Cancer is defined as the continuous uncontrolled growth of cells. The entire population of cells within a cancer arises from a single cell that has incurred genetic change, and hence the tumors are said to be clonal. Children with cancer are not simply little adults with cancer. They present most commonly with leukemias and lymphomas and with solid tumors of neural and mesenchymal origin. Fundamental differences in biology exist between adult and pediatric cancer. The number of DNA mutations in pediatric cancers is much fewer than that in adult cancers. This presentation highlights the biologic concepts and molecular pathways that both play dominant roles in oncogenesis and hold the most potential for therapeutic intervention.

Childhood cancer is a devastating diagnosis for any family to receive. While the causes of cancer are complex and multifaceted, one important factor that researchers are studying is genetic mutations. Genetic mutations are changes in the DNA code that can lead to abnormal cell growth and division, potentially resulting in cancer. In this blog post, we will explore the role of genetic mutations in childhood cancer development, how they are identified, and the impact they have on treatment options. Understanding the genetic factors involved in childhood cancer can help improve diagnosis and treatment strategies, offering hope for better outcomes for young patients and their families.

Introduction to Basic Cancer Neoplasm and Oncology Terms

It is divided into three major sections:

(a) Cell function—molecular events that occur within individual tumor cells (Signal Transduction, Gene Regulation),

(b) Cell behavior—responses by normal and cancer cells to external and internal stimuli (Cell Cycle, Apoptosis), and

(c) Tumor properties—behaviors that tumor cells display as a group or elicit from their environment ( Tumor metastasis and angiogenesis).

What is Differentiation and Anaplasia

Differentiation refers to the extent to which neoplastic cells resemble comparable normal cells, both morphologically and functionally.
Lack of differentiation is called anaplasia and is considered the hallmark of malignant transformation.

Among these 10 hallmarks are the classically described biologic features of sustained proliferation, resistance to cell death, and the potential to invade and metastasize.

Newer hallmarks include deregulation of cellular energetics and avoidance of immune destruction.

Importantly, nontumor stroma and the tumor microenvironment (TME) play critical roles in supporting all of the hallmarks and contribute to cancer development, metastasis, treatment resistance, and disease recurrence.

The natural history of most malignant tumors can be divided into four phases:

1) Malignant changes in the target cells, referred to as transformation.

2) Growth of the transformed cell.

3) Local invasion and

4) Distant metastasis

Cancer stem cells

A clinically detectable tumor contains a heterogeneous population of cells, which originate from the clonal growth of the progeny of a single cell, the cell within a tumor that can initiate and sustain the tumor.

Recently cancer stem cells (called tumor-initiating cells or T-IC) were identified in breast tumors and acute myeloid leukemia.

T-Ics constitute less than 2% of the cells in breast tumors and 0.1% to 1% of cells in acute myeloid leukemia. Cancer stem cells are the initial targets of transformation.

Nonlethal genetic damage lies at the heart of carcinogenesis. It is a multi-step process.

A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e. tumors are monoclonal).

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The main classes of genes involved are

1) Oncogenes

2) Tumor suppressor genes

3) Genes regulating apoptosis

4) DNA repair genes

These are the principal targets of cancer-causing mutations.

Genes that promote autonomous cell growth in cancer cells are called oncogenes. They are derived from mutations in proto-oncogenes and are characterized by the ability to promote cell growth in the absence of normal growth-promoting signals.

Unmutated cellular counterparts are called proto-oncogenes.

Products of oncogene called oncoproteins. They are devoid of important regulatory elements.

p53: Guardian of the Genome of Cancer biology

Located on chromosome 17p13.1
The p53-encoding tumor suppressor gene, TP53, is the most commonly mutated in human cancer.
p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation.
A variety of stresses trigger the p53 response pathways, including anoxia, inappropriate pro-growth stimuli (e.g. unbridled MYC or RAS activity), and DNA damage.

Mutations occurs usually somatically, not germline. The majority of pediatric malignancies express wild-type p53.

The p53 protein is a transcription factor that halts neoplastic transformation by three interlocking mechanisms

1. Activation of temporary cell cycle arrest (termed quiescence),

2. Induction of permanent cell cycle arrest (termed senescence),

3. or triggering of programmed cell death (termed apoptosis)

Protein Regulation

Translation (protein synthesis) decodes the information contained in mRNA into a polypeptide chain. Many major oncogenic signaling pathways that are deregulated in human cancers affect translation, including RAS-MAPK, PI3K-AKT-mTOR, MYC, and WNT/β-catenin.
Degradation of proteins is critical to normal cell function. Ubiquitin-proteasome system (UPS) degrades approximately 80% of proteins in cells. Bortezomib targets this UPS and is used in relapsed ALL along with standard ALL induction therapy.

Signal Transduction

It is the transmission of molecular signals from a cell’s exterior to its interior. This system is frequently subverted in oncogenesis.
Receptor tyrosine kinases (RTKs) are a major class of cell-surface receptors that initiate signaling cascades.
Mutations in RTKs are found in sarcomas, hematologic malignancies, and brain tumors. One of the most frequent is activating FLT3 mutations that occur in roughly 25% of pediatric AML patients.

Cell growth can be defined as an increase in cell mass and size rather than cell number.

Cellular proliferation is defined as an increase in cell number.

Cell-cycle checkpoints are encountered during G1 and G2 phases.
In normal cells, if DNA sequence errors are encountered, progression through the cell cycle is halted until these defects are repaired.

Apoptosis

Apoptosis, or regulated cell death, refers to an orderly dismantling of cells into component pieces, which are then efficiently consumed by neighboring cells and professional phagocytes without stimulating inflammation.

Morphologically, it is characterized by chromatin condensation and cell shrinkage in the early stage. Then the nucleus and cytoplasm fragment, forming membrane-bound apoptotic bodies that can be engulfed by phagocytes.

There is great interest in developing therapeutic approaches that are aimed at reestablishing a normal apoptotic response in cancer cells.

Most normal cells do not survive when they become detached from surrounding structures, and they induce an apoptotic program termed anoikis.

Malignant cells avoid anoikis by upregulating survival pathways, in particular through activation of AKT-mTOR and increased expression of antiapoptotic proteins such as BCL-2 and MCL-1.

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of tumor cells, non-malignant stromal tissue and the extracellular matrix that surrounds and feeds a tumor cell.

Cancer Metabolism

Cancer cells utilize glycolysis as a source of ATP generation by rewiring cellular metabolism to achieve three major needs:

1. Increased ATP production to support the increased demands;

2. Increased generation of proteins, lipids, and nucleic acids to support the anabolic state; and

3. Maintenance of redox homeostasis

Aberrant activation of the mTOR pathway is a major contributor to metabolic reprogramming.

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Source: Pizzo & Poplack’s Pediatric Oncology