Identification of Novel Pathogenic Deletions in NET Liver Metastases with Implications for TACE Therapy

Understanding the genetic landscape of neuroendocrine tumors (NETs) is critical for improving personalized therapies, including optimizing the use of trans-arterial chemoembolization (TACE). Although previous sequencing efforts have explored NETs, most employed short-read sequencing techniques that can identify single nucleotide variants (SNVs) and indels but lack the ability to detect structural variants (SVs), which involve larger genetic alterations. SVs, due to their size and ability to disrupt multiple exons, tend to have a greater functional impact on tumorigenesis. Our study identified seven novel recurrent pathogenic deletions, a subtype of SVs, in liver metastases from NETs.

Materials and Methods:

We analyzed 42 samples (32 tumor samples and 10 matched controls), with an additional 40 samples and matched controls currently being collected. A major strength of our study is the use of Optical Genome Mapping, a technique that addresses the limitations of traditional methods in detecting SVs. This approach allowed us to identify novel SVs with greater sensitivity. Established machine learning and rule-based algorithms {1-4} were employed to assess the pathogenicity of thousands of deletions. By integrating pathogenicity data with known gene functions, we identified seven novel pathogenic deletions.

Results:

Sixteen potentially pathogenic deletions were initially identified, all of which were found in at least two distinct tumor samples and absent in control samples. Four of these deletions involved known tumor suppressor genes: FAS, PTEN, CDKN2A, BAX, PPP2R1A, POLD1, and MAX. Of the remaining twelve SVs, seven deletions exhibited biologically plausible oncogenic mechanisms. One notable deletion affects the METTL13 gene, which can lead to activation of HIF-1α. Upregulation of HIF-1α has been shown to increase angiogenesis, epithelial-mesenchymal transition, and resistance to apoptosis, all of which can reduce the efficacy of TACE.

Conclusion:

Our study identified seven novel pathogenic deletions in NET liver metastases, providing new insights into the genetic drivers of tumor progression. These biomarkers hold promise for further investigation, particularly in the context of their impact on interventional radiology therapies such as TACE. Future research should focus on whether specific SVs can predict TACE efficacy, paving the way for more personalized and effective treatment strategies.