Age-Based Genetic Testing Rules May Miss Most Inherited Cancer Risk, Study Finds

A sweeping analysis of nearly 40,000 patients with solid tumors suggests that the long-standing practice of limiting inherited cancer risk testing to younger patients may be excluding the majority of people who actually carry clinically significant gene variants. The study, published in Cancer Discovery, a journal of the American Association for Cancer Research, found that if researchers had applied the conventional age cutoff of 50 years to decide who receives germline genetic testing, they would have missed roughly 72 percent of all patients in the cohort who harbored inherited pathogenic variants. The findings, drawn from one of the largest universal germline sequencing efforts reported to date, are prompting renewed calls to abandon age-based eligibility rules and instead offer genetic testing to every patient diagnosed with cancer, regardless of how old they are when the disease appears.

Germline genetic testing examines DNA inherited from a person’s parents, typically using blood or saliva samples, to identify alterations known as germline pathogenic variants. These variants are present in every cell of the body and can predispose carriers to cancer. Detecting them matters for two reasons. First, certain inherited variants have direct treatment implications, informing decisions about targeted therapies, surgical options, and surveillance strategies. Second, identifying a pathogenic variant in a patient opens the door to cascade testing, in which relatives are offered testing to determine whether they carry the same variant and therefore face elevated cancer risk themselves. In clinical practice, however, germline screening has traditionally been reserved for patients diagnosed before age 50, reflecting an assumption that cancers arising later in life are less likely to be driven by inherited predisposition.

Zsofia K. Stadler, clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, and Luis A. Diaz, Jr., head of Solid Tumor Oncology at the same institution, served as co-corresponding authors of the study. Stadler explained that the logic behind the age cutoff rests on the idea that patients with average- or late-onset cancers are less likely than those with early-onset disease to have cancers caused by inherited pathogenic variants. But she argued that this reasoning has hardened into a barrier that keeps many eligible patients from receiving potentially life-changing information. In a statement accompanying the study, she described current standard practice as, in many ways, a gatekeeper for genetic testing, and said the research team set out to quantify how much inherited cancer risk is missed when age at diagnosis is weighted too heavily.

To answer that question, the researchers performed germline genetic testing on all 39,184 patients with solid tumors seen at Memorial Sloan Kettering Cancer Center, without applying any age restriction. Testing was carried out using the MSK-Integrated Mutation Profiling of Actionable Targets, or MSK-IMPACT, assay, which analyzed DNA isolated from patients’ blood or saliva for 94 genes implicated in inherited cancer predisposition. This universal approach allowed the team to compare the actual prevalence of pathogenic variants across the entire patient population with what would have been captured under the conventional age-limited strategy.

The results were striking. Overall, 16.3 percent of all patients in the cohort harbored at least one germline pathogenic variant. When the researchers modeled what would have happened under the typical practice of restricting testing to patients under age 50, they calculated that 4,601 patients with pathogenic variants would have been excluded, amounting to 72 percent of all carriers in the cohort. In other words, the majority of patients carrying inherited cancer risk variants would never have been identified through the standard approach, leaving them without the clinical and familial benefits that come from knowing their genetic status.

The team then took a more nuanced look at how variant prevalence varies with the age at which cancer develops. Rather than relying on the standard convention of labeling any cancer diagnosed before age 50 as early-onset regardless of type, the researchers classified each patient’s cancer as early-, average-, or late-onset according to the distribution of age at onset for that specific cancer type. Early-onset was defined as occurring more than one standard deviation below the mean age at onset for the cancer type, late-onset as more than one standard deviation above the mean, and average-onset as falling within one standard deviation of the mean. This cancer-specific classification acknowledged that the typical age of diagnosis varies widely across malignancies, from relatively young ages in some tumors to much older ages in others.

Using this framework, the prevalence of germline pathogenic variants was 18.4 percent among patients with early-onset cancers, 15.6 percent among those with average-onset cancers, and 12.3 percent among those with late-onset cancers. The decline with age was real, but far shallower than the age-based testing policy presumes. Even among patients whose cancers appeared late relative to the norm for their tumor type, more than one in ten carried an inherited pathogenic variant, a prevalence high enough to carry substantial clinical consequence.

The distinction between variant categories sharpened the picture further. High-penetrance variants, which are more likely to produce the cancer-predisposing effect with which they are associated, occurred in 9.1 percent of patients with early-onset cancers, 5.5 percent of those with average-onset cancers, and 2.6 percent of those with late-onset cancers. Moderate-penetrance variants showed a flatter distribution, appearing in 3.3 percent, 3.4 percent, and 2.5 percent of early-, average-, and late-onset cases respectively. Taken together, high- and moderate-penetrance pathogenic variants, which carry potential implications for cancer treatment strategies, were found in about 9.7 percent of all patients in the cohort. According to Stadler, the persistence of these clinically actionable variants among older patients demonstrated that a uniform screening cutoff at age 50 is insufficient, and she emphasized that the study showed the value of universal germline genetic testing regardless of age.

The authors argue that the findings should reshape clinical standards. Hereditary cancer can occur at any age, Diaz said, and the field should move toward a new standard in which genetic testing is considered for every patient diagnosed with cancer, regardless of age. He noted that the manuscript shows relying on age at diagnosis misses a substantial proportion of patients with germline pathogenic variants and provides strong support for moving toward universal germline genetic testing in patients with cancer. Stadler added that universal testing would give clinicians insights into a patient’s cancer that could guide treatment, while also enabling greater use of cascade testing among relatives. She cautioned, however, that cascade testing remains one of the most underused opportunities in cancer prevention, noting that once a hereditary cancer predisposition variant is identified in one patient, testing relatives becomes highly targeted and informative, yet only a minority of eligible relatives currently undergo testing.

As with any single-institution study, the findings come with caveats that the authors themselves acknowledged. The research was conducted at one major tertiary cancer center, a setting that may not reflect the demographics or referral patterns of community oncology practices. Certain cancer types were over- or underrepresented in the cohort, and the patient population was predominantly of European and Ashkenazi Jewish ancestry, both groups in which certain founder pathogenic variants are relatively common. Generalizing the results to more diverse populations will require further study. The work was funded by grants from the National Institutes of Health and Memorial Sloan Kettering Cancer Center, and the authors disclosed a range of professional relationships and intellectual property interests in keeping with journal policy. Even with these limitations, the scale of the dataset and the magnitude of the gap it exposes, nearly three-quarters of variant carriers overlooked by age-based rules, make a compelling case that the era of age-restricted germline testing in oncology may be drawing to a close, with universal testing poised to become the new benchmark of care.

Subject of Research: Universal germline genetic testing for inherited cancer risk in patients with solid tumors

Article Title: Current age-based genetic testing in patients with cancer may miss majority of inherited gene variants

Article References: Current age-based genetic testing in patients with cancer may miss majority of inherited gene variants. (n.d.). Original publication

Image Credits: AI Generated

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Keywords: germline genetic testing, hereditary cancer, pathogenic variants, cancer predisposition, age cutoff, universal testing, cascade testing, MSK-IMPACT, solid tumors, Cancer Discovery, Memorial Sloan Kettering, precision oncology