Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status

Objective: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis.

Background: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk.

Methods: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model.

Results: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status.

Conclusions: Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Journal Annals of Surgery
Authors Hidetaka Kawamura et al
DATE 06 May 2024
Microenvironmental reorganization in braintumors following radiotherapy andrecurrence revealed by hyperplexedimmunofluorescence…

The tumor microenvironment plays a crucial role in determining response totreatment. This involves a series of interconnected changes in the cellularlandscape, spatial organization, and extracellular matrix composition. How-ever, assessing these alterations simultaneously is challenging from a spatialperspective, due to the limitations of current high-dimensional imagingtechniques and the extent of intratumoral heterogeneity over large lesionareas. In this study, we introduce a spatial proteomic workflow termedHyperplexed Immunofluorescence Imaging (HIFI) that overcomes these lim-itations. HIFI allows for the simultaneous analysis of > 45 markers in fragiletissue sections at high magnification, using a cost-effective high-throughputworkflow. We integrate HIFI with machine learning feature detection, graph-based network analysis, and cluster-based neighborhood analysis to analyzethe microenvironment response to radiation therapy in a preclinical model ofglioblastoma, and compare this response to a mouse model of breast-to-brainmetastasis. Here we show that glioblastomas undergo extensive spatial reor-ganization of immune cell populations and structural architecture in responseto treatment, while brain metastases show no comparable reorganization. Ourintegrated spatial analyses reveal highly divergent responses to radiationtherapy between brain tumor models, despite equivalent radiotherapy benefit.

Journal Nature Communications
Authors Spencer S Watson et al
DATE 15 April 2024
Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues

Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.

Journal Cancer Discovery
Authors Mònica Sánchez-Guixé et al
DATE 19 March 2024
Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer

Co-culture of intestinal organoids with a colibactin-producing pks+E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pks+E. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ∼12% of CRC genomes and even in whole exome sequencing data, representing a crucial step toward pinpointing the mutagenic activity of distinct pks+E. coli strains.

Journal Cancer Cell
Authors Axel Rosendahl Huber et al
DATE 11 March 2024
Extrachromosomal DNA in cancer

Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with poor outcomes. When it was discovered over 60 years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer. The non-chromosomal inheritance of ecDNA during cell division results in high oncogene copy number, intra-tumoural genetic heterogeneity and rapid tumour evolution that contributes to treatment resistance and shorter patient survival. In addition, the circular architecture of ecDNA results in altered patterns of gene regulation that drive elevated oncogene expression, potentially enabling the remodelling of tumour genomes. The generation of clusters of ecDNAs, termed ecDNA hubs, results in interactions between enhancers and promoters in trans, yielding a new paradigm in oncogenic transcription. In this Review, we highlight the rapid advancements in ecDNA research, providing new insights into ecDNA biogenesis, maintenance and transcription and its role in promoting tumour heterogeneity. To conclude, we delve into a set of unanswered questions whose answers will pave the way for the development of ecDNA targeted therapeutic approaches.

Team eDyNAmiC
Journal Nature Reviews Cancer
Authors Xiaowei Yan, Paul Mischel & Howard Chang
DATE 26 February 2024