Tina Alano

Age at diagnosis among patients with cancer is a predictor of pathogenic germline variant prevalence, yet age thresholds often misclassify genetic risk. We performed germline sequencing of 39,184 unselected patients with solid malignancies spanning 32 tumor types, interrogating >90 cancer predisposition genes independent of clinical suspicion. Patients were stratified into early-, average-, and late-onset groups based on standard deviations from tumor-specific mean age at diagnosis. Pathogenic variant prevalence inversely correlated with age at diagnosis: 18.4% in early-onset tumors, 15.6% in average-onset tumors, and 12.3% in late-onset tumors (P < 0.001). Variants in high/moderate-penetrance genes accounted for the enrichment in early-onset cases (12.4%, early-onset; 8.9%, average-onset; 5.1%, late-onset; P < 0.001). Restricting hereditary cancer testing to patients diagnosed before age 50, as is typically done, would miss 4,601 pathogenic variant carriers, 72% of all variants detected. These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases. Significance: Across 32 solid tumor types in a pan-cancer cohort, we found enrichment of germline pathogenic variants among patients with subtype-specific early-onset cancer. Using age 50 as a testing cutoff misses most patients with inherited predisposition, supporting universal germline genetic testing for all individuals diagnosed with cancer.

Genomically matched targeted therapies guided by MSK-IMPACT testing (n=22).

Clonality assessment of known oncogenic mutations in the female GCT cohort.

Patient demographic data for the female patients in the Extragonadal GCT cohort (both Make-an-IMPACT and internal MSK patients, n=16)

Supplementary Figure 2. Overview of the analytical pipeline for interpretation of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA).

Supplementary Figure 1. Overview of the workflow involved from patient outreach, screening, enrollment, testing and return of results to local physician/patient.

Supplementary Table 2. Clinical, demographic and molecular characteristics of pediatric solid tumor patients enrolled on the Make an Impact program.

Supplementary Table 1. Table representing country of referral for patients enrolled on the Make An Impact program (n = 63).

Supplementary Table 3. Clinical, demographic and molecular characteristics of pediatric CNS tumor patients enrolled on the Make an Impact program.

Purpose: To address financial barriers that limit access to genomic profiling and precision medicine, philanthropy-supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system tumors. Experimental Design: Tumor DNA or cerebrospinal fluid (CSF)-derived ctDNA was analyzed using the MSK-IMPACT assay, supplemented by targeted RNA panel sequencing in select cases. The results were returned to the patients/families and treating oncologists. Results: Sixty-three patients from 11 countries had successful MSK-IMPACT testing. The results provided clinically relevant new diagnostic or prognostic information in 41% and 38% of patients with solid and central nervous system tumors, respectively. Potentially therapeutically actionable alterations were identified in 44% of pediatric solid tumor and 21% of pediatric CSF-derived ctDNA samples, respectively. Four patients subsequently received molecularly guided therapy, resulting in partial responses in two and prolonged stable disease in one. Serial tumor and CSF sampling identified resistance mutations in two patients, informing additional molecularly targeted therapy recommendations. Conclusions: The Make-an-IMPACT program provided global access to state-of-the-art tumor and CSF genomic profiling across a diverse cohort of patients with pediatric cancer, providing clinically relevant and actionable diagnostic, prognostic, and therapeutic information reported in real-time to patients and local physicians.