Iceberg graphic representing childhood cancers and underlying genetic mutations.

Childhood Cancer: When Immunity Fails

Kai Mendoza in Health & Wellness December 2025 • 4 min read.

"Unraveling the role of germline mutations and immunodeficiencies in pediatric cancers."

The diagnosis of cancer in a child inevitably raises questions about its origins, especially concerning hereditary or congenital factors. Parents often wonder if the disease stems from an inborn syndrome or a primary immunodeficiency (PID), particularly when there's a family history of early-onset malignancies.

Researchers have long explored the connection between genetic predispositions and cancer, guided by the 'multi-mutation' hypothesis and the 'cancer immunosurveillance' theory. The former, solidified by Nordling and Knudson, examines environmental genotoxic causes and inherent predispositions. The latter, championed by Burnet, posits that immune system defects can lead to cancer development. These theories help in understanding why some children are more susceptible to cancer.

Recent advances in genome sequencing and technology have pinpointed numerous genetic underpinnings of various diseases, offering targeted therapies. However, the causes of most childhood cancers remain elusive, suggesting multifaceted factors. In PIDs, both genetic defects and reduced immune surveillance may play a role. Maturation arrests, functional impairment of immune cells, and DNA-repair defects can predispose cells to malignant transformation. Simultaneously, weakened immune surveillance, chronic inflammation, and infections can further promote cancer development.

Why Primary Immunodeficiency Matters in Childhood Cancer

Iceberg graphic representing childhood cancers and underlying genetic mutations.

Malignancies are more prevalent and tend to manifest earlier in individuals with primary immunodeficiency (PID). Compared to the general population, the relative risk of cancer is higher in PID patients, with studies indicating that 4-25% develop malignancy during their lifetime. This heightened risk underscores the importance of understanding the interplay between immunodeficiency and cancer.

Certain PID subtypes, such as common variable immunodeficiency (CVID) and other hypogammaglobulinemia-related PIDs, are frequently linked to malignancies. In these cases, the incidence of carcinomas (particularly gastric and intestinal) and lymphomas increases from early adulthood. Furthermore, rare DNA repair defects, such as Nijmegen breakage syndrome (NBS) and ataxia telangiectasia, significantly elevate malignancy risk.

Nijmegen breakage syndrome (NBS): Up to 42% of patients develop malignancies.
Ataxia telangiectasia: Approximately 25% of patients are affected by malignancies.

The treatment of malignancies in PID patients is more complex and associated with poorer outcomes. Organ toxicities, pre-existing conditions, and heightened infection risks during oncological treatment contribute to management challenges. Current guidelines lack specific protocols for managing malignancies in PID patients, highlighting the need for tailored approaches.

Looking Ahead: Improving Outcomes for Children with PIDs and Cancer

The results suggest that primary immunodeficiencies (PIDs) do not directly facilitate tumor immune escape, but instead, malignancies in PID patients stem from inherent risks of cell transformation, chronic inflammation, and infections.

Continued research into germline mutations and cancer predisposition in childhood is essential. As we uncover more of these genetic underpinnings, future therapies can target specific cancer pathways, potentially improving treatment outcomes.

Improved communication between hematologists, oncologists, and immunologists is critical to enhancing care and treatment for children with PIDs and cancer. By working together, these specialists can optimize prophylaxis, screening, and treatment strategies, ultimately improving the quality of life and survival rates for affected children.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1097/mop.0000000000000680, Alternate LINK

Title: The Iceberg Map Of Germline Mutations In Childhood Cancer

Subject: Pediatrics, Perinatology and Child Health

Journal: Current Opinion in Pediatrics

Publisher: Ovid Technologies (Wolters Kluwer Health)

Authors: Oliver Kindler, Franz Quehenberger, Martin Benesch, Markus G. Seidel

Published: 2018-12-01

Everything You Need To Know

What are the 'multi-mutation' hypothesis and the 'cancer immunosurveillance' theory, and how do they relate to childhood cancer?

The 'multi-mutation' hypothesis, developed by Nordling and Knudson, suggests that cancer arises from a combination of environmental factors and inherent genetic predispositions. The 'cancer immunosurveillance' theory, championed by Burnet, proposes that a properly functioning immune system can identify and eliminate cancerous or precancerous cells. Defects in the immune system, therefore, can lead to cancer development.

Why is it important to understand primary immunodeficiency (PID) in the context of childhood cancer?

Primary immunodeficiencies (PIDs) are genetic disorders affecting the immune system. In individuals with PIDs, malignancies are more prevalent and tend to manifest at an earlier age. Compared to the general population, the relative risk of cancer is significantly higher in PID patients, with studies showing that 4-25% of these individuals develop malignancy during their lifetime. This increased risk underscores the critical connection between immunodeficiency and cancer development.

Which primary immunodeficiency (PID) subtypes are most frequently linked to malignancies, and what types of cancers are commonly associated with them?

Certain primary immunodeficiency (PID) subtypes, such as common variable immunodeficiency (CVID) and other hypogammaglobulinemia-related PIDs, are frequently associated with malignancies, particularly carcinomas (especially gastric and intestinal) and lymphomas. Furthermore, rare DNA repair defects, like Nijmegen breakage syndrome (NBS), where up to 42% of patients develop malignancies, and ataxia telangiectasia, affecting approximately 25% of patients, significantly elevate malignancy risk.

What are the challenges in treating malignancies in patients with primary immunodeficiencies (PIDs), and why are specific guidelines lacking?

Treating malignancies in individuals with primary immunodeficiencies (PIDs) presents considerable challenges. The increased risk of organ toxicities, pre-existing conditions, and heightened susceptibility to infections during oncological treatment complicates management. Currently, there are no specific, established guidelines or protocols for managing malignancies in PID patients, underscoring the necessity for tailored and individualized treatment approaches. Further research is needed to address these complexities and improve outcomes.

Do primary immunodeficiencies (PIDs) directly contribute to tumor immune escape, or are other factors more significant in the development of malignancies in these patients?

The understanding is that primary immunodeficiencies (PIDs) do not inherently cause tumors to evade immune detection. Instead, malignancies in PID patients arise due to inherent risks, such as defects in cell transformation mechanisms, chronic inflammation, and persistent infections. These factors create an environment conducive to cancer development. While immune escape mechanisms can still play a role, the primary drivers in PID-associated cancers appear to be these underlying conditions.