Genomics of adult and pediatric solid tumors

Abstract

Different types of cancers exhibit disparate spectra of genomic alterations (germline and/or somatic). These alterations can include single nucleotide variants (SNVs), copy number alterations (CNAs) or structural changes (e.g. gene fusions and chromosomal rearrangements). Identification of those genomic alterations has provided the opportune element to derive new strategies for molecular-based precision medicine of adult and pediatric cancers including risk assessment, non-invasive detection, molecular diagnosis and personalized therapy. Moreover, it is now becoming clear that the spectra of genomic-based alterations and mechanisms in pediatric malignancies are different from those predominantly occurring in adult cancer. Adult cancers on average exhibit substantially higher mutational burdens compared with the vast majority of childhood tumors. Accumulating evidence also suggests that the type of genomic alterations frequently encountered in adult cancers is different from those observed in pediatric malignancies. In this review, we discuss the state of knowledge on adult and pediatric cancer genomes (or "mutatomes"), specifically focusing on solid tumors. We present an overview of mutational signatures and processes in cancer as well as comprehensively compare and contrast the diverse spectra of genomic alterations (somatic and familial) among major adult and pediatric solid tumors. The review also discusses the role of genomics in molecular-based precision medicine of adult and pediatric solid malignancies as well as comprehending resistance mechanisms to various targeted therapies. In addition, we present a perspective that discusses upon emerging concepts in cancer genomics including intratumoral heterogeneity, the precancer (premalignant) genome as well as the interface between the host immune response and tumor genome - immunogenomics - as they relate to adult and pediatric tumors.

Keywords: Cancer genomics; driver mutations; genomic medicine; mutation signatures; mutation spectra; precision medicine.

Figure 1

Reported spectrum of significantly mutated driver genes in pediatric and adult cancers. A. Most common recurrently mutated genes in adult cancers. B. Most common recurrently mutated genes in pediatric cancers. Different types of cancers are denoted by different colors, and the frequency (%) of the mutated gene in each cancer is represented by the upper margin of the respective cancer. For each bar/mutated gene the top four tumors with recurrence of the mutated gene are depicted. Mutated genes in blue represent common recurrently mutated genes in both pediatric and adult cancers. Data for the significantly mutated genes in adult and pediatric cancer were retrieved from cBioPortal for Cancer Genomics [249,250] and St. Jude Cloud PeCan, respectively.