Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

Pleguezuelos-Manzano, Cayetano; Puschhof, Jens; Huber, Axel Rosendahl; Hoeck, Arne van; Wood, Henry M.; Nomburg, Jason; Gurjao, Carino; Manders, Freek; Dalmasso, Guillaume; Stege, Paul B.; Paganelli, Fernanda L.; Geurts, Maarten H.; Beumer, Joep; Mizutani, Tomohiro; Miao, Yi; Linden, Reinier van der; Elst, Stefan van der; García, K. Christopher; Top, Janetta; Willems, Rob J. L.; Giannakis, Marios; Bonnet, Richard; Quirke, Philip; Meyerson, Matthew; Cuppen, Edwin; Boxtel, Ruben van; Clevers, Hans

doi:10.1038/s41586-020-2080-8

Cited by 632 publications

(474 citation statements)

References 44 publications

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“…Prostatic inflammation may likewise drive the formation of proliferative inflammatory atrophy (PIA), a putative prostate cancer precursor lesion 10,11 . In addition to stimulating inflammation, bacteria can produce potent genotoxins that incite DNA damage, as has been described in the pathogenesis of colon cancer [12][13][14][15][16][17][18] . Therefore, we questioned whether bacterial infections are associated with oncogenic TMPRSS2:ERG gene fusions in human prostate specimens.…”

Section: Main Textmentioning

confidence: 99%

“…Infection of human cells with colibactin-producing E. coli strains induces DNA damage including DNA adducts, DNA double-strand breaks, DNA cross-links, and genomic instability [12][13][14][15][16] . Colibactin-producing bacteria are present in the human gastrointestinal microbiota and associated with colorectal cancer 12,13,17,18,27 . Colibactin-producing E. coli are also known uropathogens and are common among isolates from men with bacterial prostatitis 28 .…”

Section: Main Textmentioning

confidence: 99%

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Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

Shrestha

Coulter

Guzman

et al. 2020

Preprint

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Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

Shrestha

Coulter

Guzman

et al. 2020

Preprint

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“…A recent study has reported a significant carcinogenic role of a metabolic genetic toxic substance named colibactin secreted by Escherichia coli. 141 This great discovery has ignited interest in the microbiota-produced carcinogens. Similar to intestinal microbiota, substances produced by oral microbiota might also be associated with carcinogenesis.…”

Section: Production Of Carcinogenic Substancesmentioning

confidence: 99%

Role of the oral microbiota in cancer evolution and progression

Sun

Tang

et al. 2020

Cancer Medicine

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Bacteria identified in the oral cavity are highly complicated. They include approximately 1000 species with a diverse variety of commensal microbes that play crucial roles in the health status of individuals. Epidemiological studies related to molecular pathology have revealed that there is a close relationship between oral microbiota and tumor occurrence. Oral microbiota has attracted considerable attention for its role in in‐situ or distant tumor progression. Anaerobic oral bacteria with potential pathogenic abilities, especially Fusobacterium nucleatum and Porphyromonas gingivalis, are well studied and have close relationships with various types of carcinomas. Some aerobic bacteria such as Parvimonas are also linked to tumorigenesis. Moreover, human papillomavirus, oral fungi, and parasites are closely associated with oropharyngeal carcinoma. Microbial dysbiosis, colonization, and translocation of oral microbiota are necessary for implementation of carcinogenic functions. Various underlying mechanisms of oral microbiota‐induced carcinogenesis have been reported including excessive inflammatory reaction, immunosuppression of host, promotion of malignant transformation, antiapoptotic activity, and secretion of carcinogens. In this review, we have systemically described the impact of oral microbial abnormalities on carcinogenesis and the future directions in this field for bringing in new ideas for effective prevention of tumors.

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“…SBSA and SBSB are found in some normal intestinal crypts from some normal individuals and are predominantly acquired during childhood 26,41 . SBSA is likely due to colibactin, a mutagenic product of a strain of E.coli sometimes present in the colon microbiome 26,42 . SBS10a, SBS10b and SBS28 were previously found in the subsets of colorectal, endometrial and other cancer types with somatically acquired POLE mutations 7,9 (Fig.…”

Section: Mutational Signaturesmentioning

confidence: 99%

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Robinson

Coorens

Palles

et al. 2020

Preprint

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Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol e and Pol d replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.POLE and POLD1 exonuclease domain mutations can also be inherited through the germline causing a rare autosomal dominant familial cancer predisposition syndrome, known as Polymerase Proofreading Associated Polyposis (PPAP), characterised primarily by early-onset colorectal and endometrial tumours 16,17 . It is plausible that an increased somatic mutation rate underlies this cancer predisposition and high somatic mutation loads have been reported in the small number of neoplasms analysed from such individuals 17 . However, whether the mutation rate is elevated in normal cells, or just in neoplastic cells, is not known. If elevated in normal cells, the magnitude of the increase, whether it is raised over the whole lifespan, the range of tissues and fraction of cells in each tissue it affects, and the impact of subsequent neoplastic change are important questions to address in elucidating the pathogenesis of neoplastic transformation.Accrual of somatic mutations has been proposed as the primary biological mechanism underlying ageing 18-21 . This hypothesis is based on the premises that a) mutations accumulate throughout life; and b) higher mutation loads cause widespread malfunction of cell biology. Recent reports have confirmed that the somatic mutation burden in normal cells does increase during life in a more or less linear manner 22-30 , compatible with a causal role for somatic mutations in ageing. However, somatic mutations could, in principle, accumulate without significant biological consequences. Thus, study of individuals with inherited POLE or POLD1 exonuclease domain mutations could provide insi...

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Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

Cited by 632 publications

References 44 publications

Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

Role of the oral microbiota in cancer evolution and progression

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

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