Extreme Downregulation of Chromosome Y and Cancer Risk in Men
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Le résumé fourni par la source
BACKGROUND: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer. METHODS: We advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the Genotype Tissue-Expression Project (n = 371) and its association with cancer status across 12 cancer studies from The Cancer Genome Atlas (n = 1774) and seven other studies (n = 7562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, and a Fisher's test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided. RESULTS: EDY was likely to occur in multiple nondiseased tissues (P < .001) and was statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (false discovery rate = 0.028). EDY strongly associated with cancer risk in men (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.58 to 8.46, P = .002), adjusted by LOY and age, and its variability was largely explained by several genes of the nonrecombinant region whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95% CI = 1.32 to 6.01, P = .007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95% CI = 3.70 to 8.59, false discovery rate < 0.001) and EGFR overexpression along with SRY hypomethylation and nonrecombinant region hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns. CONCLUSIONS: EDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect women compared with men from cancer risk.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Extreme Downregulation of Chromosome Y and Cancer Risk in Men
- Date Crossref
- 16/01/2020
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Barcelona Institute for Global Health pays non établi dans la noticeÉtablissement de santé
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Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública pays non établi dans la noticeStructure de recherche
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Centre for Genomic Regulation pays non établi dans la noticeOrganisation à but non lucratif
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University of Tartu Estonian Genome Centre Science Centre pays non établi dans la noticeUniversité ou école supérieure
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Universitat Pompeu Fabra pays non établi dans la noticeUniversité ou école supérieure
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Women's and Children's Hospital pays non établi dans la noticeÉtablissement de santé
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Centre for Biomedical Network Research on Rare Diseases pays non établi dans la noticeStructure de recherche
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South Australian Health and Medical Research Institute Women's and Children's Hospital pays non établi dans la noticeÉtablissement de santé
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Hospital del Mar Research Institute pays non établi dans la noticeÉtablissement de santé
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The University of Adelaide pays non établi dans la noticeUniversité ou école supérieure
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Universitat Autònoma de Barcelona pays non établi dans la noticeUniversité ou école supérieure
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Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP) pays non établi dans la noticeInstitution
Barcelona Institute for Global Health, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública et Centre for Genomic Regulation, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.