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Updated: Mar 19, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Molecular driver alterations and their clinical relevance in cancer of unknown primary site
Harald Löffler1, Nicole Pfarr2,3, Mark Kriegsmann2
1Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
Abstract:
Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.
Insights
Molecular profiling of cancer of unknown primary (CUP) reveals frequent mutations in driver genes like TP53 and KRAS. These genetic alterations impact patient survival and offer potential therapeutic targets for CUP treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer of unknown primary (CUP) comprises metastatic solid tumors lacking a detectable primary site, predominantly adenocarcinomas or undifferentiated carcinomas.
- Current therapies for CUP offer limited efficacy, highlighting the need for improved diagnostic and therapeutic strategies.
- Understanding the molecular characteristics of CUP is crucial for personalized treatment and accurate tumor classification.
Purpose of the Study:
- To investigate the molecular landscape of cancer of unknown primary (CUP) in adenocarcinoma and undifferentiated carcinoma subtypes.
- To identify frequently mutated or altered genes and assess their correlation with clinical outcomes.
- To explore the potential for targeted therapies based on identified molecular alterations in CUP.
Main Methods:
- Massive parallel multigene sequencing of 50 cancer-relevant genes was performed on a cohort of 55 CUP patients.
- Analysis included identification of tumor-specific mutations, amplifications, and deletions.
- Clinical data, including progression-free survival (PFS) and overall survival (OS), were correlated with molecular findings.
Main Results:
- Genetic alterations were detected in 84% of CUP cases, with TP53 (55%), KRAS (16%), and CDKN2A (9%) being the most frequently mutated genes.
- CDKN2A was also the most frequently deleted gene (15%).
- KRAS and CDKN2A mutations were associated with poorer PFS and OS, while wildtype TP53 and female sex indicated a more favorable prognosis. 15% of cases had targetable mutations.
Conclusions:
- The majority of cancer of unknown primary tumors harbor mutations in key driver genes.
- Specific mutations, such as in KRAS and CDKN2A, significantly influence patient prognosis.
- A subset of CUP patients may benefit from targeted therapies based on their tumor's molecular profile, underscoring the importance of molecular diagnostics in CUP management.
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