Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli 公告 2020-02-27 14:53:03 Written By Kym Kilbourne Title: Characterization of Cancer Mutational Signatures Induced by Genotoxic pks+ Escherichia coli Research Background The incidence of colorectal cancer (CRC) is associated with specific members of the gut microbiota. Pathogenic Escherichia coli (E. coli) strains carrying the pks island can synthesize a genotoxin known as colibactin, which alkylates DNA adenine residues, leading to DNA double-strand breaks. Although these bacteria are known to be associated with CRC, their direct contribution to mutations in tumorigenesis has not been confirmed. Research Objective This study aims to investigate whether these bacteria directly cause DNA mutations and identify specific mutational signatures by culturing human intestinal organoids in vitro and exposing them to E. coli carrying the pks island. Research Methods Cloned human intestinal organoids were co-cultured with E. coli carrying the pks island. Whole-genome sequencing (WGS) was used to analyze organoids before and after exposure to identify mutational signatures. Mutation differences between organoids exposed to pks+ E. coli and non-carrying pks- were compared. Research Results Discovery of Mutational Signatures Researchers discovered a unique single base substitution (SBS-pks) and insertion/deletion (ID-pks) mutational signature in human intestinal organoids co-cultured with pks+ E. coli through whole-genome sequencing. This signature was not observed in organoids co-cultured with pks- mutant E. coli, indicating that it is specific to pks+ E. coli. Signature Details: - SBS-pks Signature: This signature is characterized by T>N (T to any nucleotide) substitutions, occurring in specific DNA sequence contexts, particularly when there is an adenine (A) three base positions upstream of T. - ID-pks Signature: This signature is characterized by the loss of a single T in a homopolymer run of Ts, with an A homopolymer upstream of these Ts. Validation of Mutational Signatures in Human Cancer Genomes Researchers detected the SBS-pks and ID-pks signatures in two independent human cancer genomic datasets, which included 5876 human cancer genomes, especially more common in colorectal cancer. In a Dutch cohort of 3668 solid cancer metastases, researchers identified an SBS signature highly similar to SBS-pks through non-negative matrix factorization (NMF). In Genomics England's 100,000 Genomes Project, which included 2208 primarily primary colorectal cancer tumors, researchers also found an enrichment of SBS-pks and ID-pks signatures. Association of Mutational Signatures with CRC Driver Genes Researchers further analyzed whether these mutational signatures could lead to driver gene mutations in colorectal cancer. They examined the most common driver gene mutations in seven CRC patient cohorts and found that 112 (2.4%) CRC driver gene mutations matched the target motif of colibactin. Notably, the APC gene, one of the most frequently mutated genes in colorectal cancer, had 5.3% of its driver gene mutations matching the target sites of SBS-pks or ID-pks. Early Contribution of Mutational Signatures Researchers also assessed whether the SBS-pks mutational signature contributed early to the mutational load in colorectal cancer metastasis samples. They confirmed this by evaluating the levels of SBS-pks and ID-pks in clonal (pre-metastatic) or non-clonal (post-metastatic) mutations. SBS-pks and ID-pks accumulate in colorectal cancer even at earlier stages, suggesting that these mutational signatures may emerge at the early stages of colorectal cancer development. Rare Occurrence of Mutational Signatures in Non-Colorectal Cancer Tumors Researchers also found that, in addition to colorectal cancer, one head and neck cancer and three urothelial tumors showed significant SBS-pks and ID-pks signatures, indicating that pks+ bacteria may play a role outside the colon. These findings suggest that pks+ E. coli may also play a role in cancer types other than colorectal cancer, providing a new direction for future research to explore the role of pks+ E. coli in other cancer types and their potential therapeutic implications. Research Significance This study describes a unique mutational signature in colorectal cancer, implying that this mutational process directly stems from past exposure to bacteria producing colibactin with the pks island. This discovery provides a new perspective on how the gut microbiota affects the development of colorectal cancer and may aid in the development of new prevention and treatment strategies. Conclusion Long-term exposure to E. coli carrying the pks island can induce unique single base substitution (SBS) and insertion/deletion (indel) mutational signatures in human intestinal organoids. These findings offer new insights into the pathogenesis of colorectal cancer and may have significant implications for cancer prevention and treatment. Paper Link https://pmc.ncbi.nlm.nih.gov/articles/PMC8142898/ Kym Kilbourne
Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli 公告 2020-02-27 14:53:03 Written By Kym Kilbourne Title: Characterization of Cancer Mutational Signatures Induced by Genotoxic pks+ Escherichia coli Research Background The incidence of colorectal cancer (CRC) is associated with specific members of the gut microbiota. Pathogenic Escherichia coli (E. coli) strains carrying the pks island can synthesize a genotoxin known as colibactin, which alkylates DNA adenine residues, leading to DNA double-strand breaks. Although these bacteria are known to be associated with CRC, their direct contribution to mutations in tumorigenesis has not been confirmed. Research Objective This study aims to investigate whether these bacteria directly cause DNA mutations and identify specific mutational signatures by culturing human intestinal organoids in vitro and exposing them to E. coli carrying the pks island. Research Methods Cloned human intestinal organoids were co-cultured with E. coli carrying the pks island. Whole-genome sequencing (WGS) was used to analyze organoids before and after exposure to identify mutational signatures. Mutation differences between organoids exposed to pks+ E. coli and non-carrying pks- were compared. Research Results Discovery of Mutational Signatures Researchers discovered a unique single base substitution (SBS-pks) and insertion/deletion (ID-pks) mutational signature in human intestinal organoids co-cultured with pks+ E. coli through whole-genome sequencing. This signature was not observed in organoids co-cultured with pks- mutant E. coli, indicating that it is specific to pks+ E. coli. Signature Details: - SBS-pks Signature: This signature is characterized by T>N (T to any nucleotide) substitutions, occurring in specific DNA sequence contexts, particularly when there is an adenine (A) three base positions upstream of T. - ID-pks Signature: This signature is characterized by the loss of a single T in a homopolymer run of Ts, with an A homopolymer upstream of these Ts. Validation of Mutational Signatures in Human Cancer Genomes Researchers detected the SBS-pks and ID-pks signatures in two independent human cancer genomic datasets, which included 5876 human cancer genomes, especially more common in colorectal cancer. In a Dutch cohort of 3668 solid cancer metastases, researchers identified an SBS signature highly similar to SBS-pks through non-negative matrix factorization (NMF). In Genomics England's 100,000 Genomes Project, which included 2208 primarily primary colorectal cancer tumors, researchers also found an enrichment of SBS-pks and ID-pks signatures. Association of Mutational Signatures with CRC Driver Genes Researchers further analyzed whether these mutational signatures could lead to driver gene mutations in colorectal cancer. They examined the most common driver gene mutations in seven CRC patient cohorts and found that 112 (2.4%) CRC driver gene mutations matched the target motif of colibactin. Notably, the APC gene, one of the most frequently mutated genes in colorectal cancer, had 5.3% of its driver gene mutations matching the target sites of SBS-pks or ID-pks. Early Contribution of Mutational Signatures Researchers also assessed whether the SBS-pks mutational signature contributed early to the mutational load in colorectal cancer metastasis samples. They confirmed this by evaluating the levels of SBS-pks and ID-pks in clonal (pre-metastatic) or non-clonal (post-metastatic) mutations. SBS-pks and ID-pks accumulate in colorectal cancer even at earlier stages, suggesting that these mutational signatures may emerge at the early stages of colorectal cancer development. Rare Occurrence of Mutational Signatures in Non-Colorectal Cancer Tumors Researchers also found that, in addition to colorectal cancer, one head and neck cancer and three urothelial tumors showed significant SBS-pks and ID-pks signatures, indicating that pks+ bacteria may play a role outside the colon. These findings suggest that pks+ E. coli may also play a role in cancer types other than colorectal cancer, providing a new direction for future research to explore the role of pks+ E. coli in other cancer types and their potential therapeutic implications. Research Significance This study describes a unique mutational signature in colorectal cancer, implying that this mutational process directly stems from past exposure to bacteria producing colibactin with the pks island. This discovery provides a new perspective on how the gut microbiota affects the development of colorectal cancer and may aid in the development of new prevention and treatment strategies. Conclusion Long-term exposure to E. coli carrying the pks island can induce unique single base substitution (SBS) and insertion/deletion (indel) mutational signatures in human intestinal organoids. These findings offer new insights into the pathogenesis of colorectal cancer and may have significant implications for cancer prevention and treatment. Paper Link https://pmc.ncbi.nlm.nih.gov/articles/PMC8142898/ Kym Kilbourne
