International Journal of Cancer最新文献

{"title":"Birth characteristics and the risk of childhood brain tumors: A case-control study in Ontario, Canada.","authors":"Sierra Cheng, John R McLaughlin, M Catherine Brown, James Rutka, Eric Bouffet, Cynthia Hawkins, A Elizabeth Cairney, Adrianna Ranger, Adam J Fleming, Donna L Johnston, Mark Greenberg, David Malkin, Rayjean J Hung","doi":"10.1002/ijc.35287","DOIUrl":"https://doi.org/10.1002/ijc.35287","url":null,"abstract":"<p><p>Various birth characteristics may influence healthy childhood development, including the risk of developing childhood brain tumors (CBTs). In this study, we aimed to investigate the association between delivery methods, obstetric history, and birth anthropometrics with the risk of CBTs. This study used data from the Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) which included children 0-15 years of age and newly diagnosed with CBTs from 1997 to 2003. Multivariable logistic regressions were performed to explore the association between delivery methods, obstetric history, and birth anthropometric variables, with subsequent CBT development. Models were adjusted for maternal and index child characteristics, and stratified by histology where sample size permitted. The use of assistive instruments (forceps or suction) during childbirth was significantly associated with overall CBTs (OR 1.84, 95% CI 1.30-2.61) and non-glial tumors (OR 2.57, 95% CI 1.60-4.13). Compared to first-born children, those second-born or greater had a lower risk of overall CBT development (OR 0.74, 95% CI 0.55-0.98), and glial histological subtype. All other birth characteristic variables explored were not associated with CBTs. The use of assistive devices such as forceps or suction during vaginal delivery carries potential risks, including increased risk of CBT development. There is an inverse association between birth order and CBTs, and future studies examining early childhood common infection may be warranted.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors.","authors":"Colleen B McGrath, Alaina H Shreves, Megan R Shanahan, Hannah E Guard, Manelisi V Nhliziyo, Claire H Pernar, Kathryn L Penney, Tamara L Lotan, Michelangelo Fiorentino, Lorelei A Mucci, Konrad H Stopsack","doi":"10.1002/ijc.35279","DOIUrl":"https://doi.org/10.1002/ijc.35279","url":null,"abstract":"<p><p>The most common somatic alteration in primary prostate cancer is the TMPRSS2:ERG gene fusion, which may be caused or promoted by distinct etiologic factors. The objective of this systematic review was to assess epidemiologic evidence on etiologic factors for prostate cancer by tumor TMPRSS2:ERG fusion status in human populations. Of 3071 publications identified, 19 cohort or case-control studies from six distinct study populations were included in this systematic review. Etiologic factors included germline genetic variants, circulating hormones, and dietary and lifestyle factors. Taller height, higher total and free testosterone levels, and fewer trinucleotide repeats in AR were possibly associated with higher risk of TMPRSS2:ERG-positive prostate cancer. Excess body weight, greater vigorous physical activity, higher lycopene intake, and the use of calcium channel blockers were associated with lower risk of TMPRSS2:ERG-positive prostate cancer. Diabetes and family history of prostate cancer were associated with both TMPRSS2:ERG-positive and TMPRSS2:ERG-negative prostate cancer. Prostate cancer germline variants had suggestive differential associations with TMPRSS2:ERG-positive or TMPRSS2:ERG-negative prostate cancer. However, results were based on few distinct study populations and generally had low precision, underscoring the need for replication. In conclusion, prostate cancer with TMPRSS2:ERG fusion is an etiologically distinct subtype that may be, in part, preventable by addressing modifiable and hormonally acting etiologic factors that align with the established mechanistic role of TMPRSS2:ERG in androgen, insulin, antioxidant, and growth factor pathways.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choline kinases: Enzymatic activity, involvement in cancer and other diseases, inhibitors","authors":"Jan Korbecki,&nbsp;Mateusz Bosiacki,&nbsp;Patrycja Kupnicka,&nbsp;Katarzyna Barczak,&nbsp;Paweł Ziętek,&nbsp;Dariusz Chlubek,&nbsp;Irena Baranowska-Bosiacka","doi":"10.1002/ijc.35286","DOIUrl":"10.1002/ijc.35286","url":null,"abstract":"<p>One of the aspects of tumor metabolism that distinguish it from healthy tissue is the phosphorylation of choline by choline kinases, which initiates the synthesis of phosphatidylcholine. Presently, there is a lack of comprehensive reviews discussing the current understanding of the role of choline kinase in cancer processes, as well as studies on the anti-tumor properties of choline kinase inhibitors. To address these gaps, this review delves into the enzymatic and non-enzymatic properties of CHKα and CHKβ and explores their precise involvement in cancer processes, particularly cancer cell proliferation. Additionally, we discuss clinical aspects of choline kinases in various tumor types, including pancreatic ductal adenocarcinoma, ovarian cancer, lung adenocarcinoma, lymphoma, leukemia, hepatocellular carcinoma, colon adenocarcinoma, and breast cancer. We examine the potential of CHKα inhibitors as anti-tumor drugs, although they are not yet in the clinical trial phase. Finally, the paper also touches upon the significance of choline kinases in non-cancerous diseases.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 7","pages":"1314-1325"},"PeriodicalIF":5.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoid promotes metastasis of colorectal cancer via co-regulation of glucocorticoid receptor and TET2","authors":"Yanwei Song,&nbsp;Shuqiang Ren,&nbsp;Shumei Wu,&nbsp;Weidong Liu,&nbsp;Chenghao Hu,&nbsp;Siting Feng,&nbsp;Xinyu Chen,&nbsp;Rui Tu,&nbsp;Fei Gao","doi":"10.1002/ijc.35285","DOIUrl":"10.1002/ijc.35285","url":null,"abstract":"<p>Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation sequencing (ChIP-seq) were used with antibodies of glucocorticoid receptor (GR) and ten-eleven translocation enzymes (TET) family proteins (TET1, TET2, TET3). Drug repositioning was performed through the Connectivity Map database, using common target genes of GR and TET2 in HEK293 and HCT116 cell lines and differentially expressed genes (DEGs) of colorectal cancer (CRC). Cell migration and invasion were tested in CRC cell lines with varying GR expression, that is, HCT116 and HT29 cell lines. Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced invasion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis. This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 8","pages":"1572-1582"},"PeriodicalIF":5.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers","authors":"Asta Försti,&nbsp;Filip Ambrozkiewicz,&nbsp;Magdalena Marciniak,&nbsp;Jan Lubinski,&nbsp;Kari Hemminki","doi":"10.1002/ijc.35283","DOIUrl":"10.1002/ijc.35283","url":null,"abstract":"<p>A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein–protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes <i>CHEK2</i>, <i>EXO1</i>, <i>FAAP24</i>, <i>FANCI</i>, <i>MCPH1</i>, <i>POLL</i>, <i>PRC1</i>, <i>RECQL</i>, <i>RECQL5</i>, <i>RRM2</i>, <i>SHCBP1</i>, <i>SMC2</i>, <i>XRCC1</i>, in addition to <i>CDK18</i>, <i>ENDOV</i>, <i>ZW10</i> and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 7","pages":"1393-1403"},"PeriodicalIF":5.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.35283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of the WID-qEC test to detect uterine cancers in black women with abnormal uterine bleeding: A prospective observational cohort study in Ghana","authors":"Sebastian Ken-Amoah,&nbsp;Elisa Redl,&nbsp;Bright K. S. Domson,&nbsp;James E. Barrett,&nbsp;Lena Schreiberhuber,&nbsp;Chiara Herzog,&nbsp;Rupali Arora,&nbsp;Allison Jones,&nbsp;Iona Evans,&nbsp;Dan Reisel,&nbsp;Esther Lamptey-Mills,&nbsp;Vincent B. Nachinab,&nbsp;Theodora Pepera,&nbsp;Adeola Olaitan,&nbsp;Dorcas Obiri-Yeboah,&nbsp;Patrick K. Akakpo,&nbsp;Martin Widschwendter","doi":"10.1002/ijc.35260","DOIUrl":"10.1002/ijc.35260","url":null,"abstract":"<p>The burden of uterine cancer is growing and, in the US and UK, mortality rates are poorest among black women. Early detection of these cancers is critical and poor performance of ultrasound in black women may contribute to adverse outcomes. Limited data on this topic are available from Africa. We assessed whether a simple DNA methylation test, the WID-qEC, enables detection of all epithelial uterine (endometrial and cervical) cancers in women presenting with abnormal uterine bleeding (AUB) in Ghana. Among 118 women ≥40 years presenting with AUB, 106 consented to the study and a cervicovaginal sample was obtained for WID-qEC testing. Subsequent to ultrasound assessment 102 women had a cervical or endometrial biopsy. Histopathology, ultrasound and WID-qEC testing were analyzed and compared. Among the 102 volunteers, 8 and 15 were diagnosed with endometrial and cervical cancer (EC and CC), respectively. The receiver operating characteristic (ROC) area under the curve (AUC) was 0.56 (95% confidence interval [CI] 0.25–0.86) for sonographic endometrial thickness (ET) and 0.98 (95% CI 0.94–1.00) for the WID-qEC test. Sensitivity and specificity of the prespecified ET ≥5 mm were 66.7% (95% CI 24.1–94.0) and 22.7 (95% CI 12.0–38.2) and for the prespecified WID-qEC SUM-PMR ≥ 0.3 were 100% (95% CI 56.1–100.0) and 76.1 (96%CI 60.9–86.9), respectively. In addition, 15 CCs were detected by the WID-qEC test [sensitivity 100% (95% CI 74.7–100.0)]. The WID-qEC test accurately detects both EC and CC in black women presenting with AUB.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 5","pages":"1055-1064"},"PeriodicalIF":5.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.35260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma”","authors":"","doi":"10.1002/ijc.35262","DOIUrl":"10.1002/ijc.35262","url":null,"abstract":"<p>Jia LF, Wei SB, Gan YH, et al. Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma. <i>Int J Cancer</i> 2014;135(10):2282-2293. doi:10.1002/ijc.28667.</p><p>We apologize for this error.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 5","pages":"E4"},"PeriodicalIF":5.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.35262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of chronic liver disease and liver cancer with glyphosate and its metabolites in Thailand.","authors":"Daxesh P Patel, Christopher A Loffredo, Benjarath Pupacdi, Siritida Rabibhadana, Panida Navasumrit, Jittiporn Chaisaingmongkol, Leila Toulabi, Majda Haznadar, Bhavik Dalal, Mohammed Khan, Joshua Stone, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Anuradha Budhu, Chulabhorn Mahidol, Xin W Wang, Frank J Gonzalez, Mathuros Ruchirawat, Curtis C Harris","doi":"10.1002/ijc.35282","DOIUrl":"https://doi.org/10.1002/ijc.35282","url":null,"abstract":"<p><p>Glyphosate [N-(phosphonomethyl) glycine], a systemic herbicide, is used globally (825 million kg/year) in 750+ formulations. The International Agency for Research on Cancer classified glyphosate is a probable human carcinogen (Group 2A), but epidemiological studies have been lacking for its association with liver cancer and chronic liver disease. We analyzed urine specimens from 591 patients with newly diagnosed liver cancer, chronic liver disease (CLD), and healthy individuals from five different medical centers between 2011 to 2016 in Thailand. Gas chromatography electrospray ionization mass spectrometry (GC-ESI/MS) was used to quantify glyphosate and its metabolites, aminomethylphosphonic acid (AMPA) and phosphoric acid (PPA) to study their levels in urine of hepatocellular carcinoma (HCC) and CLD patients in comparison to matched healthy individuals. Significantly higher levels of glyphosate were found in CLD patients compared to HCC cases and hospital controls, while significantly elevated levels of both AMPA and PPA were observed in HCC and CLD patients compared to hospital controls. Glyphosate and its metabolites were also detected at low to moderately high levels in convenience samples of food products and drinking water. These results raise concerns about the potential role of glyphosate in chronic liver disease and liver cancer risk.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-matched analysis of MRI evaluating the tumor infiltrating lymphocytes in hepatocellular carcinoma","authors":"Mengqi Huang,&nbsp;Chenyu Song,&nbsp;Xiaoqi Zhou,&nbsp;Huanjun Wang,&nbsp;Yingyu Lin,&nbsp;Jifei Wang,&nbsp;Huasong Cai,&nbsp;Meng Wang,&nbsp;Zhenpeng Peng,&nbsp;Zhi Dong,&nbsp;Shi-Ting Feng","doi":"10.1002/ijc.35281","DOIUrl":"10.1002/ijc.35281","url":null,"abstract":"<p>Tumor-infiltrating lymphocytes (TILs) play critical roles in the tumor microenvironment and immunotherapy response. This study aims to explore the feasibility of multi-parametric magnetic resonance imaging (MRI) in evaluating TILs and to develop an evaluation model that considers spatial heterogeneity. Multi-parametric MRI was performed on hepatocellular carcinoma (HCC) mice (<i>N</i> = 28). Three-dimensional (3D) printing was employed for tissue sampling, to match the multi-parametric MRI data with tumor tissues, followed by flow cytometry analysis and next-generation RNA-sequencing. Pearson's correlation, multivariate logistic regression, and receiver operating characteristic (ROC) curve analyses were utilized to model TIL-related MRI parameters. MRI quantitative parameters, including T1 relaxation times and perfusion, were correlated with the infiltration of leukocytes, T-cells, CD4+ T-cells, CD8+ T-cells, PD1 + CD8+ T-cells, B-cells, macrophages, and regulatory T-cells (correlation coefficients ranged from −0.656 to 0.482, <i>p</i> &lt;.05) in tumor tissues. TILs were clustered into inflamed and non-inflamed subclasses, with the proportion of T-cells, CD8+ T-cells, and PD1 + CD8+ T-cells significantly higher in the inflamed group compared to the non-inflamed group (43.37% vs. 25.45%, 50.83% vs. 34.90%, 40.45% vs. 29.47%, respectively; <i>p</i> &lt;.001). The TIL evaluation model, based on the Z-score combining Kep and T1post, was able to distinguish between these subgroups, yielding an area under the curve of 0.816 (95% confidence interval 0.721–0.910) and a cut-off value of −0.03 (sensitivity 68.4%, specificity 91.3%). Additionally, the Z-score was related to the gene expression of T-cell activation, chemokine production, and cell adhesion. The tissue-matched analysis of multi-parametric MRI offers a feasible method of regional evaluation and can distinguish between TIL subclasses.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 8","pages":"1634-1643"},"PeriodicalIF":5.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.35281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extensive epigenomic dysregulation is a hallmark of homologous recombination deficiency in triple-negative breast cancer","authors":"Youdinghuan Chen,&nbsp;Lucas A. Salas,&nbsp;Jonathan D. Marotti,&nbsp;Nicole P. Jenkins,&nbsp;Chao Cheng,&nbsp;Todd W. Miller,&nbsp;Arminja N. Kettenbach,&nbsp;Brock C. Christensen","doi":"10.1002/ijc.35274","DOIUrl":"10.1002/ijc.35274","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with substantial disease heterogeneity, limited treatment options, and dismal clinical outcomes. Some TNBCs display homologous recombination deficiency (HRD), a phenotype with elevated genomic burden and worse prognosis if left untreated but chemotherapeutic sensitivity. While the molecular landscape of TNBC is distinct from other breast cancer subtypes, the TNBC-specific link between HRD and epigenome-wide methylation has not been established. This study reports two independent cohorts of TNBC tumors (<i>n</i> = 32 and <i>n</i> = 58) with HRD and epigenomic landscapes measured by the Multiplex Ligation-dependent Probe Amplification assay and the Illumina MethylationEPIC arrays, respectively. Genome-wide copy number and methylation alterations were significantly higher in HRD (all <i>p</i> &lt;.05). Methylation of genome-wide repeat element <i>Alu</i> and transcriptional regulatory regions were significantly lower in HRD (all <i>p</i> &lt;.05). An age-adjusted epigenome-wide association study of the continuous HRD probability scores revealed significant loci (all FDR &lt;0.05) that were depleted from the CpG-rich “island” regions often seen in gene promoters but enriched in the CpG-poor “open sea” regions localized to gene enhancers. The significant loci implicated well-known candidate genes involved in the epithelial-to-mesenchymal transition, Wnt signaling, and DNA damage response. Supervised machine learning of HRD with nucleotide-specific methylation as the input enabled clinically relevant tumor stratification. Taken together, this study provides novel biological and translational insights into HRD in TNBCs.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"156 6","pages":"1191-1202"},"PeriodicalIF":5.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}