Over the past three decades, cancer genetics has transformed precision oncology. Germline testing has advanced from single-gene Sanger sequencing to parallel sequencing of hundreds of genes, while tumor (somatic) testing has expanded with the rise of targeted therapies based on point mutations, copy number changes and other alterations.
These advances have reduced costs and broadened patient access. At City of Hope, both germline and somatic testing are routinely integrated into patient care to allow for effective personalized treatment while minimizing side effects.
Benefits of an integrated interpretation
Germline tumor and circulating tumor DNA (ctDNA) assays are often ordered independently, each serving distinct purposes. Yet their greatest value emerges when interpreted together, as individual tests provide only limited insight. For example, tumor-only sequencing misses approximately 10% of germline variants and may leave uncertainty about whether a variant reflects inherited risk, a passenger alteration or a true driver. Thus, both germline and somatic testing are required to diagnose hereditary cancer syndromes and identify therapeutic targets.
Integration also refines germline interpretation. Somatic findings can provide supporting evidence for the pathogenicity of variants of uncertain significance (VUS). For instance, microsatellite instability in a tumor with a germline VUS in a mismatch repair gene or homologous recombination deficiency (HRD) in a tumor with a germline VUS in an HRD gene raises suspicion for pathogenicity. While not sufficient for immediate reclassification, such evidence contributes to the cumulative case that ultimately guides interpretation (Table 1). City of Hope is contributing to this body of knowledge for the benefit of cancer patients.
Examples of somatic findings supportive of pathogenicity of a germline VUS
| Somatic Finding | Gene in which Germline VUS was identified |
|---|---|
| Homologous Recombination Deficiency | BRCA1, BRCA2, PALB2, ATM, RAD51C, RAD51D, BARD1, BRIP1 |
| Microsatellite Instability | MLH1, MSH2, MSH6, PMS2, EPCAM 3’ deletions |
| Tumor Signature 6, 15, 21, 26, & 46 | MLH1, MSH2, MSH6, PMS2, EPCAM 3’ deletions |
| Tumor Signature 36 | MUTYH (biallelic) |
| Tumor Signature 30 | NTHL1 (biallelic) |
| Tumor Signature 10 | POLE, POLD1 |
| Second “hit” in same gene | Any Tumor Suppressor Gene |
Patient engagement
Despite its clinical value, dual testing remains difficult for patients to understand. Terms such as germline and somatic are non-intuitive, and the concept of incidental hereditary findings from tumor testing can be confusing. This makes it difficult for patients to understand why they might need both tests, which test(s) they have undergone and differences in the results of the tests.
Research has shown that structured educational approaches, like videos, interactive online tools and pre- and post-test genetic counseling enhance comprehension and facilitate informed decision-making. Engaging patients in the process of creating these materials can optimize their usefulness.
Back to the future
Over the past decade, research has demonstrated the benefits of integrating germline and somatic data for both risk prediction and treatment selection. Oncology is now advancing beyond DNA sequencing toward multi-omics, incorporating transcriptomics, proteomics, epigenetics and digital pathology. City of Hope and its affiliate Translational Genomics Research Institute (TGen) are collaborating to usher this burgeoning field forward.
Research has shown that structured educational approaches, like videos, interactive online tools and pre- and post-test genetic counseling enhance comprehension and facilitate informed decision-making.
This integration is evident in clinical practice; for example, combining immunohistochemistry for MLH1 protein loss with MLH1 promoter methylation testing distinguishes sporadic epigenetic events from germline mutations in colorectal cancer. Such cross-modal assays clarify germline VUS, much as family pedigrees once informed variant interpretation. Increasingly, cancer centers are standardizing frameworks that combine germline genotype, tumor phenotype and clinical context to achieve more rigorous and clinically meaningful variant classification. Together, these advances mark a new era of precision oncology in which integrated germline, somatic and multi-omic data guide risk prediction and therapeutic decision-making, ultimately improving patient care.
City of Hope® is one of the largest and most advanced cancer research and treatment organizations in the U.S. City of Hope harnesses leading-edge, genomic-driven insights and best-in-class oncologists to improve patient outcomes and quality of life. Our precision medicine program empowers patients to make the best clinical decisions for themselves and their loved ones in partnership with cancer specialists. To learn more about City of Hope, visit: www.cityofhope.org.
