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Genetic characterisation of molecular targets in carcinoma of unknown primary
B Clynick1, B Dessauvagie1,2, G Sterrett1,3
1School of Biomedical Sciences (M504), The University of Western Australia, 35 Stirling Hwy, Crawley, WA, 6009, Australia.
Background:
Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions.
Methods:
Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations.
Results:
Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1).
Conclusion:
Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.
Insights
Actionable mutations were found in over half of carcinoma of unknown primary (CUP) tumors, offering new personalized treatment possibilities. This genetic profiling can guide targeted therapies for CUP patients, improving outcomes.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Carcinoma of unknown primary (CUP) is a metastatic cancer lacking a clear origin, often leading to poor prognosis and limited treatment options.
- Current treatments for CUP typically involve broad-spectrum chemotherapy, highlighting the need for more personalized approaches.
- Mutation profiling presents a promising avenue for developing novel treatment strategies for CUP patients.
Purpose of the Study:
- To investigate the presence of actionable, oncogenic driver mutations in carcinoma of unknown primary (CUP) tumors.
- To determine if identifying these mutations can inform and improve treatment decisions for CUP patients.
- To explore the potential for personalized cancer management in CUP based on genetic profiling.
Main Methods:
- DNA was extracted from 21 formalin-fixed paraffin-embedded CUP samples.
- Targeted gene panels were employed to sequence up to 76 known cancer-related genes.
- Variants were analyzed to identify biologically relevant and actionable mutations.
Main Results:
- Mutations were detected in 81% (17/21) of CUP cases, with 52% (11/21) harboring potentially actionable mutations.
- The most frequent variants identified were in TP53 (47%), KRAS (12%), MET (12%), and MYC (12%).
- Distinct molecular profiles were observed across CUP histological subtypes, with adenocarcinomas and poorly differentiated carcinomas showing enrichment in signal transduction pathway genes, while squamous cell carcinomas had more cell cycle and DNA repair gene variants.
Conclusions:
- The majority of CUP tumors harbor mutations in biologically relevant genes.
- Approximately half of the identified mutations offer potential novel treatment avenues not typically considered for CUP.
- Genetic profiling of CUP tumors can reveal actionable mutations, paving the way for personalized treatment strategies.
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