It has been recently reported that the population of Fusobacterium, particularly Fusobacterium nucleatum (Fn), is overrepresented in colorectal cancers and adenomas. The promoting effects of Fn infection on adenoma and/or carcinoma formation have been shown in ApcMin/+mice. Characteristics of Fn-associated CRC were identified through studies using human CRC cohorts, and include right-sided colon location, CpG island methylation phenotype-high (CIMP-H), high level of microsatellite instability (MSI-H), and poor patient prognosis. A subset of Fn-associated CRC exhibits a low level of microsatellite instability (MSI-L) and elevated microsatellite alterations in selected tetra-nucleotide repeats (EMAST) induced by translocation of MSH3 from the nucleus to the cytoplasm in response to oxidative DNA damage or inflammatory signals. The association between CIMP/MSI-H and Fn-infection can be explained by the role of the mismatch repair (MMR) protein complex formed between MSH2 and MSH6 (MutSα) to repair aberrant bases generated by ROS to form 7,8-dihydro-8-oxo-guanine (8-oxoG). Clustered 8-oxoGs formed at CpG-rich regions including promoters by ROS is refractory to base excision repair (BER). Under these conditions, MutSα initiates repair in cooperation with DNA methyltransferases (DNMTs) and the polycomb repressive complex 4 (PRC4). DNMTs at damaged sites methylate CpG islands to repress transcription of target genes and promote repair reactions. Thus, continuous generation of ROS through chronic Fn infection may initiate 1) CIMP-positive adenoma and carcinoma in an MSH2/MSH6-dependent manner, and/or 2) MSI-L/EMAST CRC in an MSH3-dependent manner. The poor prognosis of Fn-associated CRC can be explained by Fn-induced immune-evasion and/or chemo-resistance.
Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.
Black Americans (BA) have higher incidence and higher mortality rates for colorectal cancers (CRC) as compared to White Americans (WA). While there are several identified risk factors associated with the development of CRC and evidence that high levels of adequate screening can reduce differences in incidence for CRC between BA and WA, there remains little data regarding patient co-morbid contributions towards survival once an individual has CRC. Here we set out to identify patient risk factors that influenced overall survival in a cohort of 293 BA and 348 WA with colon cancer. Amid our cohort, we found that patients' age, tobacco usage, and pre-diagnosed medical conditions such as hypertension and diabetes were associated with shorter overall survival (OS) from colon cancer. We identified pre-diagnosed hypertension and diabetes among BA were responsible for one-third of the colon cancer mortality disparity compared with WA. We also identified long-term regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, was associated with shorter OS from colon cancer among WA >65 years of age, but not younger WA patients or any aged BA patients. Our results raise the importance of not only treating the colon cancer itself, but also taking into consideration co-morbid medical conditions and NSAID usage to enhance patient OS. Further evaluation regarding adequate treatment of co-morbidities and timing of NSAID continuance after cancer therapy will need to be studied.
Black Americans (BA) have higher incidence and higher mortality rates for colorectal cancers (CRC) as compared to White Americans (WA). While there are several identified risk factors associated with the development of CRC and evidence that high levels of adequate screening can reduce differences in incidence for CRC between BA and WA, there remains little data regarding patient co-morbid contributions towards survival once an individual has CRC. Here we set out to identify patient risk factors that influenced overall survival in a cohort of 293 BA and 348 WA with colon cancer, ages 40 to 84 years old, with at least 10 years of follow- up. We utilized the logistic regression test for statistical associations, the Kaplan- Meier method with log rank test for survival analyses, and Cox Proportional Hazards Models for covariate independence. Amid our cohort, we found that patients’ age, tobacco usage, and pre-diagnosed medical conditions such as hypertension and diabetes were associated with shorter overall survival (OS) from colon cancer. We identified pre-diagnosed hypertension (19.6% contribution) and diabetes (12% contribution) among BA were together responsible for nearly one-third of the colon cancer mortality disparity compared with WA. We also identified long-term regular use (>5 years aggregated years of drug use) of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, was associated with shorter OS from colon cancer among WA >65 years of age (Hazard Ratio 1.76, 95% confidence interval 1.12-2.77), but not younger WA patients or any aged BA patients. Our results raise the importance of not only treating the colon cancer itself, but also taking into consideration co-morbid medical conditions and NSAID usage to enhance patient OS. Further evaluation regarding adequate treatment of co-morbidities and timing of NSAID continuance after cancer therapy will need to be studied. Citation Format: Minoru Koi, Yoshiki Okita, Erika Koeppe, Elena M. Stoffel, Joseph A. Galanko, Nikki McCoy, Temitope Keku, John M. Carethers. Co-morbid risk factors and NSAID use among white and black Americans that predicts overall survival from diagnosed colon cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-222.
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