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Extreme Downregulation of Chromosome Y and Cancer Risk in Men.
J Natl Cancer Inst. 2020 Sep 01; 112(9):913-920.JNCI

Abstract

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.

Authors+Show Affiliations

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain. Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.Center for Genomics Regulation, Barcelona, Spain.Estonian Genome Centre Science Centre, University of Tartu, Tartu, Estonia.Genetics Unit, Universitat Pompeu Fabra, Institut Hospital del Mar d'Investigacions Mediques (IMIM), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Women's and Children's Hospital, South Australian Health and Medical Research Institute & University of Adelaide, Adelaide, Australia.Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain. Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Department of Mathematics, Universitat Autònoma de Barcelona, Bellaterra, Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31945786

Citation

Cáceres, Alejandro, et al. "Extreme Downregulation of Chromosome Y and Cancer Risk in Men." Journal of the National Cancer Institute, vol. 112, no. 9, 2020, pp. 913-920.
Cáceres A, Jene A, Esko T, et al. Extreme Downregulation of Chromosome Y and Cancer Risk in Men. J Natl Cancer Inst. 2020;112(9):913-920.
Cáceres, A., Jene, A., Esko, T., Pérez-Jurado, L. A., & González, J. R. (2020). Extreme Downregulation of Chromosome Y and Cancer Risk in Men. Journal of the National Cancer Institute, 112(9), 913-920. https://doi.org/10.1093/jnci/djz232
Cáceres A, et al. Extreme Downregulation of Chromosome Y and Cancer Risk in Men. J Natl Cancer Inst. 2020 Sep 1;112(9):913-920. PubMed PMID: 31945786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extreme Downregulation of Chromosome Y and Cancer Risk in Men. AU - Cáceres,Alejandro, AU - Jene,Aina, AU - Esko,Tonu, AU - Pérez-Jurado,Luis A, AU - González,Juan R, PY - 2019/07/12/received PY - 2019/10/31/revised PY - 2019/12/11/accepted PY - 2021/01/16/pmc-release PY - 2020/1/17/pubmed PY - 2020/1/17/medline PY - 2020/1/17/entrez SP - 913 EP - 920 JF - Journal of the National Cancer Institute JO - J. Natl. Cancer Inst. VL - 112 IS - 9 N2 - 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. SN - 1460-2105 UR - https://www.unboundmedicine.com/medline/citation/31945786/Extreme_down-regulation_of_chromosome_Y_and_cancer_risk_in_men L2 - https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djz232 DB - PRIME DP - Unbound Medicine ER -
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