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Observational Study
. 2025 Jan 18;20(1):30.
doi: 10.1186/s13023-025-03543-4.

Colorectal cancer in Lynch syndrome families: consequences of gene germline mutations and the gut microbiota

Affiliations
Observational Study

Colorectal cancer in Lynch syndrome families: consequences of gene germline mutations and the gut microbiota

Xuexin Wang et al. Orphanet J Rare Dis. .

Abstract

Background: Lynch syndrome (LS)-associated colorectal cancer (CRC) always ascribes to pathogenic germline mutations in mismatch repair (MMR) genes. However, the penetrance of CRC varies among those with the same MMR gene mutation. Thus, we hypothesized that the gut microbiota is also involved in CRC development in LS families.

Methods: This prospective, observational study was performed from December 2020 to March 2023. We enrolled 72 individuals from 9 LS families across six provinces in China and employed 16S rRNA gene amplicon sequencing to analyze the fecal microbiota components among LS-related CRC patients (AS group), their spouses (BS group), mutation carriers without CRC (CS group), and non-mutation carriers (DS group) using alpha and beta diversity indices.

Results: There were no apparent differences in age or gender among the four groups. Alpha and beta diversity indices exhibited no significant differences between the AS and BS groups, verifying the role of germline mutations in the occurrence of CRC in LS families. Beta diversity analysis exhibited significant differences between the AS and CS groups, revealing the importance of the gut microbiota for the occurrence of CRC in LS families. A greater difference (both alpha and beta diversity indices) was shown between the AS and DS groups, demonstrating the combined impact of the gut microbiota and genetic germline mutations on the occurrence of CRC in LS families. Compared with those in the CS and DS groups, we identified ten microbial genera enriched in the AS group, and one genus (Bacteroides) decreased in the AS group. Among the elevated genera in the AS group, Agathobacter, Coprococcus and Prevotellaceae_NK3B31_group were butyrate-producing genera.

Conclusion: This study found the development of CRC in the LS families can be attributed to the combined effects of gene germline mutations as well as the gut microbiota and provided novel insights into the prevention and treatment of CRC in the LS families.

Keywords: 16S rRNA gene amplicon sequencing; Butyrate-producing bacteria; Colorectal cancer; Germline gene mutation; Gut microbiota; Lynch syndrome.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Seventh Medical Center of Chinese PLA General Hospital (no. 2020–090). Sample collection was conditioned to the patient´s signing of written informed consent. Consent for publication: Not applicable. Competing interests: The authors have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
The flow chart of this study. *In this cohort, we analyzed the gut microbiota of only 8 patients in the AS group whose spouses were included in the BS group
Fig. 2
Fig. 2
Gut microbiota analysis between Lynch Syndrome-related colorectal cancer patients (AS group) and their spouses (BS group). (a-c) The chao1 diversity, observed features diversity, and simpson diversity indices displayed the alpha diversity in the AS and BS groups. (d) Beta diversity of gut microbiota in the AS and BS groups using principal coordinate analysis (PCoA). (e) Differential gut microbiota between the AS and BS groups. (f) LEfSe analysis between the AS and BS groups. P < 0.05 indicated statistically significant
Fig. 3
Fig. 3
Gut microbiota analysis between Lynch Syndrome-related colorectal cancer patients (AS group) and mutation carriers without CRC (CS group). (a-c) The chao1 diversity, observed features diversity and simpson diversity indices in the AS and CS groups. (d) Beta diversity was analyzed by principal coordinate analysis (PCoA) in the AS and CS groups. (e) Differential microbiota between the AS and CS groups. (f) LEfSe analysis between the AS and CS groups. P < 0.05 indicated statistically significant
Fig. 4
Fig. 4
Gut microbiota analysis between Lynch Syndrome-related colorectal cancer patients (AS group) and non-mutation carriers (DS group). (a-c) The chao1 diversity, observed features diversity and simpson diversity indices in the AS and DS groups. (d) Beta diversity was analyzed by principal coordinate analysis (PCoA) in the AS and DS groups. (e) Differential microbiota between the AS and CS groups. (f) LEfSe analysis between the AS and DS groups. P < 0.05 indicated statistically significant

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