Chromosomal instability and aneuploidy as causes of cancer drug resistance

Lukow, Devon A.; Sheltzer, Jason M.

doi:10.1016/j.trecan.2021.09.002

Cited by 49 publications

(53 citation statements)

References 82 publications

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“…Kjeldsen et al pointed out that chromosome instability, the process that gives rise to aneuploidy, could promote tumorigenesis by increasing genetic heterogeneity and promoting tumor evolution (26). Recent studies suggested that aneuploidy might have clinical relevance as a prognostic marker and potential therapeutic target in tumors (6,27). CENPM is a component of the CENPA-NAC (nucleosome-associated) complex, and plays a critical role in assembly of kinetochores proteins, mitotic progression and chromosome segregation during cell division (28).…”

Section: Discussionmentioning

confidence: 99%

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The prognostic value and mechanisms of centromere protein M in patients with lung adenocarcinoma

Qi¹,

Niu²,

Li³

et al. 2022

Transl Cancer Res TCR

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Background: Centromere protein M (CENPM) has been reported to exert important roles in promoting tumor initiation and progression. However, the expression, effect, impact on prognosis and underlying mechanism of CENPM in lung adenocarcinoma (LUAD) remain unclear. Methods: Seventy-eight paired clinical samples of LUAD and corresponding adjacent non-tumor (ANT) tissues were obtained. The clinical pathological data and clinical outcome were tested, including univariate and multivariate Cox regression model. The relationship between CENPM expression and LUAD prognosis were identified according to the data obtained from the Cancer Genome Atlas (TCGA) database. Then, we explored the protein and mRNA levels of CENPM in LUAD and paired ANT tissues, and analyzed the correlation between CENPM and LUAD overall survival in our patients. In vitro studies, LUAD cell lines were treated with CENPM-short hairpin RNA (shRNA) (shCENPM), or transfected with CENPM overexpression plasmids with or without LY294002 (PI3K inhibitor) treatment. Cell proliferation ability was determined through cell counting kit-8 (CCK-8) assays. Cell cycle and apoptosis were detected by flow cytometer. The migration and invasion ability were assessed through Transwell assay. In vivo studies, the growth of xenografts in nude mice were evaluated after shCENPM stimulated cells injection, and the proliferation and apoptosis of xenografts were also analyzed.Results: CENPM was significantly upregulated in LUAD patients compared with healthy controls, and CENPM upregulation was relevant to the higher pathological stages and poor survival rates in our LUAD patients. The bioinformatics analysis also revealed similar trends. CENPM could promote cell proliferation, cause alterations in cell cycle progression, enhance cell migration and invasion capacity, promote apoptosis in LUAD cell lines and promote the growth of xenografts in nude mice via regulation of AKT1/mTOR signaling pathway.Conclusions: CENPM was upregulated in LUAD patients, and it correlated with higher pathological stages and poor survival rates. CENPM could affect cell proliferation, cell cycle, cell migration and invasion capacity, and apoptosis in LUAD cell lines via regulation of AKT1/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…pointed out that chromosome instability, the process that gives rise to aneuploidy, could promote tumorigenesis by increasing genetic heterogeneity and promoting tumor evolution ( 26 ). Recent studies suggested that aneuploidy might have clinical relevance as a prognostic marker and potential therapeutic target in tumors ( 6 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

The prognostic value and mechanisms of centromere protein M in patients with lung adenocarcinoma

Qi¹,

Niu²,

Li³

et al. 2022

Transl Cancer Res TCR

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“…Many common cancers are characterised by chromosomal instability (CIN) and as a result, extensive copy number aberrations (CNAs) 1,2 . CNAs alter the number of copies of genomic regions in a cell, thus creating a background of genomic variation on which evolution can act 3 .…”

Section: Introductionmentioning

confidence: 99%

scAbsolute: measuring single-cell ploidy and replication status

Schneider

Macintyre

Markowetz

2022

Preprint

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Chromosomal instability is a common characteristic of many cancers. Chromosomally instable tumour cells exhibit frequent copy number aberrations (CNAs) and a wide variation in the amount of DNA in cancer cells, referred to as cell ploidy. High levels of ploidy, in particular, are associated with whole genome doubling (WGD), a widespread macro-evolutionary event in tumour history. Individual cells' genomes are also undergoing replication as part of the cell cycle, and this constitutes an important covariate for single-cell genome analysis. Accurate and unbiased measurement of single-cell ploidy and replication status, including WGDs, based on DNA sequencing data is important for many downstream applications, such as detecting genomic variants, quantifying intratumour heterogeneity, and reconstructing tumour evolutionary phylogenies. Here we present scAbsolute, an approach to measure ploidy and replication status in single cells using scalable stochastic variational inference with a constrained Dirichlet Process Gaussian Mixture Model. We demonstrate its accuracy across three sequencing technologies (10X, DLP, ACT) and different cell lines and tumour samples. We address the problem of identifying cells with double the amount of DNA, but otherwise identical copy number profiles as is the case after WGD, solely based on sequencing information. Finally, we provide a robust and general method for identifying cells undergoing DNA replication. scAbsolute provides a scalable and unbiased way of ascertaining single-cell ploidy and replication status, paving the way for accurate detection of CNAs and WGDs in single-cell DNA sequencing data.

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“…Such studies have permitted the mapping of the landscape of clonal and subclonal SCNAs [6][7][8][9][10][11][12], and have revealed a relationship between SCNA intra-tumour heterogeneity and poor prognosis in multiple tumour types [6,8,[13][14][15][16]. Additionally, chromosomal instability and aneuploidy have been associated with and proposed as causes of cancer drug resistance [17] and linked to metastasis [18][19][20][21]. Inference of SCNAs and quantification of their intra-tumour heterogeneity is therefore of clinical importance and a prerequisite for understanding tumour evolution.…”

Section: Introductionmentioning

confidence: 99%

Refphase: Multi-sample reference phasing reveals haplotype-specific copy number heterogeneity

Watkins

Colliver

Huska

et al. 2022

Preprint

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Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample reference phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.

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Chromosomal instability and aneuploidy as causes of cancer drug resistance

Cited by 49 publications

References 82 publications

The prognostic value and mechanisms of centromere protein M in patients with lung adenocarcinoma

The prognostic value and mechanisms of centromere protein M in patients with lung adenocarcinoma

scAbsolute: measuring single-cell ploidy and replication status

Refphase: Multi-sample reference phasing reveals haplotype-specific copy number heterogeneity

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