The emerging clinical relevance of genomic profiling in neuroendocrine tumours

Abstract

Background Neuroendocrine tumours (NETs) arise from hormone-producing or nervous system cells and can develop from anywhere in the body. They have heterogeneous origins from skin to gastrointestinal track and a complicated histology. Thus, there is an inevitable need for genomic profiling to determine the exact genetics of each tumour for prognosis and treatment strategies to overcome the disease’s complexity. For this purpose, next-generation-sequencing (NGS) is the most reliable methodology for both germ-line and somatic studies to make a clinical diagnosis. In this study, we analyse liquid biopsies, formalin fixed paraffin embedded (FFPE) tissues, and peripheral blood samples for their ability to provide information for actionability. Methods A customized multi-gene panel comprised of Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB), Succinate Dehydrogenase Complex Subunit C (SDHC), Cell Division Cycle 73(CDC73), Calcium Sensing Receptor (CASR), Platelet Derived Growth Factor Receptor Alpha (PDGFRA), Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA), Ret Proto-Oncogene (RET), Succinate Dehydrogenase Complex Assembly Factor 2(SDHAF2), Menin 1(MEN1), Succinate Dehydrogenase Complex Subunit D (SDHD), MYC Associated Factor X (MAX) and Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A) genes was constructed to assess multiple specimen types including: 3 liquid biopsies, 6 FFPE tissues, and 26 peripheral blood samples from 35 unique NET patients. Quality-control and bioinformatics analyses were performed using QCI-Analyze and QCI-Interpret. Results The three liquid biopsies and the 6 FFPE tissue samples were evaluated for somatic mutations; while the 26 peripheral blood samples were analysed using the germ-line pipeline. Five (55.6%) of the nine patients that were studied for somatic changes carried actionable mutations related to therapy sensitivities. Through the germ-line studies, we observed a 50% positivity rate for disease predisposition with 16 variants classified according to ACMG (American College of Medical Genetics) Standards and Guidelines. Conclusions Genomic profiling medicine is an emerging area of clinical oncology and has become crucial for disease and patient management by providing a precision approach; this is especially true for rare diseases including rare cancers such as NETs. Notably, this study emphasized the relevance of multiple distinctive biological sample types for use in the genetic testing of cancers to help with the choice of therapy to maximize the likelihood of a positive clinical outcome.

Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The Role of ctDNA in Real-World Practice

“…Although molecular profiling of WdNETs has been widely utilised to better understand the biology of these malignancies, true precision medicine therapeutic approaches in this patient group are currently non-existent [ 13 ]. Other series exploring targetable alterations in WdNETs have reported a higher rate of targetable alterations [ 6 , 10 ], which may be due to the differing definitions of “targetable” used, which ideally should follow evidence-based definitions [ 14 ]. It would also be of interest to understand how many of those patients were actually matched to a specific treatment based on the molecular alteration identified.…”

“…In addition, it is extremely difficult to make a decision about the right technology to apply (whole-genome, whole-exome or RNA-sequencing) in an extremely volatile context regarding the cost and constant evolution of technology. Cell-free DNA may offer an easily accessible, alternative source of fresh tumour material for genomic characterisation; the profiling of its DNA fraction, namely ctDNA, has proven informative and clinically useful in different cancer types, and may also find application in patients with NENs [ 10 , 11 ]. In addition, ctDNA readouts, if detectable, can be measured over time to monitor changes in tumour burden and genomic profile.…”

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey

“…However, we speculate that most of these VUS were detected in cancer patients may be supportive of their pathogenic potential. That's the reason of why all the most recent studies are focusing on the effects of rare variants that are hardly classified not only in cancer but also in rare diseases such as immunodeficiencies [ [17] , [18] , [19] ]. Even the VUSs have no functional studies supporting their pathogenicity, this study may provide as the first case series covering the all Turkey and a sourceful data for future functional studies or case based reportings and analysis.…”

The Molecular Biology of Midgut Neuroendocrine Neoplasms

“…A recent study explored the use of next-generation sequencing in peripheral blood samples, liquid biopsies, and formalin-fixed paraffin-embedded samples of NEN tumors to test for mutations that could inform treatment pathways ( 46 ). While peripheral blood (which would indicate only germline mutations) indicated 16 variants predisposing to NEN development in 50% of patients tested, the novel aspect of the study was its use of liquid biopsies.…”