Cancer genome profiling uncovers hidden inherited cancer risk in one in ten patients

Comprehensive cancer genome profiling, a form of tumor sequencing designed to find actionable somatic mutations that can guide treatment, is also turning up something its users may not be looking for: inherited, or germline, pathogenic variants that explain why a patient developed cancer in the first place. A prospective interventional trial now reports how often these constitutional variants surface when tumor profiling is carried out according to the recommendations of the European Society of Medical Oncology, and how many of them would be missed under current genetic testing guidelines.

The study, registered at ClinicalTrials.gov as NCT06020625, enrolled patients with solid cancers in whom molecular assessment was already clinically indicated based on national guidelines, and referred them for comprehensive cancer genome profiling. When the tumor sequencing suggested a variant might be constitutional rather than somatic, patients were sent on for germline testing. The analysis presented covers the first two years of the program, from January 2022 to December 2023.

Of 2,688 samples from 2,674 patients with a completed profiling report, more than half came from gynecologic cancers, specifically endometrial and ovarian tumors. Sixteen percent of the patients were referred for genetic evaluation because of 527 suspected constitutional pathogenic or likely pathogenic variants, and compliance with genetic counselling in that referred group reached 80 percent.

Germline testing was ultimately performed in 331 patients. Among them, 73 percent harbored at least one pathogenic or likely pathogenic variant, and 66 percent of the variants flagged by tumor sequencing were confirmed to be genuinely germline. In other words, the tumor report acted as a reasonably reliable but imperfect screen: a substantial majority of suspected constitutional findings held up, while about a third did not, underscoring the need for confirmatory germline testing rather than treating the tumor report alone as diagnostic of inherited risk.

Two categories of confirmed findings stand out from the results. First, 16 percent of the germline variants were secondary findings, meaning they were discovered incidentally rather than because the patient’s tumor pattern or family history pointed to them. Second, 20 percent of the confirmed on-tumor germline pathogenic variants sat in moderate-risk genes, variants that current guidelines would generally not have triggered. Both groups represent inherited cancer risk that would have gone undetected if tumor profiling had been interpreted purely through a somatic, treatment-oriented lens.

The yield extended beyond the tumor sequencing itself. Twenty additional constitutional pathogenic variants were identified in 19 patients on the basis of other somatic tests or through additional tests requested following genetic counselling, accounting for 0.7 percent of the entire cohort. Taken together, constitutional pathogenic variants were detected in about 10 percent of this unselected solid tumor cohort, a figure the authors describe as a relevant fraction given that many of the findings were secondary results or moderate-penetrance gene variants that would not have been found under existing guidelines.

The trial’s design matters for how the results should be read. Because enrollment was restricted to patients in whom molecular assessment was already clinically indicated, the cohort is not a general cancer population, and the reported detection rates apply to this guideline-selected group of solid tumor patients rather than to all people with cancer. As an early-access, peer-reviewed accepted version of the article, the report is citable but remains subject to further edits before the final version of record.

From a clinical standpoint, the study supports a model in which comprehensive cancer genome profiling is deliberately paired with systematic genetic counselling rather than treated as a purely therapeutic tool.

Subject of Research: Detection of germline pathogenic variants through comprehensive cancer genome profiling in solid tumor patients

Article Title: Germline pathogenic variants identification through comprehensive cancer genome profiling

Article References: Duranti, S., Panfili, A., Nero, C., Marino, I., Mozzetta, I., Rossi, S., Maneri, G., Pasciuto, T., Giacò, L., Minucci, A., Giannarelli, D., Fagotti, A., Fanfani, F., Bria, E., Salvatore, L., Calegari, M. A., Iacovelli, R., Peris, K., Trozzi, R., … Genuardi, M. (2026). Germline pathogenic variants identification through comprehensive cancer genome profiling. Genome Medicine. https://doi.org/10.1186/s13073-026-01762-3

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01762-3

Keywords: cancer genomics, germline variants, comprehensive genome profiling, hereditary cancer syndromes, genetic counselling, secondary findings, moderate-risk genes, somatic mutations, solid tumors, gynecologic cancers, precision oncology, clinical trial