The hidden inheritance behind cancer risk and development

Some things are written into our stories long before we ever get to tell them ourselves. Hidden within our DNA are genetic variations that can influence disease risk, treatment response and other aspects of human health. Called genetic predisposition, this inherited susceptibility is helping researchers better understand why certain diseases develop and how they can be detected, treated and, in some cases, prevented.

While genetic predisposition can increase the likelihood of developing a disease, it does not guarantee it. Instead, predisposition reflects the complex relationship between genetics, environment and lifestyle. Some people may inherit genetic variants that elevate their risk for cancer or other diseases, while others may carry protective variants that reduce risk. 

Understanding these differences is helping researchers identify individuals who may benefit from earlier screening, targeted prevention strategies and more personalized approaches to care.

“Genes are segments of DNA that carry instructions that influence how the body develops and functions. When a gene is altered, those instructions can change in ways that affect disease risk and development,” said Kim Nichols, MD, St. Jude Division of Cancer Predisposition director and Department of Oncology member. “At St. Jude, we’re particularly interested in genes and genetic changes that increase cancer risk. There are genes that normally help protect the body from cancer, but when they are altered, there is a higher chance that cancer can occur.”

Nichols’s team combines specialized clinical care and innovative research to improve outcomes for children and families at inherited risk of cancer. Her research focuses on understanding the genetic factors that contribute to cancer development and progression, how those risks vary across families, and how that knowledge can be used to enhance screening for new cancers, inform approaches to cancer treatment, and guide strategies for cancer prevention.

The impact of these efforts is becoming increasingly clear. Large-scale genomic studies have revealed that inherited cancer-predisposing variants are present across a wide range of pediatric cancers, providing new insight into the role genetics plays in disease development.

Uncovering inherited cancer risk

Cancer predisposition is identified by analyzing a person’s DNA for variants associated with an increased risk of cancer. Testing is often the first step in determining whether a child or family carries an inherited cancer risk. Historically, the identification of patients at increased risk for inherited cancer syndromes relied on a combination of family history, tumor type, physical manifestations and tumor genomic findings. While these factors remain important, advances in genomic technologies have expanded clinicians’ ability to detect cancer-predisposing variants and to identify at-risk individuals who may otherwise go unrecognized. 

“Comprehensive genomic sequencing of tumors and paired normal tissues has become an important tool for identifying inherited cancer risk,” said Nichols. “It helps us determine whether a genetic change is specific to the tumor or indicative of an underlying hereditary condition.”

Testing has expanded from single gene-by-gene analysis to large-scale sequencing approaches that can evaluate many genes all at the same time. This broader genomic view has enabled researchers to study cancer predisposition across larger patient populations, uncover patterns among patients with specific cancer types, and better understand how inherited genetic factors contribute to disease development and outcomes.

In a study led by Nichols and published in 2021 in Cancer Discovery, researchers used whole-genome sequencing, whole-exome sequencing and RNA sequencing to analyze tumor and germline genomes from more than 300 children with newly diagnosed or relapsed cancers. They found that nearly one in five patients carried an inherited pathogenic variant in a known cancer-predisposing gene, showcasing the important role of genetic risk factors in pediatric cancer. This study helped researchers better understand how these inherited variants contributed to cancer development and identify genetic changes with diagnostic, prognostic and therapeutic relevance.

Identifying the hidden genes linked to cancer predisposition

Advances in genomic sequencing are not only helping researchers identify known cancer-predisposing variants but also revealing new genes that may contribute to inherited cancer risk. By studying large groups of children with cancer, researchers can uncover genetic changes that were previously unknown to be associated with disease susceptibility.

In a 2025 study published in the Journal of Clinical Oncology, Nichols and colleagues conducted the first comprehensive analysis of more than 180 DNA damage repair genes to identify genetic changes associated with cancer predisposition. DNA repair genes are known for being frequently altered in tumor cells, but their contribution to inherited cancer susceptibility is not well understood.

Their work identified SMARCAL1, a gene involved in DNA repair, as a novel cancer predisposition gene linked to osteosarcoma. In a separate study published in the Journal of the National Cancer Institute, co-led by Lillian Guenther, MD, Department of Oncology, researchers independently identified SMARCAL1 as a cancer predisposition gene, strengthening the evidence for its role in inherited osteosarcoma risk.

Findings such as these may ultimately influence clinical care, as newly identified predisposition genes can help guide genetic testing, risk assessment and surveillance strategies for patients and families. Identifying individuals with inherited risk may allow clinicians to implement targeted screening approaches to detect osteosarcoma earlier, when tumors may be more responsive to treatment.

What pediatric thyroid cancer reveals about inherited cancer risk

As researchers continue to identify new cancer predisposition genes, they are also investigating how inherited risk influences specific cancer types and how these discoveries can inform patient care. Pediatric thyroid carcinoma is rare in children, but it has also been observed as a subsequent malignancy following an initial cancer diagnosis. To better understand the role of inherited genetic variants in pediatric thyroid cancer, Nichols and her team examined germline testing results from children diagnosed with the disease. 

The study, published in 2025 in Clinical Cancer Research, showed that a meaningful proportion of patients carried variants in known cancer-predisposing genes, suggesting that inherited risk may play a more significant role in pediatric thyroid cancer than previously recognized. The findings also highlight patterns that can help guide clinical decision-making. The work identified several clinical characteristics associated with an increased likelihood of harboring a cancer-predisposing variant, such as children diagnosed before age 11, those diagnosed with medullary thyroid carcinoma, and those with a prior cancer history.

These findings highlight the importance of genetic counseling and testing for affected children and may help clinicians identify patients who may benefit from additional surveillance and risk assessment.

Genetic risk across generations 

Genetic cancer risk often becomes most apparent when it clusters within families — when multiple generations develop the same or related cancers. These patterns offer a valuable window into inherited susceptibility and how genetic changes may be passed through families to influence cancer risk. At the same time, separating true inherited risk from shared environmental or lifestyle influences has long been a challenge in the field.

To better understand this relationship, researchers studied families with multiple cases of Hodgkin lymphoma, a cancer that has long shown evidence of familial clustering. In a study published in 2023 in Blood, Nichols and Jun J. Yang, PhD, Department of Pharmacy & Pharmaceutical Sciences, conducted whole-genome sequencing in high-risk families with more than one affected close relative. They identified inherited genetic variants that co-occurred with disease across family members, suggesting a link between these genetic changes and cancer occurrence within families.

Results showed that some genetic variants appeared in multiple families, while others were unique to individual families. Taken together, findings from both individual patient studies and family-based analyses reinforce a central theme in cancer predisposition research: Inherited risk reflects a complex landscape of genetic variation across individuals and families.

Preclinical pathways to prevention

 As researchers continue to map inherited cancer risk across individuals, cancer types and families, a clear picture of its complexity is emerging. These findings not only improve our understanding of where risk exists but also raise a new, more forward-looking question.

 Can this knowledge be used to influence risk? Early preclinical studies suggest this may be possible. PAX5 is a gene involved in normal B-cell development, and certain inherited alterations in this gene can increase the risk of developing B-cell acute lymphoblastic leukemia. In a study of PAX5-related leukemia risk, Nichols and colleagues tested whether targeting related biological pathways could change disease development in genetically at-risk individuals. 

In the study, published in 2022 in Cancer Research, early-life treatment with a JAK1/2 inhibitor — a drug that blocks key signals involved in cell growth — significantly reduced leukemia development in Pax5+/- mice that were genetically predisposed to the disease.

While these findings are still limited to preclinical models, they provide an important proof of concept: Inherited cancer risk may not only be something we detect, but in select contexts, something we may eventually be able to modify by targeting biological pathways influenced by inherited genetic variation.

A shifting understanding of cancer risk from discovery to care

Altogether, these findings reveal a hidden biological framework of cancer risk — one that is dynamic, context-dependent, and shaped by inherited genetic variation across individuals and families. These discoveries are helping clinicians identify patients at increased risk, refine approaches to genetic testing and surveillance and deepen understanding of how cancer develops. At the same time, emerging research is exploring whether this knowledge can extend beyond early cancer detection to interventions that prevent cancer in the first place, reflecting a broader shift in the field from simply identifying genetic risk to understanding its biological consequences and considering how it may shape future approaches to prevention and care.

“As we better understand the genetic and biological framework of cancer predisposition,” said Nichols, “we can begin to think more broadly about how to detect risk earlier and positively change the outcomes for patients and their family members through early detection and prevention, both locally and around the world.”