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The gut microbiome has emerged as a key contributor to cancer biology. Prior studies have focused on individual cancers and often overlook comorbidities, obscuring whether reported associations are specific to a cancer type. Here, we present findings from a real-world mixed-cancer cohort (Mayo Clinic Cancer Microbiome), comprising 1,364 cancer patients and 287 healthy controls. By applying a framework to account for non-specific microbiome associations with cancer, comorbidities, and demographic and clinical variables, we identified 341 cancer-associated species across five cancer classes that represent the most plausible contributors to cancer pathogenesis. Within cancer classes, we found lower levels of fecal bile acids and C. scindens in early-onset breast cancer and elevated lactate and Veillonella parvula in early-onset colorectal cancer. Additionally, Anaerostipes hadrus encoding dihydropyrimidine dehydrogenase was protective against 5-fluorouracil-induced diarrhea. These findings demonstrate the strength of our cohort and provide a foundational resource for the discovery of cancer-specific microbiome signatures and predictive biomarkers.