Publications by authors named "JiHoon E Joo"

Article Synopsis
  • - DNA methylation is an important epigenetic mechanism that regulates gene expression, and DNMT inhibitors are used extensively in research to study this process.
  • - Researchers developed a CRISPR-based method called SAM-DNMT3A that unexpectedly induces global DNA methylation, regardless of the specific DNA target.
  • - This approach reveals a potential therapeutic vulnerability in ER-positive breast cancer and emphasizes the need for careful use of CRISPR technology in methylation studies.
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  • Colorectal cancers (CRCs) linked to biallelic germline variants show specific mutational signatures (SBS18+SBS36 and SBS30) that could also be present in adenomas, which are precursors to CRCs.
  • A study sequenced DNA from adenomas and CRCs in biallelic cases and compared them with sporadic cases to investigate these signatures.
  • Results indicated that adenomas in biallelic cases had similar mutational signature proportions as their corresponding CRCs, suggesting testing adenomas could enhance the detection of biallelic cases and improve variant classification for better CRC prevention strategies.
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Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip.

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  • The study examined the connection between certain bacteria (pks E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum) and colorectal cancer (CRC) by analyzing DNA samples from various cohorts.
  • Results revealed that pks E. coli is linked to male CRC patients and a specific APC gene mutation, mainly in early-onset cases, while F. nucleatum correlates with various cancer traits including DNA repair deficiencies and specific tumor locations.
  • The findings suggest that pks E. coli might cause DNA damage related to the identified mutation, and F. nucleatum exists in both hereditary and sporadic factors of DNA mismatch repair deficiencies, highlighting the importance of the tumor environment for bacterial colon
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  • The study investigates a unique multi-generation family affected by colorectal cancer (CRC) with pathogenic variants in the BRCA1 and RNF43 genes, which are linked to breast/ovarian cancer and Serrated Polyposis Syndrome, respectively.
  • Out of 105 families eligible for Familial Colorectal Cancer Type X, this particular family underwent whole exome sequencing, revealing 10 carriers of a BRCA1 variant and 8 of an RNF43 variant, with some individuals developing CRC.
  • The analysis showed loss of heterozygosity in CRC tumors related to both genes, indicating that both BRCA1 and RNF43 play critical roles in the development of CRC through digenic inheritance and homologous recombination
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  • * A study analyzed 28 tumors from 25 patients with variants of uncertain significance (VUS) in MMR genes to evaluate how specific tumor characteristics help classify these genetic variants.
  • * The results reclassified 28% of VUS as likely pathogenic, with the majority confirming features like microsatellite instability and MMR deficiency, suggesting that recognizing these characteristics can enhance clinical decision-making.
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Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.

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Background: MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.

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  • Routine screening for DNA mismatch repair (MMR) deficiency in certain tumors often results in unresolved cases labeled as suspected Lynch syndrome (SLS), with a study involving 135 such cases across Australia and New Zealand.
  • Targeted sequencing of tumors and matched blood samples revealed that 86.9% of these SLS cases could be classified into specific subtypes, primarily through the detection of double somatic MMR mutations.
  • The research indicates that implementing tumor-focused testing and MLH1 methylation assays in clinical settings can effectively clarify SLS diagnoses, leading to better surveillance and screening for patients.
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  • The study investigates the role of a specific mutational signature (SBS88) in colorectal cancer (CRC), which is linked to a bacteria that produces a genotoxin called colibactin.
  • About 7.5% of the CRC cases studied were found to be SBS88-positive, with a notable prevalence in the distal colon and rectum, and demonstrated distinct somatic mutations associated with colibactin-induced DNA damage.
  • SBS88-positive CRCs were linked to better survival rates compared to negative cases, suggesting this mutational signature could help identify a unique subtype of CRC that may influence treatment and prevention approaches.
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Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values.

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Article Synopsis
  • Routine screening for DNA mismatch repair deficiency in colorectal, endometrial, and sebaceous skin tumors has led to many unresolved cases suspected of Lynch syndrome, affecting 135 patients across Australia and New Zealand.
  • Targeted panel sequencing of tumors and matched blood DNA helped resolve 86.9% of these suspected cases by identifying various factors, including epimutations and germline MMR variants, with double somatic mutations being the most common cause.
  • The study suggests that incorporating tumor sequencing and methylation assays into clinical diagnostics could reduce unresolved cases and improve patient surveillance and screening strategies.
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DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array.

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Objective: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO) clinical criteria and by colorectal cancer (CRC).

Method: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry.

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Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. Tumor features, individually and in combination, derived from whole-exome sequenced (WES) colorectal cancers (CRCs) and panel-sequenced CRCs, endometrial cancers (ECs), and sebaceous skin tumors (SSTs) were assessed for their accuracy in detecting dMMR. CRCs (n = 300) with WES, where mismatch repair status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, and MSISensor), Catalogue of Somatic Mutations in Cancer tumor mutational signatures, and somatic mutation counts.

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Background: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts.

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Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training ( = 7,431) and validation ( = 4,307) samples.

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Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.

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Genetic variants in are associated with longevity. Here, we assessed whether blood DNA methylation at was associated with cancer risk, survival, and mortality. We used data from eight prospective case-control studies of breast ( = 409 cases), colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869), and urothelial ( = 428) cancer and B-cell lymphoma ( = 438).

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Inflammatory memory involves the molecular and cellular 'reprogramming' of innate immune cells following exogenous stimuli, leading to non-specific protection against subsequent pathogen exposure. This phenomenon has now also been described in non-hematopoietic cells, such as human fetal and adult endothelial cells. In this study we mapped the cell-specific DNA methylation profile and the transcriptomic remodelling during the establishment of inflammatory memory in two distinct fetal endothelial cell types - a progenitor cell (ECFC) and a differentiated cell (HUVEC) population.

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Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2).

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Objective: In previous studies using Illumina Infinium methylation arrays, we have identified DNA methylation marks associated with cancer predisposition and progression. In the present study, we have sought to find appropriate technology to both technically validate our data and expand our understanding of DNA methylation in these genomic regions. Here, we aimed to assess the repeatability of methylation measures made using QIAseq targeted methyl panel and to compare them with those obtained from the Illumina HumanMethylation450 (HM450K) assay.

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Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort.

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We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC.

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