Y chromosome loss in cancer drives growth by evasion of adaptive immunity

Abdel-Hafiz, Hany A.; Schafer, Johanna M.; Chen, Xingyu; Xiao, Tong; Gauntner, Timothy; Li, Zihai; Theodorescu, Dan

doi:10.1038/s41586-023-06234-x

Cited by 78 publications

(38 citation statements)

References 66 publications

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“…2). All CENP-B protein signals colocalized with CENPB-sat signals while, on 12 centromeres, we could detect CENPB-sat signals only (8,14,15,16,19,20,22,25,27,30,31 and X) (Fig. 2).…”

Section: Chromosomal Localization Of Cenp-a Cenp-b and Cenp-c Protein...mentioning

confidence: 88%

“…The results of several studies suggested that CENP-B may stabilize CENP-A and CENP-C maintenance at centromeres, increasing centromere strength and segregation fidelity of chromosomes (14,23,24). Interestingly, loss of the Y chromosome is observed in multiple cancer types, suggesting a high frequency of mis-segregation for this CENP-B negative chromosome (25). It was also proposed that CENP-B participates in the formation of pericentromeric heterochromatin (26) since its depletion causes the disruption of the H3K9me3 environment around centromeres, with subsequent erosion of heterochromatin and genome instability (27,28).…”

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confidence: 99%

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CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres

Cappelletti,

Piras,

Biundo

et al. 2024

Preprint

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Background While CENP-A is the epigenetic determinant of the centromeric function, the role of CENP-B, the sole centromeric protein binding a specific DNA sequence (CENP-B-box), remains elusive. In the few mammalian species analyzed so far, the CENP-B box is contained in the major satellite repeat that is present at all centromeres. We previously demonstrated that, in the genus Equus, whose species underwent rapid and recent evolution, numerous centromeres lack any satellite repeat. Results In four Equus species, CENP-B is expressed but does not bind the satellite-free and the majority of satellite-based centromeres while it is localized at several ancestral now inactive centromeres. Centromeres lacking CENP-B are functional and recruit normal amounts of CENP-A and CENP-C. The absence of CENP-B is related to the lack of CENP-B boxes rather than to peculiar features of the protein itself. CENP-B boxes are comprised in a previously undescribed repeat which is not the major satellite bound by CENP-A. Comparative sequence analysis suggested that this satellite was centromeric in the equid ancestor, lost centromeric function during evolution and gave rise to a shorter CENP-A bound repeat not containing the CENP-B box but being enriched in dyad symmetries. Conclusions We propose that the uncoupling between CENP-B and CENP-A may have played a role in the extensive evolutionary reshuffling of equid centromeres. This study provides new insights into the complexity of centromere organization in a largely biodiverse world where the majority of mammalian species still have to be studied.

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“…2). All CENP-B protein signals colocalized with CENPB-sat signals while, on 12 centromeres, we could detect CENPB-sat signals only (8,14,15,16,19,20,22,25,27,30,31 and X) (Fig. 2).…”

Section: Chromosomal Localization Of Cenp-a Cenp-b and Cenp-c Protein...mentioning

confidence: 88%

mentioning

confidence: 99%

CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres

Cappelletti,

Piras,

Biundo

et al. 2024

Preprint

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“…Through pathway enrichment analysis, we observed a signi cant enrichment of CD8 + T cells when KDM5D is highly expressed. Recently, Hani et al demonstrated that LOY (Loss of Y chromosome) can promote tumor formation and growth by inducing the exhaustion of CD8 + T cells, evading adaptive immunity, and enhancing the effectiveness of immune checkpoint blockade (ICB) in tumors [22]. LOY is characterized by the loss or extreme downregulation of the Y chromosome, encoding KDM genes, with age, which serves as a risk marker for male cancer [23,24].…”

Section: Discussionmentioning

confidence: 99%

Y-Linked Lysine(K) Demethylase 5D as a regulator of sex-specific bladder cancer metastasis and prognosis

Ran,

Liu,

Zhang

et al. 2023

Preprint

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Background Current research in clinical oncology is focused on exploring gender-based variations in cancer risk and prognosis. Male bladder cancer incidence significantly surpasses that in females across the world. While several factors contribute to variations in cancer susceptibility between sex, a burgeoning body of research underscores the signififcance of distinct activity levels in Y-linked tumor suppressor genes in males and females. Here, we investigate the role of Y-linked lysine(K) demethylase 5D (KDM5D) in the prognosis and metastasis of bladder cancer. Methods By conducting Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR), Western Blot, immunohistochemistry, fluorescence, tumor microenvironment analysis, and bioinformatics pathway analysis on bladder cancer cell lines, bladder cancer tissues, adjacent normal epithelial tissues, combined with statistical analysis using SPSS, Results it was found that KDM5D is low expression in male bladder cancer. Moreover, this underexpression is associated with higher recurrence and metastasis rates. In silico analysis suggests that KDM5D may influence tumor metastasis or recurrence through inflammation response and EMT. Conclusion These findings not only provide evidence to support further precision medicine efforts but also offer new insights for bladder cancer recurrence or metastasis.

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“…For example, a study which induced TET2-associated CHIP in mice suggested a mechanistic link to CVD based on expression of inflammatory chemokines in macrophages 13 , while a mouse model of mLOY demonstrated a mechanism of producing CVD through fibrotic deposition in the extracellular matrix 14 . Additionally, deletion of chromosome Y by CRISPR-Cas9 produced more aggressive bladder cancer tumors by means of T-cell exhaustion 15 . It has also been suggested that there are bidirectional relationships between mLOY and transcriptional dysregulation that lead to differences in disease phenotypes that are dependent on mLOY cell lineage 8 .…”

Section: Introductionmentioning

confidence: 99%

Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Francis,

Gorman,

Bigdeli

et al. 2024

Preprint

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Mosaic loss of chromosome Y (mLOY) is a common somatic mutation in leukocytes of older males. mLOY was detected in 126,108 participants of the Million Veteran Program: 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic. In multi-ancestry genome-wide association analysis, we identified 323 genome-wide significant loci, 167 of which were novel—more than doubling the number of known mLOY loci. Tract-based ancestry deconvolution resolved local inflation at AFR lead SNPs. Transcriptome-wide associations yielded 2,297 significant genes, including seven additional novel genes; integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Thirty-two significant traits found in a phenome-wide polygenic score scan were used in Mendelian randomization (MR). MR implicated six traits as causal influences on mLOY: triglycerides, high-density lipoprotein, smoking, body mass index, testosterone, and sex hormone-binding globulin; and found influence of mLOY on plateletcrit, prostate cancer, lymphocyte percentage, and neutrophil percentage. These results mark a major step forward in our understanding of the genetic architecture of mLOY and its associated risks.

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Y chromosome loss in cancer drives growth by evasion of adaptive immunity

Cited by 78 publications

References 66 publications

CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres

CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres

Y-Linked Lysine(K) Demethylase 5D as a regulator of sex-specific bladder cancer metastasis and prognosis

Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

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