Chromosome instability and aneuploidy as context-dependent activators or inhibitors of antitumor immunity

Kuang, Xiaohong; Li, Jian

doi:10.3389/fimmu.2022.895961

Cited by 8 publications

(7 citation statements)

References 103 publications

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“…The fundamental aspects of chromosomal instability include changes in chromosome copy number, which leads to the emergence of cells with aneuploidy, as well as alterations in chromosome structure. These changes can include polyploidy, chromosomal translocations, genomic chaos, and non-clonal chromosomal aberrations[ 24 ].…”

Section: Ucad Application Prospectsmentioning

confidence: 99%

Prospects in the application of ultrasensitive chromosomal aneuploidy detection in precancerous lesions of gastric cancer

Qian,

Xie,

Zhao

et al. 2024

World J Gastrointest Surg

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Gastric cancer (GC) is a prevalent malignant tumor within the digestive system, with over 40% of new cases and deaths related to GC globally occurring in China. Despite advancements in treatment modalities, such as surgery supplemented by adjuvant radiotherapy or chemotherapeutic agents, the prognosis for GC remains poor. New targeted therapies and immunotherapies are currently under investigation, but no significant breakthroughs have been achieved. Studies have indicated that GC is a heterogeneous disease, encompassing multiple subtypes with distinct biological characteristics and roles. Consequently, personalized treatment based on clinical features, pathologic typing, and molecular typing is crucial for the diagnosis and management of precancerous lesions of gastric cancer (PLGC). Current research has categorized GC into four subtypes: Epstein-Barr virus-positive, microsatellite instability, genome stability, and chromosome instability (CIN). Technologies such as multi-omics analysis and gene sequencing are being employed to identify more suitable novel testing methods in these areas. Among these, ultrasensitive chromosomal aneuploidy detection (UCAD) can detect CIN at a genome-wide level in subjects using low-depth whole genome sequencing technology, in conjunction with bioinformatics analysis, to achieve qualitative and quantitative detection of chromosomal stability. This editorial reviews recent research advancements in UCAD technology for the diagnosis and management of PLGC.

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Section: Ucad Application Prospectsmentioning

confidence: 99%

Prospects in the application of ultrasensitive chromosomal aneuploidy detection in precancerous lesions of gastric cancer

Qian,

Xie,

Zhao

et al. 2024

World J Gastrointest Surg

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“…390 This could be attributed to genomic alterations that produce neoantigens, which are recognized by the immune cells, and thus activate the adaptive immune response. 391 Consequently, CIN can activate anti-tumor immune responses, thereby subjecting tumor cells to the selection pressure imposed by the immune system, which subsequently eliminates them. 391 However, CIN could also contribute to pro-tumor immune response.…”

Section: Cin Paradoxmentioning

confidence: 99%

The two sides of chromosomal instability: drivers and brakes in cancer

Hosea,

Hillary,

Naqvi

et al. 2024

Sig Transduct Target Ther

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Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the “just-right” model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

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“…Chromosomal instability (CIN), a hallmark of chromothripsis, has been extensively studied in terms of its association with immunity [17,18]. Copy number alteration burden, particularly a copy number loss burden, is associated with reduced gene expression with respect to immune-related pathways.…”

Section: Introductionmentioning

confidence: 99%

Chromothripsis is correlated with reduced cytotoxic immune infiltration and diminished responsiveness to checkpoint blockade immunotherapy

Chu¹,

Zheng²,

Cheng³

et al. 2023

Theranostics

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Background: Chromothripsis caused massive, clustered genomic rearrangements is prevalent in cancer and is considered a new paradigm for tumorigenesis and progression. In this study, we investigated the association among chromothripsis, anti-tumor immune responses, and responsiveness to immune checkpoint blockade (ICB). Methods: Quantification of immune cell infiltration and functional enrichment of immune-related signaling pathways were performed in the discovery set (n = 9403) and the validation set (n = 1140). we investigated the association between chromothripsis and anti-tumor immune responses. In the immunotherapy cohort, copy number alteration-based chromothripsis scores (CPSs) were introduced to assess the extent of chromothripsis to evaluate its association with responsiveness to ICB. Results: In the discovery set and the validation set, the ratios of CD8 + T cells to Tregs, TAMs, and MDSCs were significantly lower in tumors with chromothripsis (P = 1.5 × 10 − 13 , P = 5.4 × 10 − 8 , and P = 1.2 × 10 − 4 , respectively, TCGA; P = 1.0 × 10 − 13 , P = 3.6 × 10 − 15 , and P = 3.3 × 10 − 3 , respectively, PCAWG). The relevant pathways underlying the antitumor immune effect were significantly enriched in tumors without chromothripsis. Chromothripsis can be used as an independent predictor, and patients with low-CPSs experienced longer overall survival (OS) after immunotherapy [HR, 1.90; 95% confidence interval, 1.10−3.28; P = 0.019]. Conclusions: Our findings highlight the reduced cytotoxic immune infiltration in tumors with chromothripsis and enhanced immunosuppression in the tumor microenvironment. Chromothripsis can thus be used as a potential indicator to help identify patients who will respond to ICB, which could complement established biomarkers.

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Chromosome instability and aneuploidy as context-dependent activators or inhibitors of antitumor immunity

Cited by 8 publications

References 103 publications

Prospects in the application of ultrasensitive chromosomal aneuploidy detection in precancerous lesions of gastric cancer

Prospects in the application of ultrasensitive chromosomal aneuploidy detection in precancerous lesions of gastric cancer

The two sides of chromosomal instability: drivers and brakes in cancer

Chromothripsis is correlated with reduced cytotoxic immune infiltration and diminished responsiveness to checkpoint blockade immunotherapy

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