Origins and Evolution of Pediatric Cancers

“Nothing in biology makes sense except in the light of evolution” was Dobzhansky's bold but persuasive claim, and nothing is as natural in biology as natural selection. It has been occurring for approximately 3 billion years whenever heritable traits vary in replicating populations, affecting the survival and reproductive fitness of molecules, unicellular or multicellular organisms, each in the face of environmental selective pressures.

When complex multicellular organisms evolved some 600 million years ago, the potential for individual cells to be selectable, or to clone, was suppressed or rendered subservient to the fitness of the entire individual. Two classic exceptions to this rule exist, however: the immune system and cancer. In the former, lymphoid cells genetically diversify their immunoglobulin heavy chain in B cells or T-cell receptor in T cells antigen recognition gene segments by recombinase-mediated rearrangement to produce more than 10 ¹¹ potentially selectable variants, collectively covering the recognition of essentially any infectious antigenic epitope. This naturally selected or adaptive system is under tight network control, although collapse of regulation can result in autoimmune disease or lymphoid cell cancers.

All pediatric and adult cancers are nonphysiologic, nonbeneficial clonal evolutions that follow the same rules of engagement as speciation in ecosystems ( Fig. 39-1 ). They are, in essence, breaking a 600-million-year-old covenant. It has been known for some time that cancer is a paradigmatic Darwinian, adaptive system. The implications for cancer risk, progression of disease, prognosis, drug resistance, and clinical response have only more recently been appreciated. Genomics has contributed significantly to this sharpness of focus, just as it has reinforced the underlying principles of evolutionary phylogeny and natural selection of species and variants. As in speciation, what emerges in cancer in terms of functionally important mutations (the so-called drivers ) or subclones is the consequence of selective pressures exercised via the tissue habitat or ecosystem ( Fig. 39-2 ), with outcome being heavily modulated both by variation in inherited susceptibility and by chance. Inherited susceptibility is a marked feature of pediatric cancers, both in terms of familial syndromes and in sporadic cases with little or no family history, as revealed by genomewide association studies. The element of chance applies in both cancer and evolution in general because mutations arise throughout the genome in a stochastic manner and independently of the functions encoded by particular genes. For mutations to have a functional impact in cancer requires that they occur in a manner that alters protein function (and consequently cell fitness) and in the appropriate context with respect to cell type and the presence (or absence) of other mutations with which they may be epistatic or interactive. The vast majority of mutations are neutral passengers of no consequence. The mutations we see recurrently are the result of natural or therapeutic selection.

As clones evolve over time (within a few years for most pediatric cancers compared with decades for adult carcinomas) they also move in space or throughout tissue ecosystems, both within the primary site and to secondary sites. This characteristic has important implications for biopsy-based sampling, because anything other than the complete tumor will be a biased selection of subclones. This phenomenon has been well documented for adult cancers, and we assume that the same phenomenon must apply to most if not all pediatric solid tumors.

In evolutionary or Darwinian selection, it is the phenotype that is the focus of selectability—for example, a predator with sharp teeth, a thermoresistant bacteria, or a drug-resistant bacterium or cell. In addition, stable phenotypes are initiated and sustained by genotypic alterations that are either mutational or epigenetic. However, any evolutionary system must have a “unit of selection,” which is defined classically as any unit that replicates and in which a stable phenotype is linked to survival and/or reproductive success. For bacteria and protists, this unit is the single cell. For multicellular organisms, it is the entire individual. For cancer it will be somatic cells but probably not every cancer cell. The key attribute of any unit of selection is extensive replicative potential plus expression of the selectable phenotype. Extensive replication capacity, or self-renewal, is the key and exclusive feature of cancer stem cells. The numbers of stem cells vary greatly in individual cancers and are generally increased in frequency with progression of disease and clinical malignancy. In addition, the stem cell state may not be entirely stable, and under some circumstances (microenvironmental or mutational), non–stem cell progenitors can acquire or reacquire stem cell status. Despite these variables, it is likely that cancer stem cells are the units of selection that drive and sustain the evolution of cancer clones and are the repositories of drug resistance.

Pediatric Versus Adult Cancers

All cancers are consequences of stable variation in somatic cells that facilitate clonal escape. However, fundamental differences exist between pediatric and adult cancers ( Table 39-1 ). The most striking of these differences is the context of tissue or cell type involved, which in turn can be rationalized in terms of underlying risk factors. Most adult cancers are the consequences of protracted environmental or lifestyle exposures to epithelia. In contrast, most pediatric cancers can best be viewed as developmental accidents arising during very restricted windows of tissue morphogenesis in the embryo or fetus when particular stem or progenitor cells are proliferating. This view is supported by the finding that many of the inherited gene variants that contribute to the risk of pediatric cancer and many of the somatic mutations that are restricted to the cancer cells themselves are encoded by genes that are critical for the normal developmental biology and differentiation of the cells involved. Very few pediatric cancers are attributable to any known in utero external exposure (i.e., via the pregnant mother), despite an epidemiologic quest to find them lasting decades. This is not to say that pediatric cancers are not subject to variable risk factors. Aside from inherited variation in susceptibility, the numbers of cells at risk and proliferative stress may play a part. Higher birth weight is consistently associated with excess risk of pediatric cancer and may operate by simply increasing the number of proliferating “target” cells at risk. Patterns or timing of infection (especially in affluent, “hygienic” societies) may promote or trigger the clinical development of childhood B-cell precursor acute lymphoblastic leukemia (ALL). This mechanism is likely to operate via proliferative stress on preleukemic clones that are generated in utero (rather than via specific viral transformation). Similarly, the striking peak of incidence of long bone osteosarcoma in adolescents might reflect the clinical emergence of a cancer initiated long before (prenatally) but promoted by the proliferative stress of the long bone growth spurt associated with puberty.

TABLE 39-1

Differences Between Pediatric and Adult Cancers

Variable	Pediatric	Adult
Predominant lineage origins	Transient/developmental tissue progenitors in embryo and fetus Fetal blood	Epithelia Adult blood
Time frame of natural history	Months to 15 yr	2-3 decades
Number of “driver” mutations required	2 (?)	5-8 (?)
Genetic instability	Rare	Common
Major risk factors	Endogenous proliferative stress (?)	Genotoxic exposures, persistent proliferative stress (hormonal), or infection
Cumulative risk	~1 in 800 (0-15 yr)	~1 in 3 (16-90 yr)
Age-associated incidence distribution	Defined, age-linked peak incidence in infancy or childhood	Increases as power of age ^*

* Some exceptions are testicular cancer and Hodgkin lymphoma in young adults and choriocarcinoma.

A few types of cancer occur in both children and ageing adults, with acute leukemias and gliomas being clear examples. However, it is interesting that the genetics or mutational spectrum of these cancers, and probably their etiology, is very different according to age. Two nonexclusive “seed or soil” interpretations of this distinction have been proposed. One interpretation is that the mutations are different because the microenvironments and selective pressures are different, resulting in different mutant genes providing clonal advantage. A second interpretation is that the mutations are cell context–sensitive and that the cell type of origin is different and developmentally constrained. Evidence for the latter interpretation came from mouse modeling of the impact of GATA1 mutations, which revealed that the cellular targets that, with this mutation, lead to acute megakaryocytic leukemia in infants with Down syndrome, are developmentally restricted to the yolk sac and fetal liver.

The tissue distribution, composite phenotypes (or cell type), and gene expression profiles of pediatric cancers provide a strong indication of the possible lineage and cell type or origin, and this indication is endorsed by animal models ( Table 39-2 ). Subtypes of some cancers, such as medulloblastoma, may have distinct developmental origins. No unambiguous way exists to identify precisely when and where any childhood cancer is initiated by somatic mutations. Most mutations are assumed to originate prenatally either in the embryo or the developing fetus, possibly when the cell lineage stem or progenitor cell “targets” are under maximum risk from proliferation.

TABLE 39-2

Developmental, Lineage Origins of Pediatric Cancers

1.	Central nervous system	Gliomas	Glial precursor (different brain regions)
		Ependymoma	Radial glial cells
		Medulloblastoma *
		(i)	Cerebellum (granule neuron precursor cells)
		(ii)	Dorsal brain stem
2.	Neuroblastoma		Embryonic neural crest cells
3.	Rhabdomyosarcoma		Muscle stem/progenitor cells (Satellite cells?)
4.	Hepatoblastoma		Embryonic liver precursor cells (?)
5.	Osteosarcoma		Bone progenitor cells
6.	Retinoblastoma		Embryonal retinoblasts
7.	Ewing sarcoma		Mesenchymal stem cells (?)
8.	Wilms tumor		Embryonic urogenital ridge (mesenchymal) progenitor/stem cells
9.	Acute leukemias		Fetal, hematopoietic stem/progenitor cells
		(i) Childhood ALL	B (or T) progenitor cells (fetal liver or bone marrow)
		(ii) Infant ALL	Fetal B/monocytic progenitor?
		(iii) AML	Myeloid restricted stem/progenitor cells
		(iv) Down syndrome AMKL	Fetal liver megakaryocytic erythroid progenitors

ALL, Acute lymphoblastic leukemia; AMKL, acute megakaryoblastic leukemia; AML, acute myelogenous leukemia.

* More distinctive subtypes in terms of cellular and anatomic origin probably exist than are listed here.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here