Relazione Scientifica IRE 2018
Attività del 2017
This is a translational, inter-department, multidisciplinary, collaborative group that has been recently set up and endorsed under the authority of the IRE Scientific Direction. The Genomics Workgroup is meant to act as an incubator for ideas and technologies. Its aim is to expedite the systematic application of methods for nucleic acid analysis, including Next Generation Sequencing (NGS), Nanostring, and digital PCR (dPCR), to institutional programs with a strong clinical-translational impetus and practice-changing potential. The group embeds diverse areas of expertise, from routine molecular diagnosis to basic research. It includes Surgeons, Pathologists and Clinical Pathologists, Medical Oncologists, Radiation Therapists, Medical Imaging experts, Geneticists, Molecular Biologists, Biotechnologists, Bioinformaticians and Biostatisticians. Staff Members from our BioBank (tissue and body fluids sections) provide input and criticism. The group meets monthly for update and discussion. Attention is paid to major Medline breakthroughs, theory advancements, and the biotech world altogether. Intramural programs and new ideas are extensively reviewed and collegially discussed.
Leveraging on the power of clinical NGS, two important goals have been achieved in 2017. On the one hand we have filed 369 molecular diagnostic reports on germline DNA (heredofamilial cancer), and >1800 on tumor tissue DNA (somatic aberrations), providing our clinical departments with advanced, state-of-art options for cancer prevention, diagnosis, and therapy. On the other hand, we have considerably enhanced and streamlined our bioinformatic pipeline with the acquisition of an NGS-dedicated Cluster Biocomputing server. This provides computational power and seamless knowledgebase searching abilities, including the possibility to match actionable mutations with ongoing clinical trials. Semi-automatic reporting and intranet-accessible, anonymized cloud storage optimize molecular diagnosis and personnel labor, foster cross-cutting communication among the clinics and the labs, and rule out many potential sources of human error.
Moreover, for research purposes we have adopted targeted DNA and RNA sequencing, as well as Whole Exome Sequencing and other innovative genomic platforms to identify somatic or germline mutations (SNV), copy number variations (CNV), small insertions/deletions, and gene fusions. The combination with other molecular markers and clinical data enables us to discover biomarkers which will ultimately improve prediction of survival and response to therapy. Transcriptomic and epigenomic approaches are routinely applied to investigate transcriptional signatures and pathways influenced by specific treatments, or cancer-relevant transcription factors, and to compare tumor to normal tissue (RNA-Seq and ChIP-Seq, ATAC-Seq, respectively).
The Genomics Workgroup is also involved in several projects promoted by the Alleanza Contro il Cancro (Alliance Against Cancer, ACC) network, particularly in the context of the Lung, Breast, and Sarcoma working groups. The institute will be one of the very first to run the Lung Chip developed by ACC Genomics, aimed at assigning novel target therapies through expanded DNA profiling. In the ACC-immuno working group, that aims to find novel biomarkers for the response to immunotherapy in Non Small Cell Lung Cancer, the Genomics Workgroup is one of the main hubs for RNA sequencing and bioinformatic analysis.
These activities on tissue DNA are complemented and integrated by ‘liquid biopsy’. Since February 2017 we have assigned an EGFR mutational status in 114 different blood samples from 74 patients with lung cancer, providing a minimally invasive, recursive, longitudinal strategy to monitor and assign target therapy. Additionally, several small-size pilot studies are ongoing integrating serial blood drawing with tissue DNA/RNA data. This is a very informative approach to better understand clonal evolution and tumor dynamics. With successive snapshots of tumor vulnerability and resistance, we can now better distinguish primary, adaptive, and secondary resistance events in the standard-of-care as well as exploratory settings.
Our current organization workflow is depicted in the figure. Our patients are both the study subject and the commissioners of better therapy. The NGS group aims at banning empiricism from cancer therapy and resorting to innovative trial schemes based on molecular knowledge.