Dataset Information

Establishing the Link between X-Chromosome Aberrations and TP53 Status, with Breast Cancer Patient Outcomes.

ABSTRACT: Ubiquitous to normal female human somatic cells, X-chromosome inactivation (XCI) tightly regulates the transcriptional silencing of a single X chromosome from each pair. Some genes escape XCI, including crucial tumour suppressors. Cancer susceptibility can be influenced by the variability in the genes that escape XCI. The mechanisms of XCI dysregulation remain poorly understood in complex diseases, including cancer. Using publicly available breast cancer next-generation sequencing data, we show that the status of the major tumour suppressor TP53 from Chromosome 17 is highly associated with the genomic integrity of the inactive X (Xi) and the active X (Xa) chromosomes. Our quantification of XCI and XCI escape demonstrates that aberrant XCI is linked to poor survival. We derived prognostic gene expression signatures associated with either large deletions of Xi; large amplifications of Xa; or abnormal X-methylation. Our findings expose a novel insight into female cancer risks, beyond those associated with the standard molecular subtypes.

SUBMITTER: Caramia F

PROVIDER: S-EPMC10526523 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Establishing the Link between X-Chromosome Aberrations and <i>TP53</i> Status, with Breast Cancer Patient Outcomes.

Caramia Franco F Speed Terence P TP Shen Hui H Haupt Ygal Y Haupt Sue S

Cells 20230911 18

Ubiquitous to normal female human somatic cells, X-chromosome inactivation (XCI) tightly regulates the transcriptional silencing of a single X chromosome from each pair. Some genes escape XCI, including crucial tumour suppressors. Cancer susceptibility can be influenced by the variability in the genes that escape XCI. The mechanisms of XCI dysregulation remain poorly understood in complex diseases, including cancer. Using publicly available breast cancer next-generation sequencing data, we show ...[more]

PMID: 37759468

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Project description:In cases of nuclear and radiological accidents, public health and emergency response need to assess the magnitude of radiation exposure regardless of whether they arise from disaster, negligence, or deliberate act. Here we report the establishment of a national reference dose-response calibration curve (DRCC) for dicentric chromosome (DC), prerequisite to assess radiation doses received in accidental exposures. Peripheral blood samples were collected from 10 volunteers (aged 20-40 years, median = 29 years) of both sexes (three females and seven males). Blood samples, cytogenetic preparation, and analysis followed the International Atomic Energy Agency EPR-Biodosimetry 2011 report. Irradiations were performed using 320 kVp X-rays. Metafer system was used for automated and assisted (elimination of false-positives and inclusion of true-positives) metaphases findings and DC scoring. DC yields were fit to a linear-quadratic model. Results of the assisted DRCC showed some variations among individuals that were not statistically significant (homogeneity test, P = 0.66). There was no effect of age or sex (P > 0.05). To obtain representative national DRCC, data of all volunteers were pooled together and analyzed. The fitted parameters of the radiation-induced DC curve were as follows: Y = 0.0020 (±0.0002) + 0.0369 (±0.0019) * D + 0.0689 (±0.0009) * D 2. The high significance of the fitted coefficients (z-test, P < 0.0001), along with the close to 1.0 p-value of the Poisson-based goodness of fit (χ2 = 3.51, degrees of freedom = 7, P = 0.83), indicated excellent fitting with no trend toward lack of fit. The curve was in the middle range of DRCCs published in other populations. The automated DRCC over and under estimated DCs at low (<1 Gy) and high (>2 Gy) doses, respectively, with a significant lack of goodness of fit (P < 0.0001). In conclusion, we have established the reference DRCC for DCs induced by 320 kVp X-rays. There was no effect of age or sex in this cohort of 10 young adults. Although the calibration curve obtained by the automated (unsupervised) scoring misrepresented dicentric yields at low and high doses, it can potentially be useful for triage mode to segregate between false-positive and near 2-Gy exposures from seriously irradiated individuals who require hospitalization.

Dataset Information

Establishing the Link between X-Chromosome Aberrations and TP53 Status, with Breast Cancer Patient Outcomes.

Publications

Establishing the Link between X-Chromosome Aberrations and <i>TP53</i> Status, with Breast Cancer Patient Outcomes.

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