Up to 5% of Americans – approximately 17 million people – may be living with genetic mutations that increase their susceptibility to cancer, regardless of family history or lifestyle factors, according to new research published in in JAMA. The findings suggest that genetic predisposition to cancer may be more common than previously understood and highlight the potential benefits of broader genetic screening.
The study, led by researchers at Cleveland Clinic, analyzed health records and genetic sequencing data from over 400,000 participants in the National Institutes of Health’s All of Us Research Program. Researchers identified more than 3,400 unique mutations across 72 genes commonly associated with cancer risk. “Genetic testing has traditionally been reserved for individuals with strong family histories or other high-risk indicators,” explained Dr. Joshua Arbesman, a practicing dermatologist and researcher at Cleveland Clinic. “Our findings show that many people with pathogenic variants fall outside those criteria, suggesting we may be missing opportunities for early detection, and prevention.”
This research builds on prior work by Dr. Arbesman and Dr. Ying Ni, which demonstrated that genetic predisposition to melanoma was 7.5 times higher than previously estimated by national guidelines. This earlier finding underscored the potential for underrecognition of genetic cancer risk in routine clinical settings.
Understanding the Genetic Landscape of Cancer Risk
The most frequently identified cancer-related gene in the study was MUTYH, with 1.33% of the population carrying a disease-relevant mutation. However, the associated condition – polyposis, characterized by polyp formation, often in the colon – is relatively rare. This is because, in many cases, mutations in both copies of the MUTYH gene are required to significantly elevate risk, resulting in an estimated frequency of 1 in 20,000 to 1 in 40,000.
The second most common gene affected was BRCA2. Carrying a mutation in this gene is associated with a lifetime risk of 45-69% for breast cancer and around 60% for prostate cancer. Variants in the MITF gene, which can increase the risk of melanoma, were also frequently observed.
Impact on Cancer Incidence and Diagnosis
The study revealed that 26.4% of individuals carrying these cancer risk mutations had already been diagnosed with cancer, compared to 19.7% of those without the mutations. However, researchers emphasize that the majority of cancers are not caused by inherited mutations, but rather by changes that accumulate over a lifetime due to factors such as UV radiation, exposure to carcinogens, smoking, and random errors during cell division.
The age of cancer diagnosis varied significantly depending on the specific gene involved. Individuals carrying mutations in the STK11 gene, associated with Peutz-Jeghers syndrome (a rare inherited disorder increasing the risk of cancers in the digestive tract, lungs, and other organs), received their first cancer diagnosis at an average age of 31.4 years. Conversely, those with variants in the AIP gene were diagnosed at a later average age of 70.8 years, typically with gastrointestinal cancers.
The Role of BRCA Genes
Mutations in BRCA genes are well-known for their association with increased cancer risk. In women, BRCA mutations can dramatically elevate the lifetime risk of breast cancer, potentially increasing it to 60-85% compared to the general population risk of around 12%. The risk of ovarian cancer also increases significantly, from approximately 1% in the general population to as high as 44% in carriers of a BRCA1 mutation.
For men with a BRCA1 mutation, the risk of prostate cancer is approximately 29%, compared to 12% in those without the genetic alteration. Importantly, only one altered copy of the gene is needed to substantially increase risk.
Implications for Screening and Prevention
The findings underscore the potential for expanded genetic screening to identify individuals at risk who might not otherwise be identified through traditional risk assessment methods. This could lead to more personalized cancer prevention strategies and earlier detection through targeted screening programs. However, it’s crucial to remember that carrying a cancer-related mutation does not guarantee the development of cancer.
“These results highlight the importance of regular cancer screenings for all Americans – not just those with a family history or other risk factors,” Dr. Arbesman stated. Further research is needed to determine the optimal strategies for implementing broader genetic screening and counseling to maximize its benefits while minimizing potential harms, such as anxiety and unnecessary interventions.
As of , research continues to refine our understanding of the complex interplay between genetics and cancer risk, paving the way for more effective prevention and treatment strategies.
