This review investigates the role of aneuploidy and chromosome instability (CIN) in the aging brain. Aneuploidy refers to an abnormal chromosomal count, deviating from the normal diploid set. It can manifest as either a deficiency or excess of chromosomes. CIN encompasses a broader range of chromosomal alterations, including aneuploidy as well as structural modifications in DNA. We provide an overview of the state-of-the-art methodologies utilized for studying aneuploidy and CIN in non-tumor somatic tissues devoid of clonally expanded populations of aneuploid cells.CIN and aneuploidy, well-established hallmarks of cancer cells, are also associated with the aging process. In non-transformed cells, aneuploidy can contribute to functional impairment and developmental disorders. Despite the importance of understanding the prevalence and specific consequences of aneuploidy and CIN in the aging brain, these aspects remain incompletely understood, emphasizing the need for further scientific investigations.This comprehensive review consolidates the present understanding, addresses discrepancies in the literature, and provides valuable insights for future research efforts.

Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy.

Copy number alterations (CNAs) are frequently found in malignant tissues. Different approaches have been used for CNA detection. However, it is not easy to detect a large panel of CNA targets in heterogenous tumors.
We have developed a CNAs detection approach through quantitatively analyzed allelic imbalance by allelotyping single nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Furthermore, the copy number changes were quantified by real-competitive PCR (rcPCR) to distinguish loss of heterozygosity (LOH) and genomic amplification. The approach was used to validate the CNA regions detected by next generation sequencing (NGS) in early-stage lung carcinoma.
CNAs were detected in heterogeneous DNA samples where tumor DNA is present at only 10% through the SNP based allelotyping. In addition, two different types of CNAs (loss of heterozygosity and chromosome amplification) were able to be distinguished quantitatively by rcPCR. Validation on a total of 41 SNPs from the selected CNA regions showed that copy number changes did occur, and the tissues from early-stage lung carcinoma were distinguished from normal.
CNA detection by MALDI-TOF MS can be used for validating potentially interesting genomic regions identified from next generation sequencing, and for detecting CNAs in tumor tissues consisting of a mixture of neoplastic and normal cells.

Phyllodes tumour (PT) of breast is a rare biphasic neoplasm. Recent next generation sequencing analyses had revealed novel genetic alterations in PT but lacked a further characterisation of their relationship to different PT features and outcome. Here, using targeted sequencing, we examined a panel of 90 recurrently altered or cancer related genes in 88 PT samples (including 49 benign, 25 borderline and 14 malignant PT). Twenty-three genes showed alterations in at least 8.0% of cases. Alterations were significantly higher with an increasing grade of PT (p=0.033), particularly for copy number alterations. The top ten alterations were TERT promoter (58.0%), MED12 (53.4%), RARA (22.8%), FLNA (19.3%), SETD2 (15.9%), SYNE1 (18.2%), PCLO (15.9%), KMT2D (14.3%), CDKN2A (15.9%) and DNAH11 (14.8%). Alterations in CDKN2A/B, EGFR, TP53, PIK3CA, PTEN and ARID1B (p≤0.039) were associated with a higher grade. Analysing alterations based on common pathways indicated a significant correlation of cell cycle pathway and epigenetic alterations with a higher PT grade (p=0.036 and 0.075 respectively). Interestingly, recurrences were not correlated with tumour grade, but related to the presence of RARA mutation (p=0.011) and the absence of alterations in epigenetic pathway (p=0.031). Analysis of synchronous pair of PT showed more differences in gene mutations with divergent MED12 mutation. By contrast, the recurrent samples showed similar genetic alterations as the primary tumours. In summary, we characterised genetic alterations in PTs of different grades and confirmed the recurrent alterations observed in earlier studies. In addition, current data implicated the roles of cell cycle, epigenetic and RARA changes in PT recurrence and tumourogenesis.

Inhibin subunit βA (INHBA) is a protein-coding gene belonging to the transforming growth factor β (TGFβ) superfamily, which is associated with the development of a variety of cancers. However, the role of INHBA in head and neck squamous cell carcinoma (HNSC) remains unclear. The expression profile and prognostic significance of INHBA in HNSC were assessed using a variety of informatics methods. The level of INHBA expression was significantly higher in patients with HNSC, and it was correlated with sex, tumor-node-metastasis (TNM) stage, histological grade, and human papillomavirus (HPV) status. Kaplan-Meier (K-M) analysis indicated that poor overall survival (OS) and disease-free survival (DFS) were significantly associated with INHBA upregulation in HNSC. INHBA overexpression was validated as an independent poor prognostic factor by multivariate Cox regression, and including INHBA expression level in the prognostic model could increase prediction accuracy. In addition, copy number alterations (CNAs) of INHBA and miR-217-5p downregulation are potential mechanisms for elevated INHBA expression in HNSC. In conclusion, INHBA may represent a promising predictive biomarker and candidate target for anti-TGFβ therapy in HNSC.

Malignant transformation of fibrous dysplasia (FD) is very rare and little is known about this occurrence.
We present the detailed clinical course of three cases of osteosarcoma arising from FD of the jaws and explore the genetic aberrations by Sanger sequencing, whole-exome sequencing (WES) and immunohistochemistry (IHC). A literature review of important topics related to this occurrence was also performed.
It was observed that patients with secondary sarcoma from FD showed a wide range of ages, with most during the third decade. Female and males were equally affected. Craniofacial bones and femurs were the most affected sites. High-risk factors for this occurrence included polyostotic FD, McCune-Albright syndrome and excess growth hormone. Notably, a potential relationship between thyroid hormones and sarcoma development was suggested in one patient, who began to show malignant features after hypothyroidism correction. Sanger sequencing revealed GNAS mutations of FD retained in all malignant tissues. Additionally, abnormal TP53 was demonstrated in all three cases by WES and IHC. WES also revealed two other driver mutations, ROS1 and CHD8, and large amounts of somatic copy number alterations (CNAs) where various oncogenes and tumour suppressors are located.
This study demonstrated and reviewed the clinical features and risk factors for a rare occurrence, secondary sarcoma from FD, and provided important new knowledge about its genetics.

Intratumor heterogeneity (ITH) is associated with tumor development, prognosis, immune evasion and therapeutic effects. We proposed the Defining ITH based on EntRopy (DITHER) algorithm for evaluating ITH. We first evaluated the entropies of somatic mutation profiles and copy number alteration (CNA) profiles in a tumor, respectively, and defined their average as the ITH level for the tumor. Using DITHER, we analyzed 33 cancer types from The Cancer Genome Atlas (TCGA) program. We demonstrated that the ITH defined by DITHER had the typical properties of ITH, namely its strong correlations with tumor progression, unfavorable phenotype, genomic instability and immune evasion. Compared with two other ITH evaluation methods: MATH and PhyloWGS, the DITHER ITH had more prominent characteristics of ITH. Moreover, different from MATH and PhyloWGS, DITHER scores were positively correlated with tumor purity, suggesting that DITHER tends to capture the ITH between tumor cells. Interestingly, microsatellite instability (MSI)-high tumors had significantly lower DITHER scores than microsatellite stability (MSS)/MSI-low tumors, although the former had significantly higher tumor mutation loads than the latter. It suggests that the hypermutability of MSI is homogeneous between different cellular populations in bulk tumors. The DITHER ITH may provide novel insights into tumor biology and potential clinical applications.

In glioma, kinesin family member 23 (KIF23) is up-regulated and plays a vital role in oncogenesis. However, the mechanism underlying KIF23 overexpression in malignant glioma remains to be elucidated. This study aims to find potential causes of KIF23 high expression at genome level. To clarify this issue, we obtained point mutation and copy number alterations (CNAs) of KIF23 in 319 gliomas using whole-exome sequencing. Only two glioma samples with missense mutations in KIF23 coding region were identified, while 7 patients were detected with amplification of KIF23. Additional analysis showed that KIF23 amplification was significantly associated with higher expression of KIF23. Gene ontology analysis indicated that higher copy number of KIF23 was associated TNF-α signaling pathway and mitotic cell circle checkpoint, which probably caused by subsequent upregulated expression of KIF23. Moreover, pan-cancer analysis showed that gaining of copy number was significantly associated with higher expression of KIF23, consolidating our findings in glioma. Thus, it was deduced that elevated KIF23 expression in glioma tended to be caused by DNA copy number amplification, instead of mutation.

BACKGROUND: Copy number alterations (CNAs), due to their large impact on the genome, have been an important contributing factor to oncogenesis and metastasis. Detecting genomic alterations from the shallow-sequencing data of a low-purity tumor sample remains a challenging task.
RESULTS: We introduce Accucopy, a method to infer total copy numbers (TCNs) and allele-specific copy numbers (ASCNs) from challenging low-purity and low-coverage tumor samples. Accucopy adopts many robust statistical techniques such as kernel smoothing of coverage differentiation information to discern signals from noise and combines ideas from time-series analysis and the signal-processing field to derive a range of estimates for the period in a histogram of coverage differentiation information. Statistical learning models such as the tiered Gaussian mixture model, the expectation-maximization algorithm, and sparse Bayesian learning were customized and built into the model. Accucopy is implemented in C++ /Rust, packaged in a docker image, and supports non-human samples, more at http://www.yfish.org/software/ .
CONCLUSIONS: We describe Accucopy, a method that can predict both TCNs and ASCNs from low-coverage low-purity tumor sequencing data. Through comparative analyses in both simulated and real-sequencing samples, we demonstrate that Accucopy is more accurate than Sclust, ABSOLUTE, and Sequenza.

UNASSIGNED: To evaluate copy number alterations (CNAs) in genes associated with penile cancer (PeC) and determine their correlation and prognostic ability with PeC.
UNASSIGNED: Whole-exome sequencing was performed for tumor tissue and matched normal DNA of 35 patients diagnosed with penile squamous cell carcinoma from 2011 to 2016. Somatic CNAs were detected using the Genome Analysis Toolkit (GATK). Retrospective clinical data were collected and analyzed. All the data were statistically analyzed using SPSS 16.0 software. The cancer-specific survival rates were estimated by Kaplan-Meier curves and compared with the log-rank test.
UNASSIGNED: CNAs in the MYCN gene was detected in 19 (amplification: 54.29%) patients. Other CNAs gene targets were FAK (amplification: 45.72%, deletion: 8.57%), TP53 (amplification: 2.86%, deletion: 51.43%), TRKA (amplification: 34.29%, deletion: 2.86%), p75NTR (amplification: 5.71%, deletion: 42.86%), Miz-1 (amplification: 14.29%, deletion: 20.00%), Max (amplification: 17.14%, deletion: 2.86%), Bmi1 (amplification:14.29%, deletion: 48.57%), and MDM2 (amplification: 5.71%, deletion: 45.72%). The CNAs in MYCN and FAK correlated significantly with patient prognosis (P<0.05). The 3-year Recurrence-free survival rate was 87.10% among patients followed up. The 5-year survival rate of patients with MYCN amplification was 69.2%, compared to 94.4% in the non-amplification group. The 5-year survival rate of patients with FAK amplification was 65.6%, compared to 94.7% in the non-amplification group. The PPI network showed that TP53 and MYCN might play meaningful functional roles in PeC.
UNASSIGNED: MYCN and FAK amplification and TP53 deletion were apparent in PeC. MYCN and TP53 were hub genes in PeC. MYCN and FAK amplification was also detected and analyzed, and the findings indicated that these two genes are predictors of poor prognosis in PeC.