A new study from Washington University School of Medicine in St. Louis challenges conventional cancer research by examining how inherited genetic mutations in healthy cells could contribute to cancer risk. Unlike previous studies that focus on mutations within tumors themselves, this research dives into how germline mutations—those inherited from parents—affect the body from birth and may predispose individuals to cancer later in life.
Published in Cell on April 14, the study analyzed the genomes of over 1,000 cancer patients, investigating how inherited mutations in blood cells lead to malfunctioning proteins. These altered proteins may interfere with vital physiological processes, raising questions about cancer susceptibility and offering potential avenues for better prevention, detection, and treatment strategies.
Dr. Li Ding, senior author of the study and a distinguished professor at WashU Medicine, emphasized the importance of understanding how both rare and common germline variants influence the body’s protein machinery. “We need to know how these variants impact the proteins that keep our bodies functioning and how they contribute to cancer risk over time,” he explained.
This research is a key component of the Clinical Proteomic Tumor Analysis Consortium, a nationwide initiative supported by the National Cancer Institute. The project aims to map all the proteins involved in cancer development and progression. While tumors typically acquire mutations over time, this study places a focus on inherited mutations—those present at birth—and their potential to alter cellular function.
Inherited mutations, such as those in the BRCA genes, are well-known for increasing the risk of breast cancer, and patients with these variants often benefit from preventive measures like increased screenings, chemotherapy, or surgeries. This study builds on this concept by analyzing healthy cell genomes, revealing that inherited genetic variants can have a significant impact on cancer risk, even before the development of tumors.
Led by Fernanda Martins Rodrigues, PhD, the study team examined the inherited genomes of 1,064 cancer patients across 10 cancer types. They identified 119 rare genetic variants known to cause cancer and several common variants that could affect the structure, quantity, and stability of proteins involved in cancer development. These findings highlight the complexity of inherited cancer risk, showing that common variants, when combined, may increase susceptibility to cancer even if no single variant is directly responsible.
“The novelty of this research is that it expands our understanding beyond the rare cancer-causing variants like those in BRCA genes,” Dr. Ding said. “We’re now looking at how common variants work together to influence cancer pathways.”
The team also introduced the concept of a polygenic risk score, which calculates an individual’s overall cancer risk based on the combination of all inherited mutations. While having a single mutation may not significantly increase cancer risk, accumulating several cancer-related mutations can heighten the likelihood of developing the disease.
The study found that patients with certain aggressive cancers, such as glioblastoma, pancreatic cancer, and some forms of lung cancer, exhibited significantly higher polygenic risk scores than healthy individuals or those with other types of cancer. Higher polygenic scores were also linked to more aggressive cancer progression.
Additionally, the research delves into how inherited mutations can alter protein structures. Two key protein modifications—small molecular tags added after protein assembly—can dramatically impact protein function, including when and where proteins become active. This detailed analysis offers crucial insights into how inherited mutations can lead to cancer by affecting protein behavior at the molecular level.
Overall, this groundbreaking study underscores the importance of examining how germline mutations affect protein function and the biological processes underlying cancer. By refining polygenic risk scores and incorporating these insights, researchers hope to enhance the accuracy of cancer risk assessments in the future, offering new opportunities for early detection and targeted prevention strategies.
Related topics:
Probiotics Show Potential in Enhancing Mood and Emotional Well-Being in Healthy Adults
4 French Wellness Trends to Embrace for a Healthier Lifestyle
The Healthy Skin Barrier Trend: What It Is and How to Achieve It
