Intraneoplastic fungal dysbiosis is associated with colorectal cancer progression and host gene mutation

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BACKGROUND: The relationship between intraneoplastic fungi and colorectal cancer (CRC) progression remains largely unclear. Here, we investigated fungal community changes in adenoma and CRC and their correlation with host genetic mutations. METHODS: We obtained 261 tissue biopsies from two geographically distinct cohorts of CRC and adenoma patients, with each individual contributing 2-5 biopsies from lesions and 2 from adjacent normal tissues. 18S ribosomal RNA gene sequencing was used for microbial profiling. Host genetic alterations including KRAS mutations and microsatellite instability (MSI) were detected concurrently. FINDINGS: Intra-neoplastic fungal composition significantly differed between CRC and adenoma in two independent cohorts, with enrichment of highly variable fungi (HVF) in CRC. Six HVFs exhibited higher abundances in adenoma and CRC compared to adjacent normal tissues with Malassezia showing a progressive increase from adenoma to CRC. Fungi intratumoral heterogeneity index also increased from adenoma through stages I to IV of CRC. Intra-tumoral fungi-fungi co-abundance analysis indicated stronger positive interactions in CRC than in adenoma, with increasingly robust links among intra-tumoral fungi along adenoma-CRC progression, primarily driven by Malassezia and Aspergillus. Furthermore, fungal heterogeneity was significantly correlated with host genetic mutations, with higher risk indices in CRC tissues harboring KRAS and MSI mutations. Thirteen fungi stratified CRC samples with KRAS mutations, achieving an area under the curve (AUC) of 0.86, while those associated with MSI status showed an AUC of 0.89. INTERPRETATION: This study demonstrates that intraneoplastic fungal community alterations occur between adenoma and CRC, with increasing heterogeneity associated with host genetic mutations, emphasizing the role of fungal dysbiosis in CRC. FUNDING: This work was supported by RGC Research Impact Fund Hong Kong (R4032-21F); RGC-CRF (C4008-23W); Strategic Seed Funding Collaboration Research Scheme CUHK (3133344); Strategic Impact Enhancement Fund CUHK (3135509); Impact case for RAE CUHK (3134277).

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