investigations have focused on known CPGs and sequenced patients without parental samples, an approach that impairs a broad evaluation of the full range of genetic mechanisms underlying pediatric cancer risk, such as de novo mutations and the identification of new candidate CPGs. Recent studies of large cohorts of pediatric cancer patients have confirmed that approximately 8-18% of patients carry a germline pathogenic variant in a broad spectrum of known CPGs [3,[5][6][7][8][9][10]. These studies also highlighted that isolated factors, such as tumor type and a positive family history of cancer, have low predictive power for the presence of germline CPG mutations.…”

DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma

“…CPS are defined by their canonical germline mutations, but also by the phenotype(s) of their associated neoplasms 197 . Each of the mutated genes with the end result of a clinical malignancy of one type or another has set molecular perturbations such as disordered genomic stability and cell cycle dysregulation as in the case of LFS [TP53] or miRNA processing in the DICER1 syndrome 198 , 199 .…”