By Dr. Patrizio Giacomini

The IRE Working Group (WG) Genomics is a multidisciplinary group spanning in expertise from basic-translational approaches to clinical Next Generation Sequencing (NGS). Although NGS is our main focus, members of the group implement many ancillary nucleic-acid-based methods for research and advanced diagnostics. Biologists, Biotechnologists, Bioinformaticians, Pathologists and Clinical Pathologists provide the WG Genomics with a solid biotech core, but all the activities (from study design to patient enrollment and treatment, through data collection and analysis) build on the strong contributions of medical oncologists, radiologists, surgeons, and Biostatisticians. Integrative approaches are being carried out including radiogenomics, liquid biopsies, whole-genome and single-cell sequencing, big data interrogation, model building and clinical trial design. The goal is to harmonize diverse skills and institutional needs into a common finalized effort (see figure).


During 2020, clinical NGS panels of increasing complexity have been employed to reflect the expansion of the druggable genome. In parallel, we have witnessed a considerable increase in the number of NGS-based diagnostic tests performed, as follows: 1120 patients (colorectal, lung, thyroid, gastric carcinomas, brain tumors, sarcoma and melanoma), 780 of whom displayed pathogenetic or likely pathogenetic alterations, and 670 had targetable or potentially targetable alterations either in the standard of care setting or in the context of ongoing clinical trials. More in general, rather than adopting the one-size-fits-all scheme so common to commercial outsourcing models, we find it most useful to tailor different NGS solutions for different clinical-pathological patient groups.

The Genomics WG entertains a close collaboration with the institutional BioBank. Whether occurring in the context of standard of care, or during a clinical trial, we do our best to biobank tissue, blood, and other body fluids for future reference, molecular ‘second look’, and retrospective analysis.

The WG Genomics includes members of our Genetic Testing Unit, focusing on the most frequent Hereditary Cancer syndromes (HCS) such as the Lynch syndrome (LS), the Peutz-Jeghers syndrome (PJS), the Juvenile polyposis syndrome (JPS), The Cowden syndrome (CS) the Hereditary Breast and Ovary Cancer syndrome (HBOC), APC-associated polyposis and MUTYH-associated polyposis (AAP and MAP), and the Multiple Endocrine Neoplasia syndrome type 1 and type 2 (MENl and MEN2). Molecular testing is performed in the framework of genetic interview/counseling through the activities of our outpatient’s clinics. Moreover, a substantial fraction of cases are referred from other institutions all over the country. During 2020, testing 375 probands resulted in the discovery of 67 affected patients, e.g. we have further optimized the affected/tested percentage of our testing, which attests to an improved clinical-molecular integration in our multidisciplinare HCS unit.

Hereditary Cancer testing allows an in-depth cancer risk assessment for each patient, leading to improvements in health outcomes of both carriers and family members.

During 2020, the throughput of our advanced genomics facilities has been considerably expanded through the purchase of new equipment and personnel training/acquisition. This has resulted in an improved support to research projects and, most importantly, to the Molecular Tumor Board. To this end, during 2020, we have carried out 6 WES analyses, and have greatly streamlined and automatized bioinformatic support. This has resulted in both more accurate data for research purposes and an extension in our ability to investigate rare cancers and uncover unsuspected vulnerabilities in fragile patients.

Research Activities

Several studies are ongoing to identify epigenetic mechanisms involved in tumor transformation, including miRNA signatures in melanoma, head and neck cancer, and hematological malignancies. Recently, members of the Genomic Translational Group have reported that KEAP1-driven co-mutations make lung adenocarcinoma unresponsive to immunotherapy despite high Tumor Mutational Burden (Fig. …). This study helps to explain why our ability to predict the efficacy of this important class of therapeutic agents has lagged behind.

A specific combination of mutations impairs immune checkpoint blockade in lung carcinoma. Patients whose tumors hosts co-mutations (blue line) have a short overall survival compared to patients whose tumors either lack the selected set of mutations (WT, green line) or have a single mutation (SM, yellow). From Marinelli et al. Ann. Oncol.