MSKCC Study Finds Age-Based Testing Misses Substantial Proportion of Genetic Variants

Universal germline genetic testing across nearly 40,000 cancer patients at Memorial Sloan Kettering Cancer Center revealed that standard age-based screening cutoffs miss a substantial proportion of inherited pathogenic variants, challenging decades of clinical practice and prompting calls for a new standard of care regardless of patient age.

Medical guidelines have long relied on age as a primary gatekeeper for inherited cancer risk screening. Typically, clinicians restrict germline genetic testing to patients diagnosed under the age of 50, operating on the assumption that older adults with average- or late-onset cancers are far less likely to harbor hereditary mutations.

A major new study published in Cancer Discovery upends that assumption. Researchers at Memorial Sloan Kettering Cancer Center evaluated nearly 40,000 patients with solid tumors, demonstrating that an arbitrary age cutoff filters out thousands of individuals carrying actionable genetic alterations.

Memorial Sloan Kettering Study Design and Findings

Across the entire cohort, a substantial proportion of patients harbored at least one germline pathogenic variant. The data showed that restricting testing to individuals under 50 would have excluded a significant number of patients with pathogenic variants.

MSKCC Study Finds Age-Based Testing Misses Substantial Proportion of Genetic Variants — Photo: miragenews.com

The current standard practice is, in many ways, a gatekeeper for genetic testing.

Zsofia K. Stadler, MD, Clinical Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center

Zsofia K. Stadler, MD, who serves as the clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, authored the research alongside Luis A. Diaz, Jr., MD, FAACR, who holds the position of head of solid tumor oncology at Memorial Sloan Kettering Cancer Center. These investigators pointed out that hereditary cancer can occur at any chronological point in a person’s life, meaning that age cutoffs fail to capture a significant population of individuals who require genetic insight.

Prevalence Across Early, Average, and Late Onset Cancers

Rather than relying on the traditional definition of early-onset cancer as any diagnosis occurring before age 50, the investigators classified cases based on the statistical distribution of age at onset for each specific cancer type. Early-onset cancers were defined as occurring more than one standard deviation below the mean age, while late-onset cases occurred more than one standard deviation above it.

This classification revealed that inherited gene variants remain common even among older populations. The prevalence of pathogenic variants was substantial across all groups.

The study demonstrated that high- and moderate-penetrance pathologic variants occur among older patient groups at frequencies that render a uniform age cutoff insufficient. Stadler noted that moving toward universal screening practices gives clinicians the insights required to guide patient treatment strategies effectively.

Genetic Mutations Inform Cancer Treatment and Family Testing

Identifying these mutations carries direct consequences for therapeutic choices and family disease prevention. High- and moderate-penetrance variants, which hold direct implications for tailoring cancer treatment strategies, appeared in a significant portion of all patients evaluated in the cohort.

Beyond individual treatment tailoring, discovering a hereditary predisposition marker enables cascade testing, which is the process of using identified variants to flag cancer risks in the patients’ family members. However, researchers noted that cascade testing remains severely underutilized, with only a minority of eligible relatives undergoing screening despite its proven preventative value.

Readers should consult qualified healthcare professionals, such as oncologists or clinical geneticists, to discuss personal cancer risks and determine appropriate screening strategies.