Aneuploidy and complex genomic rearrangements in cancer evolution

Baker, Toby M.; Waise, Sara; Tarabichi, Maxime; Van Loo, Peter

doi:10.1038/s43018-023-00711-y

Cited by 16 publications

(5 citation statements)

References 184 publications

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“…Somatic LOH affecting large genomic regions can lead to changes in gene expression through various mechanisms including loss of functional alleles, haploinsufficiency, disruption of regulatory elements, and alterations in epigenetic modifications during tumor progression [ 83 ]. These changes can have significant implications for anti-cancer immune responses if they confer a selective advantage for immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer

Lautert-Dutra,

M. Melo,

Chaves

et al. 2024

Mol Cytogenet

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Background In prostate cancer (PCa), well-established biomarkers such as MSI status, TMB high, and PDL1 expression serve as reliable indicators for favorable responses to immunotherapy. Recent studies have suggested a potential association between CDK12 mutations and immunotherapy response; however, the precise mechanisms through which CDK12 mutation may influence immune response remain unclear. A plausible explanation for immune evasion in this subset of CDK12-mutated PCa may be reduced MHC expression. Results Using genomic data of CDK12-mutated PCa from 48 primary and 10 metastatic public domain samples and a retrospective cohort of 53 low-intermediate risk primary PCa, we investigated how variation in the expression of the MHC genes affected associated downstream pathways. We classified the patients based on gene expression quartiles of MHC-related genes and categorized the tumors into “High” and “Low” expression levels. CDK12-mutated tumors with higher MHC-expressed pathways were associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. Consistent with an inflamed tumor microenvironment (TME) phenotype, digital cytometric analyses identified increased CD8 + T cells, B cells, γδ T cells, and M1 Macrophages in this group. In contrast, CDK12-mutated tumors with lower MHC expression exhibited features consistent with an immune cold TME phenotype and immunoediting. Significantly, low MHC expression was also associated with chromosome 6 loss of heterozygosity (LOH) affecting the entire HLA gene cluster. These LOH events were observed in both major clonal and minor subclonal populations of tumor cells. In our retrospective study of 53 primary PCa cases from this Institute, we found a 4% (2/53) prevalence of CDK12 mutations, with the confirmation of this defect in one tumor through Sanger sequencing. In keeping with our analysis of public domain data this tumor exhibited low MHC expression at the RNA level. More extensive studies will be required to determine whether reduced HLA expression is generally associated with primary tumors or is a specific feature of CDK12 mutated PCa. Conclusions These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses.

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Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer

Lautert-Dutra,

M. Melo,

Chaves

et al. 2024

Mol Cytogenet

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“… 60 , 62 , 63 ecDNA, a unique form of CNAs, consists of double-stranded circular chromatids, and may serve as a robust driver of tumor genome evolution due to the absence of centromeric sequences and uneven distribution in daughter cells during mitosis. 64 Notably, ecDNA has been detected early in the progression from high-grade dysplasia in Barrett’s esophagus to esophageal adenocarcinoma (EAC). 64 , 65 Their copy number and structural complexity increased along the tumor evolutionary trajectory.…”

Section: Molecular Drivers Of Tumorigenesismentioning

confidence: 99%

“… 64 Notably, ecDNA has been detected early in the progression from high-grade dysplasia in Barrett’s esophagus to esophageal adenocarcinoma (EAC). 64 , 65 Their copy number and structural complexity increased along the tumor evolutionary trajectory. Patients who progressed to EAC exhibited higher levels of ecDNA compared to those who did not.…”

Section: Molecular Drivers Of Tumorigenesismentioning

confidence: 99%

“…Chromosomal abnormalities promote tumorigenesis through their effects on abnormal gene expression, including disruption or loss of tumor suppressors, oncogene amplification, and formation of oncogenic fusion genes. 47 , 64 Loss of the 3p arm, harboring tumor suppressor genes such as VHL , PBRM1 , BAP1 , and SETD2 , can be an initiating event in clear-cell renal cell carcinoma. An increased frequency of LOH at 9p has been observed from precancerous lesions to cutaneous squamous cell carcinoma (CSCC), possibly driven by loss of tumor suppressive gene CDKN2A in this region.…”

Section: Molecular Drivers Of Tumorigenesismentioning

confidence: 99%

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Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Zhang,

Xiao,

et al. 2024

Sig Transduct Target Ther

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Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

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“…, 2023 ). Improper mitotic spindle assembly leads to errors in chromosome segregation, which in turn fuels cellular transformation ( Sansregret and Swanton, 2017 ; Ben-David and Amon, 2020 ; Baker et al. , 2024 ).…”

Section: Introductionmentioning

confidence: 99%

Antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly

Salazar,

Ohi

2024

MBoC

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The spindle is a bipolar microtubule-based machine that is crucial for accurate chromosome segregation. Spindle bipolarity is generated by Eg5 (a kinesin-5), a conserved motor that drives spindle assembly by localizing to and sliding apart antiparallel microtubules. In the presence of Eg5 inhibitors (K5Is), KIF15 (a kinesin-12) can promote spindle assembly, resulting in K5I-resistant cells (KIRCs). However, KIF15 is a less potent motor than Eg5, suggesting that other factors may contribute to spindle formation in KIRCs. Protein Regulator of Cytokinesis 1 (PRC1) preferentially bundles antiparallel microtubules, and we previously showed that PRC1 promotes KIF15-microtubule binding, leading us to hypothesize that PRC1 may enhance KIF15 activity in KIRCs. Here, we demonstrate that 1) loss of PRC1 in KIRCs decreases spindle bipolarity, 2) overexpression of PRC1 increases spindle formation efficiency in KIRCs, 3) overexpression of PRC1 protects K5I naïve cells against the Eg5 inhibitor STLC, and 4) PRC1 overexpression promotes the establishment of K5I resistance. These effects are not fully reproduced by a TPX2, a microtubule bundler with no known preference for microtubule orientation. These results suggest a model wherein PRC1-mediated bundling of microtubules creates a more favorable microtubule architecture for KIF15-driven mitotic spindle assembly in the context of Eg5 inhibition. [Media: see text] [Media: see text] [Media: see text]

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Aneuploidy and complex genomic rearrangements in cancer evolution

Cited by 16 publications

References 184 publications

Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer

Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly

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