Related Experiment Video
Updated: Aug 2, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer
Matteo Pallocca1, Ivan Molineris2,3, Enrico Berrino3,4
1Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. matteo.pallocca@ifo.it.
Background:
The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic Profiling of solid tumours has been approved as a companion diagnostic, still no approved predictive biomarkers are available for Melanoma aside from BRAF mutations and the controversial Tumor Mutational Burden. This study presents the results of a Multi-Centre Observational Clinical Trial of Comprehensive Genomic Profiling on Target and Immuno-therapy treated advanced Melanoma.
Methods:
82 samples, collected from 7 Italian Cancer Centres of FFPE-archived Metastatic Melanoma and matched blood were sequenced via a custom-made 184-gene amplicon-based NGS panel. Sequencing and bioinformatics analysis was performed at a central hub. Primary analysis was carried out via the Ion Reporter framework. Secondary analysis and Machine Learning modelling comprising of uni and multivariate, COX/Lasso combination, and Random Forest, was implemented via custom R/Python scripting.
Results:
The genomics landscape of the ACC-mela cohort is comparable at the somatic level for Single Nucleotide Variants and INDELs aside a few gene targets. All the clinically relevant targets such as BRAF and NRAS have a comparable distribution thus suggesting the value of larger scale sequencing in melanoma. No comparability is reached at the CNV level due to biotechnological biases and cohort numerosity. Tumour Mutational Burden is slightly higher in median for Complete Responders but fails to achieve statistical significance in Kaplan-Meier survival analysis via several thresholding strategies. Mutations on PDGFRB, NOTCH3 and RET were shown to have a positive effect on Immune-checkpoint treatment Overall and Disease-Free Survival, while variants in NOTCH4 were found to be detrimental for both endpoints.
Conclusions:
The results presented in this study show the value and the challenge of a genomics-driven network trial. The data can be also a valuable resource as a validation cohort for Immunotherapy and Target therapy genomic biomarker research.
Insights
Comprehensive Genomic Profiling in advanced melanoma reveals new predictive biomarkers beyond BRAF. Mutations in PDGFRB, NOTCH3, and RET show promise for improving immunotherapy and targeted therapy outcomes.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Advanced Melanoma treatment relies on sequential Targeted and Immuno-therapy, primarily Immune-Checkpoint blockade.
- Current predictive biomarkers for Melanoma are limited to BRAF mutations and Tumor Mutational Burden (TMB).
- Comprehensive Genomic Profiling (CGP) is approved for solid tumors but lacks validated predictive biomarkers in Melanoma.
Purpose of the Study:
- To evaluate the utility of CGP in advanced Melanoma patients undergoing targeted and immunotherapy.
- To identify novel genomic biomarkers predictive of treatment response and survival.
- To assess the feasibility of a genomics-driven clinical trial network.
Main Methods:
- A Multi-Centre Observational Clinical Trial involving 82 FFPE Metastatic Melanoma samples from 7 Italian Cancer Centres.
- Next-Generation Sequencing (NGS) using a custom 184-gene amplicon panel for DNA analysis.
- Bioinformatics analysis incorporating Machine Learning models (COX/Lasso, Random Forest) for biomarker discovery.
Main Results:
- Genomic landscape analysis showed comparable Single Nucleotide Variants and INDELs to existing cohorts, validating large-scale sequencing.
- No comparability at the Copy Number Variation (CNV) level due to technical biases and sample size.
- Mutations in PDGFRB, NOTCH3, and RET correlated with improved Overall and Disease-Free Survival in Immune-Checkpoint treated patients; NOTCH4 variants were detrimental.
Conclusions:
- Genomics-driven trials offer valuable insights and present challenges in advanced Melanoma research.
- The identified genomic alterations serve as potential predictive biomarkers for immunotherapy and targeted therapy.
- This cohort provides a valuable resource for validating novel genomic biomarkers in Melanoma treatment stratification.
Related Concept Videos
03:18Non-LTR Retrotransposons
02:21Cancers Originate from Somatic Mutations in a Single Cell
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:21Cancers Originate from Somatic Mutations in a Single Cell
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...