OncoInsightBridge

By: OncoInsightBridge

A common question that arises among parents is “Why did my child get cancer?” Although there isn’t a single clear answer, many wonder how a parent’s gene variants can impact a child’s susceptibility to cancer. In adults, cancer is generally thought of as DNA damage accumulated over a long time. However, in the case when children who haven’t lived long enough to develop a lot of DNA damage develop cancer, genetics is a primary suspect. Throughout the past thirty years, scientists have made significant advancements in understanding the genetic basis of cancer. In this article, I will be providing a background on cancer-susceptibility genes, as well as giving a brief overview of what is currently known about how genetics influence the likelihood of pediatric cancer.

Introduction

Think of your DNA like a giant cookbook that contains “recipes” for coding all the proteins your body needs. Each gene is a recipe that codes for a specific protein. Gene mutations are permanent changes in the DNA sequence of a gene like typos or edits in a recipe. It may or may not be harmful, just like how a typo in the recipe may or may not alter the final result. They become pathogenic mutations when something causes a disease. Among these variations, a small percentage become cancer susceptibility genes, genes that are highly vulnerable to cancer-causing variants. They usually occur when large chunks of the genetic material gets deleted, added, duplicated, flipped around, or moved during cell division.

Impact on Cancer-Susceptibility

Sometimes, a cancer susceptibility gene is passed down from parents to offspring. Gene changes that get passed from parents to children are called germline variations, and those that cause disease are called germline pathogenic variations. They are passed on through germ cells – eggs and sperm. When a person inherits these variations, they have a genetic predisposition/susceptibility to a certain type of cancer. So far, over 100 cancer susceptibility genes have been discovered. Most of the germline variations involve loss of functions or disruption of protein reparation.

In addition to germline variants, postzygotic somatic mosaic CPG pathogenic variants, variants that are acquired during the embryo stage, are factors that may lead to pediatric cancer. Genetic mosaicism occurs when a mutation occurs in the early stages of embryonic development, leading to the presence of the mutation only in certain cells.

In some cases, germline variations clearly contribute to the origin of a child’s cancer, such as in Li-Fraumeni syndrome, a disorder that significantly increases the risk of cancer development. In other cases, the connection is more difficult to establish.

A family cancer syndrome is a condition caused by gene variations passed from parents to children that leads to a higher susceptibility of getting cancer. Some notable examples of these syndromes are:

• Hereditary Breast and Ovarian Cancer Syndrome (HBOC): This is usually caused by a mutation in the BRCA1 or BRCA2 gene. These mutations make people more likely to get breast, ovarian, and prostate cancers. If someone has the mutation, their close-related family members have a 50% chance of having that same mutation.
• Lynch syndrome: Also called hereditary non-polyposis colorectal cancer (HNPCC,) it increases a person’s risk for colon cancer, as well as ovarian, stomach, kidney, and breast cancers. It is caused by inherited mutations such as MLH1, MSH2, MSH6, PMS2, and EPCAM. These genes are supposed to help repair damaged DNA cells so when they are mutated, they are no longer able to function properly. Once again, close relatives have a 50% chance of having the same mutation.
• Li-Fraumeni Syndrome (LFS): LFS is a rare syndrome that can lead to increased chances of soft-tissue sarcoma, breast, leukemia, and adrenal cortex cancer. It is usually caused by a mutation in the TP53 gene (which obstructs the function of the protein stopping abnormal cells from growing.)

However, there is no guarantee that having a family cancer syndrome will lead to cancer. There is a spectrum. The concept of penetrance refers to the amount of people carrying an inherited mutation in the cancer susceptibility gene that will eventually develop cancer. Complete penetrance refers to a mutation where everyone with that mutation develops cancer. Since the discovery of retinoblastoma-predisposing RB1 pathogenic germline variants in 1985, many other high penetrance cancer disposition genes have been identified, including BRCA1 and BRCA2. Some other mutations are moderate or low penetrance.

Techniques Used in Genetic Analysis

Recent advancements in Next-Generation Sequencing (NGS) technologies have transformed our understanding of cancer genetics. These techniques allow scientists to create mutational profiles of tumors, which help in diagnosis and risk management, and treatment planning. They can also predict carcinogenic (having the potential to cause cancer) pathways.

• Whole Genome Sequencing (WGS) is the most comprehensive technique that identifies genetic variants in coding and non-coding regions. A WGS analysis of pediatric cancer patients found that germline variations accounted for around 10% of cancer-causing variants.
• Whole Exome Sequencing (WES) is a cost-effective approach that may detect 85% of known disease-causing variants.
• Targeted Analysis Sequencing (TAS) focuses on genes known to have strong associations with specific cancer predisposition syndromes.
•  RNA sequencing analysis detects the fusions of pathognomonic genes and helped provide information on gene transcription activity. Note that functional fusion genes are not produced for all pediatric cancers.

Why is this important?

Characterization of gene mutations is necessary to provide adequate gene counseling for pediatric cancer patients and their families in order to identify high-risk individuals and implement risk-reduction strategies. Identification of additional gene variants helps determine possible treatments and procedures. For pediatric cancer survivors, this identification can guide genetic screening to prevent late effects, such as a resurgence of a different type or stage of cancer. Additionally, understanding common gene fusion events can help determine optimal treatment therapies for specific tumors.

Unfortunately, survival rates in youths with cancer predisposition genes (CPGs) are often low, showing the necessity for increased genetic testing, to improve cancer treatments, therapies, and prevention.

Close relatives and parents of children with certain types of cancer should do screenings for germline variants. It is crucial for predisposed patients to undergo oncological genetic testing, to test for cancer, categorize, and find the best solutions as soon as possible.  

Concluding

It is clear through all these studies that the impact of genetics on pediatric cancer is very complicated and nuanced. The application of NGS technologies and genome sequencing has allowed our understanding of cancer variants and mutations to deepen; but there is still much to be undiscovered. Cheaper and faster tools are needed for more classification and sequencing of new variants. Collaborative efforts between healthcare workers, researchers, and data analysists are needed to reach the potential and benefits of genomic data. Additionally, more research must be conducted in order to understand the origin of each variation (coming from mother or father,) as well as the impact of the environment one is living in.

While we can’t change our genes, if born with a genetic predisposition, make sure to consider lifestyle choices and environmental exposures. Even for those children that are born with germline structural variants, there are additional factors at play.

Lastly, expanding our knowledge of the genetic basis of cancer predisposition will help benefit large numbers of patients and their families. To understand more about diagnosis and treatment, check out some more of our blogs. Feel free to donate to help make a difference in the lives of children and their families.                                                                                                       

References:

Manjunath, Gowrang Kasaba, et al. “Unraveling the Genetic and Singaling Landscapes of Pediatric Cancer.” Pathology – Research and Practice, vol. 263, 5 Oct. 2024, p. 155635, http://www.sciencedirect.com/science/article/abs/pii/S0344033824005466, https://doi.org/10.1016/j.prp.2024.155635.

‌ Alonso-Luna, Oscar, et al. “The Genetic Era of Childhood Cancer: Identification of High‐Risk Patients and Germline Sequencing Approaches.” Annals of Human Genetics, vol. 87, no. 3, 10 Mar. 2023, pp. 81–90, https://doi.org/10.1111/ahg.12502.

‌ Saletta, Federica, et al. “Genetic Causes of Cancer Predisposition in Children and Adolescents.” Translational Pediatrics, vol. 4, no. 2, 1 Apr. 2015, pp. 67–75, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729088/, https://doi.org/10.3978/j.issn.2224-4336.2015.04.08.

Cipri, Selene, et al. “How Genetics and Genomics Advances Are Rewriting Pediatric Cancer Research and Clinical Care.” Medicina, vol. 58, no. 10, 2 Oct. 2022, p. 1386, https://doi.org/10.3390/medicina58101386.

‌“Inherited Structural Variants Linked to Pediatric Cancer.” Cancer.gov, 4 Mar. 2025, www.cancer.gov/news-events/cancer-currents-blog/2025/structural-variants-cancer-in-children.

“New Findings about the Genetic Risks of Childhood Cancer.” Cancer.org, 2025, www.cancer.org/research/acs-research-highlights/childhood-cancer-research-highlights/new-findings-about-the-generic-risks-of-childhood-cancer.html.

 Kratz, Christian P. “Re-Envisioning Genetic Predisposition to Childhood and Adolescent Cancers.” Nature Reviews. Cancer, 3 Dec. 2024, https://doi.org/10.1038/s41568-024-00775-7. Accessed 4 May 2025.

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