Pan-Cancer Genome-Wide DNA Methylation Analyses Revealed That Hypermethylation Influences 3D Architecture and Gene Expression Dysregulation in HOXA Locus During Carcinogenesis of Cancers

Liu, Gang; Liu, Zhenhao; Sun, Xiaomeng; Xia, Xiaoqiong; Liu, Yunhe; Liu, Lei

doi:10.3389/fcell.2021.649168

Cited by 4 publications

(4 citation statements)

References 55 publications

(58 reference statements)

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“…This approach however relied on “epi-driver” genes which are defined as an “aberrantly expressed gene in cancers” 46 and lack mechanistic specificity. Interestingly, the work by Liu and colleagues 47 used a more stringent definition of a DMR than the current study (10 CpGs instead of 2). However, a main finding from that study was the differential methylation of the HOXA locus, which the current study also reports in the shared hypermethylation of HOXA3 across cancers.…”

Section: Discussionmentioning

confidence: 70%

Homeobox and Polycomb target gene methylation in human solid tumors

Blanchett,

Lau,

Pfeifer

2024

Sci Rep

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DNA methylation is an epigenetic mark that plays an important role in defining cancer phenotypes, with global hypomethylation and focal hypermethylation at CpG islands observed in tumors. These methylation marks can also be used to define tumor types and provide an avenue for biomarker identification. The homeobox gene class is one that has potential for this use, as well as other genes that are Polycomb Repressive Complex 2 targets. To begin to unravel this relationship, we performed a pan-cancer DNA methylation analysis using sixteen Illumina HM450k array datasets from TCGA, delving into cancer-specific qualities and commonalities between tumor types with a focus on homeobox genes. Our comparisons of tumor to normal samples suggest that homeobox genes commonly harbor significant hypermethylated differentially methylated regions. We identified two homeobox genes, HOXA3 and HOXD10, that are hypermethylated in all 16 cancer types. Furthermore, we identified several potential homeobox gene biomarkers from our analysis that are uniquely methylated in only one tumor type and that could be used as screening tools in the future. Overall, our study demonstrates unique patterns of DNA methylation in multiple tumor types and expands on the interplay between the homeobox gene class and oncogenesis.

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Section: Discussionmentioning

confidence: 70%

Homeobox and Polycomb target gene methylation in human solid tumors

Blanchett,

Lau,

Pfeifer

2024

Sci Rep

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“…Although other tissues did not exhibit significant sample stratification under the current sample size, future epigenetic studies may require more normal controls to avoid potential stratification issues. Additionally, during the data pre-processing stage of integrating methylation profiles from different sources, we normalized the beta value of different tissues to avoid data overfitting, of which method was also been utilized in previous studies [ 41 , 42 ]. Moreover, in the following analysis, we prioritized identifying common changes observed in at least two tissues to minimize the impact of batch effects.…”

Section: Discussionmentioning

confidence: 99%

Pan-precancer and cancer DNA methylation profiles revealed significant tissue specificity of interrupted biological processes in tumorigenesis

Zhang

et al. 2023

Epigenetics

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DNA methylation (DNAme) alterations are known to initiate from the precancerous stage of tumorigenesis. Herein, we investigated the global and local patterns of DNAme perturbations in tumorigenesis by analysing the genome-wide DNAme profiles of the cervix, colorectum, stomach, prostate, and liver at precancerous and cancer stages. We observed global hypomethylation in tissues of both two stages, except for the cervix, whose global DNAme level in normal tissue was lower than that of the other four tumour types. For alterations shared by both stages, there were common hyper-methylation (sHyperMethyl) and hypo-methylation (sHypoMethyl) changes, of which the latter type was more frequently identified in all tissues. Biological pathways interrupted by sHyperMethyl and sHypoMethyl alterations demonstrated significant tissue specificity. DNAme bidirectional chaos indicated by the enrichment of both sHyperMethyl and sHypoMethyl changes in the same pathway was observed in most tissues and was a common phenomenon, particularly in liver lesions. Moreover, for the same enriched pathways, different tissues may be affected by distinct DNAme types. For the PI3K−Akt signalling pathway, sHyperMethyl enrichment was observed in the prostate dataset, but sHypoMethyl enrichment was observed in the colorectum and liver datasets. Nevertheless, they did not show an increased possibility in survival prediction of patients in comparison with other DNAme types. Additionally, our study demonstrated that gene-body DNAme changes of tumour suppressor genes and oncogenes may persist from precancerous lesions to the tumour. Overall, we demonstrate the tissue specificity and commonality of cross-stage alterations in DNA methylation profiles in multi-tissue tumorigenesis.

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“…WDSTS episignature is robust, enabling a discovery and validation of the highly sensitive and specific signal. Hypermethylation of homeobox gene promoters (including HOX genes), is emerging as a pan-cancer signature with patient-specific DNA methylation patterns [40]. Aberrant DNA methylation is a well-documented signature at HOX loci in glioma [18].…”

Section: Discussionmentioning

confidence: 99%

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Haghshenas

Bhai

Levy

et al. 2022

IJMS

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Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

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Pan-Cancer Genome-Wide DNA Methylation Analyses Revealed That Hypermethylation Influences 3D Architecture and Gene Expression Dysregulation in HOXA Locus During Carcinogenesis of Cancers

Cited by 4 publications

References 55 publications

Homeobox and Polycomb target gene methylation in human solid tumors

Homeobox and Polycomb target gene methylation in human solid tumors

Pan-precancer and cancer DNA methylation profiles revealed significant tissue specificity of interrupted biological processes in tumorigenesis

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

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