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Updated: Dec 9, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Mutational Signature and Transcriptomic Classification Analyses as the Decisive Diagnostic Tools for a Cancer of
Roger Olofsson Bagge1, Akif Demir1, Joakim Karlsson1
1, , , , , , , , , , and , Sahlgrenska Academy, University of Gothenburg; , , , , , , , , , and , Sahlgrenska Cancer Center, University of Gothenburg; , , , , Sahlgrenska University Hospital, Gothenburg, Sweden; and , Reinier de Graaf Hospital, Delft; and University Medical Center Utrecht/Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Purpose:
Cancer of unknown primary is a group of metastatic tumors in which the standard diagnostic workup fails to identify the site of origin of the tumor. The potential impact of precision oncology on this group of patients is large, because actionable driver mutations and a correct diagnosis could provide treatment options otherwise not available for patients with these fatal cancers. This study investigated if comprehensive genomic analyses could provide information on the origin of the tumor.
Patients And Methods:
Here we describe a patient whose tumor was misdiagnosed at least three times. Next-generation sequencing, a patient-derived xenograft mouse model, and bioinformatics were used to identify an actionable mutation, predict resistance development to the targeted therapy, and correctly diagnose the origin of the tumor. Transcriptomic classification was benchmarked using The Cancer Genome Atlas (TCGA).
Results:
Despite the lack of a known primary tumor site and the absence of diagnostic immunohistochemical markers, the origin of the patient's tumor was established using the novel bioinformatic workflow. This included a mutational signature analysis of the sequenced metastases and comparison of their transcriptomic profiles to a pan-cancer panel of tumors from TCGA. We further discuss the strengths and limitations of the latter approaches in the context of three potentially incorrectly diagnosed TCGA lung tumors.
Conclusion:
Comprehensive genomic analyses can provide information on the origin of tumors in patients with cancer of unknown primary.
Insights
Comprehensive genomic analyses accurately identified the origin of a patient's cancer of unknown primary, even after multiple misdiagnoses. This approach offers new hope for targeted treatments in fatal cancers.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Cancer of unknown primary (CUP) presents a diagnostic challenge, hindering access to potentially life-saving precision oncology treatments.
- Accurate tumor origin identification is crucial for effective treatment selection in metastatic cancers.
Purpose of the Study:
- To investigate the utility of comprehensive genomic analyses in determining the primary tumor site in cases of cancer of unknown primary.
- To demonstrate how advanced molecular techniques can overcome diagnostic limitations in CUP.
Main Methods:
- Utilized next-generation sequencing, patient-derived xenograft models, and bioinformatics for tumor analysis.
- Employed mutational signature analysis and transcriptomic profiling, benchmarked against The Cancer Genome Atlas (TCGA).
Main Results:
- Successfully identified the tumor's origin despite initial misdiagnoses and lack of conventional markers.
- Demonstrated the effectiveness of a novel bioinformatic workflow in pinpointing tumor origin.
- Highlighted the strengths and limitations of transcriptomic classification using TCGA data.
Conclusions:
- Comprehensive genomic analyses are effective in determining the origin of tumors in patients with cancer of unknown primary.
- Precision oncology tools can significantly improve diagnosis and treatment options for CUP patients.
