Related Experiment Video
Updated: Jan 19, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Identification and Confirmation of Potentially Actionable Germline Mutations in Tumor-Only Genomic Sequencing
Dana Farengo Clark1,2, Kara N Maxwell1,2, Jacquelyn Powers1,2
1Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Purpose:
Tumor-only genomic profiling (TGP) is increasingly advocated for all patients with cancer given the possible therapeutic implications. It is critical to develop clinical algorithms to identify and address potentially actionable germline findings identified by TGP.
Methods:
A multidisciplinary team analyzed publicly available data for genes in which mutations are implicated in germline cancer susceptibility and established a pipeline to automate clinical referral for evaluation of TGP findings.
Results:
A total of 2,308 patients underwent TGP, with 81 patients (3.5%) identified by the automatic referral pipeline; 37 patients (1.6%) were referred outside the pipeline based on concerns by the molecular geneticist, pathologist, or oncologist regarding genotype-phenotype correlation. Thirty-one patients (38%) and 17 patients (46%) underwent germline testing from the automatic pipeline and other referrals, respectively, and of these patients, 23 (72%) and four (24%) had confirmed germline pathogenic variants (GPVs), respectively. The majority of confirmed GPVs were in automatic referral genes, with BRCA2 being most common (confirmed GPVs in 11 [85%] of 13 patients tested), followed by PALB2 (five [67%] of six patients), BRCA1 (two [40%] of five patients), MSH6 (two of three patients), and MLH1 (two of two patients). Forty-eight percent of confirmed GPVs were found in tumors known to be associated with germline mutations in the gene. Germline testing was not performed in 50 (62%) of 81 patients identified by automatic referral as a result of poor patient health or death (30%), lack of follow-up (30%), and patient refusal (30%).
Conclusion:
Of patients undergoing TGP, 5% had somatic findings triggering referral, and implementation of an automatic referral pipeline based solely on gene versus other clinical or molecular features resulted in a 74% germline confirmation. However, only 41% of referred patients underwent germline testing. Systems-based approaches are needed to identify carriers of actionable germline cancer susceptibility mutations identified by TGP.
Insights
An automated pipeline identified 3.5% of patients with potentially actionable germline findings from tumor-only genomic profiling (TGP). However, only 41% of referred patients completed germline testing, highlighting a need for improved systems to identify cancer susceptibility mutation carriers.
Area of Science:
- Genomic Medicine
- Oncology
- Clinical Genetics
Background:
- Tumor-only genomic profiling (TGP) is increasingly used in cancer care.
- TGP can reveal actionable germline findings, impacting patient management and family risk assessment.
- Identifying these germline variants requires robust clinical algorithms.
Purpose of the Study:
- To develop and evaluate a clinical algorithm for identifying potentially actionable germline findings from TGP.
- To assess the yield of germline pathogenic variants (GPVs) through an automated referral pipeline.
Main Methods:
- Analysis of publicly available data for cancer susceptibility genes.
- Establishment of an automated pipeline for clinical referral based on TGP findings.
- Multidisciplinary team review of TGP results and genotype-phenotype correlations.
Main Results:
- An automated referral pipeline identified 3.5% of 2,308 patients for germline evaluation.
- Of those referred, 72% of patients tested via the pipeline had confirmed GPVs, with BRCA2 being most common.
- Only 41% of referred patients completed germline testing due to factors like poor health or refusal.
Conclusions:
- An automated referral pipeline can identify a significant proportion of patients with actionable germline findings from TGP.
- Implementation challenges, including patient follow-through, limit the effectiveness of referral systems.
- Systems-based approaches are crucial for effectively identifying germline cancer susceptibility mutation carriers identified by TGP.
Related Concept Videos
11:15Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
09:40Novel Sequence Discovery by Subtractive Genomics
11:11Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
10:41An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues
10:34Ultra-long Read Sequencing for Whole Genomic DNA Analysis
09:37An Integrated Approach for Microprotein Identification and Sequence Analysis