MIP-2A Is a Novel Target of an Anilinoquinazoline Derivative for Inhibition of Tumour Cell Proliferation

Human Molecular Genetics

Armasu

et al. 2018

X chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women’s cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10−10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of rl disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.

Section: Discussionmentioning

confidence: 99%

Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Winham

Human Molecular Genetics

Armasu

et al. 2018

“…In cell lines, increased expression of CTPS2 was associated with reduced platinum sensitivity (carboplatin and cisplatin)[Gamazon, et al 2011], and low expression of RPS4X was associated with poor prognosis in serous ovarian cancer [Tsofack, et al 2013]. Furthermore, TRAPPC2 and DDX3X have also been identified as possible drug targets[Bol, Xie, & Raman 2015; Tokunaga, et al 2013]. …”

Section: Discussionmentioning

confidence: 99%

“…TCEANC is thought to interact with BRCA1 in ovarian tumor suppression (Hill et al, 2014), and this gene was aberrantly silenced in seven samples. TRAPPC2 protein, trafficking protein complex 2, also known as MIP-2A, may inhibit tumor proliferation and could be a potential drug target (Tokunaga et al, 2013). DDX3X, encoding DEAD-box helicase 3 X-linked, is a putative tumor suppressor, and has also been associated with escape from XCI that could contribute to male sex bias for some cancers (Bol, Xie, & Raman, 2015;Dunford et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

An integrative approach to assess X‐chromosome inactivation using allele‐specific expression with applications to epithelial ovarian cancer

Fogarty

et al. 2017

Genetic Epidemiology

X-chromosome inactivation (XCI) epigenetically silences transcription of an X chromosome in females; patterns of XCI are thought to be aberrant in women’s cancers, but are understudied due to statistical challenges. We develop a two-stage statistical framework to assess skewed XCI and evaluate gene-level patterns of XCI for an individual sample by integration of RNA sequence, copy number alteration, and genotype data. Our method relies on allele-specific expression (ASE) to directly measure XCI and does not rely on male samples or paired normal tissue for comparison. We model ASE using a two-component mixture of beta distributions, allowing estimation for a given sample of the degree of skewness (based on a composite likelihood ratio test) and the posterior probability that a given gene escapes XCI (using a Bayesian beta-binomial mixture model). To illustrate the utility of our approach, we applied these methods to data from tumors of ovarian cancer patients. Among 99 patients, 45 tumors were informative for analysis and showed evidence of XCI skewed towards a particular parental chromosome. For 397 X-linked genes, we observed tumor XCI patterns largely consistent with previously identified consensus states based on multiple normal tissue types. However, 37 genes differed in XCI state between ovarian tumors and the consensus state; 17 genes aberrantly escaped XCI in ovarian tumors (including many oncogenes), whereas 20 genes were unexpectedly inactivated in ovarian tumors (including many tumor suppressor genes). These results provide evidence of the importance of XCI in ovarian cancer and demonstrate the utility of our two-stage analysis.

“…This strongly suggests that hCAP-G2 is a promising therapeutic target for cancer therapies. In addition, simultaneously targeting hCAP-G2 and MIP-2A, another Q15-binding protein, has been demonstrated to be a promising strategy to develop antitumor drugs for intractable tumors [ 98 ]. In support of the above findings, most recent study by Zhan and colleagues [ 99 ] shows that hCAP-G2 is overexpressed in non-small cell lung cancer (NSCLC) patients and suggests the notion that the hCAP-G2 expression can be used as a prognostic biomarker in lung adenocarcinoma.…”

Section: Dysregulations or Mutations Of Subunits Of Human Condensins mentioning

confidence: 99%

Subunits of human condensins are potential therapeutic targets for cancers

Wang

Yang

et al. 2018

Cell Div

The main role of condensins is to regulate chromosome condensation and segregation during cell cycles. Recently, it has been suggested in the literatures that subunits of condensin I and condensin II are involved in some human cancers. This paper will first briefly discuss discoveries of human condensins, their components and structures, and their multiple cellular functions. This will be followed by reviews of most recent studies on subunits of human condensins and their dysregulations or mutations in human cancers. It can be concluded that many of these subunits have potentials to be novel targets for cancer therapies. However, hCAP-D2, a subunit of human condensin I, has not been directly documented to be associated with any human cancers to date. This review hypothesizes that hCAP-D2 can also be a potential therapeutic target for human cancers, and therefore that all subunits of human condensins are potential therapeutic targets for human cancers.Electronic supplementary materialThe online version of this article (10.1186/s13008-018-0035-3) contains supplementary material, which is available to authorized users.