Cancer microbiome characterization: tumor stage, location, genomic instability and patient outcome in CRC and melanoma

The microbiome's link to cancer is well-established, with evidence for its role in initiation, progression in colorectal cancer (CRC), and patient outcomes in melanoma. Additionally, microbiome modulation via fecal microbiota transplantation (FMT) is proposed to improve immunotherapy efficacy. In CRC, the microbiome presents a reproducible microbial signature, which is enriched in oral bacteria, such as Fusobacterium nucleatum and Gemella morbillorum. Despite extensive study of CRC characteristic microbes, microbiome changes in stages, in right- and left-CRC, and microsatellite stable (MSS) and instability high (MSI-H) status are not fully characterized. On the other hand, in melanoma, the microbiome has been studied to predict cancer therapy outcome, and has been associated with immune-related adverse events. In my PhD, I investigated aspects of the association between microbiome and CRC that remained uncovered, and contributed to expand over the link between melanoma, microbiome, and patient outcome. In particular, building on established and newly sequenced case-control studies, I characterized the microbiome differences in tumor stages, right- and left-CRC, and MSS/MSI-H in colorectal cancer, capitalizing on a cohort of more than 3.5 thousands individuals. This work contributed to improving the predictive potential of the gut microbiome for CRC, and to define microbiome associations with tumor stages and primary location. Enhanced taxonomic profiling revealed how all sub-clades of the well-known Fusobacterium nucleatum species are associated with CRC. CRC stages present a continuum in the microbiome composition, with few species characterizing late-stage CRC, such as Hungatella hathewayi, associated with CRC stages III-IV and Methanobrevibacter smithii with stage IV. Subspecies differential gene carriage and strain-differentiation were found for several typical gut microbes across CRC stages, such the case of Ruminococcus bicirculans and Faecalibacterium prausnitzii subclades. In addition, the microbiome of MSI-H stage IV CRC patients is significantly less diverse than the microbiome in MSS condition. When exploring the gut microbiome characteristics associated with a 2-year relapse in stage III melanoma patients undergoing cancer-therapy in the MIND-DC clinical trial, I contributed showing that microbes usually considered as beneficial, such as Faecalibacterium prausnitzii, are associated with good prognosis. Overall, my thesis project contributes to characterizing the alterations in the microbiome in cancer stages, primary tumor location and genomic instability in CRC, and to define the microbial associations in patient outcome in the MIND-DC clinical trial.