Alejandro Cáceres1,2, Aina Jene3, Tonu Esko4, Luis A Pérez-Jurado5,6, Juan R González1,2,7. 1. Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain. 2. Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. 3. Center for Genomics Regulation, Barcelona, Spain. 4. Estonian Genome Centre Science Centre, University of Tartu, Tartu, Estonia. 5. 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. 6. Women's and Children's Hospital, South Australian Health and Medical Research Institute & University of Adelaide, Adelaide, Australia. 7. Department of Mathematics, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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.
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: Sarah Minner; Adisa Kilgué; Phillip Stahl; Steffen Weikert; Michael Rink; Roland Dahlem; Margit Fisch; Wolfgang Höppner; Walter Wagner; Carsten Bokemeyer; Luigi Terracciano; Ronald Simon; Guido Sauter; Waldemar Wilczak Journal: Pathology Date: 2010-06 Impact factor: 5.306
Authors: Li Su; Wei Zhou; Kofi Asomaning; Xihong Lin; John C Wain; Thomas J Lynch; Geoffrey Liu; David C Christiani Journal: Carcinogenesis Date: 2005-11-25 Impact factor: 4.944
Authors: Andrew Churg; Rong D Wang; Hsin Tai; Xiaoshan Wang; Changshi Xie; Jin Dai; Steven D Shapiro; Joanne L Wright Journal: Am J Respir Crit Care Med Date: 2003-01-09 Impact factor: 21.405
Authors: Derek Klarin; Scott M Damrauer; Kelly Cho; Yan V Sun; Tanya M Teslovich; Jacqueline Honerlaw; David R Gagnon; Scott L DuVall; Jin Li; Gina M Peloso; Mark Chaffin; Aeron M Small; Jie Huang; Hua Tang; Julie A Lynch; Yuk-Lam Ho; Dajiang J Liu; Connor A Emdin; Alexander H Li; Jennifer E Huffman; Jennifer S Lee; Pradeep Natarajan; Rajiv Chowdhury; Danish Saleheen; Marijana Vujkovic; Aris Baras; Saiju Pyarajan; Emanuele Di Angelantonio; Benjamin M Neale; Aliya Naheed; Amit V Khera; John Danesh; Kyong-Mi Chang; Gonçalo Abecasis; Cristen Willer; Frederick E Dewey; David J Carey; John Concato; J Michael Gaziano; Christopher J O'Donnell; Philip S Tsao; Sekar Kathiresan; Daniel J Rader; Peter W F Wilson; Themistocles L Assimes Journal: Nat Genet Date: 2018-10-01 Impact factor: 38.330
Authors: Tayvia Brownmiller; Jamie A Juric; Abby D Ivey; Brandon M Harvey; Emily S Westemeier; Michael T Winters; Alyson M Stevens; Alana N Stanley; Karen E Hayes; Samuel A Sprowls; Amanda S Gatesman Ammer; Mackenzee Walker; Erik A Bey; Xiaoliang Wu; Zuan-Fu Lim; Lin Zhu; Sijin Wen; Gangqing Hu; Patrick C Ma; Ivan Martinez Journal: Cancer Res Date: 2020-07-02 Impact factor: 12.701
Authors: Hanna Davies; Edyta Rychlicka-Buniowska; Jonas Mattisson; Behrooz Torabi Moghadam; Jan P Dumanski; Jonatan Halvardson; Noemi Nagy; Kazimierz Węglarczyk; Karolina Bukowska-Strakova; Marcus Danielsson; Paweł Olszewski; Arkadiusz Piotrowski; Erin Oerton; Aleksandra Ambicka; Marcin Przewoźnik; Łukasz Bełch; Tomasz Grodzicki; Piotr L Chłosta; Stefan Imreh; Vilmantas Giedraitis; Lena Kilander; Jessica Nordlund; Adam Ameur; Ulf Gyllensten; Åsa Johansson; Alicja Józkowicz; Maciej Siedlar; Alicja Klich-Rączka; Janusz Jaszczyński; Stefan Enroth; Jarosław Baran; Martin Ingelsson; John R B Perry; Janusz Ryś; Lars A Forsberg Journal: Cell Mol Life Sci Date: 2021-04-10 Impact factor: 9.261
Authors: Juan R González; Marcos López-Sánchez; Alejandro Cáceres; Pere Puig; Tonu Esko; Luis A Pérez-Jurado Journal: BMC Bioinformatics Date: 2020-11-23 Impact factor: 3.169
Authors: Clara Domingo-Sabugo; Elizabeth Starren; Saffron A G Willis-Owen; Liming Liang; Maxim B Freidin; Madeleine Arseneault; Youming Zhang; Shir Kiong Lu; Sanjay Popat; Eric Lim; Andrew G Nicholson; Yasser Riazalhosseini; Mark Lathrop; William O C Cookson; Miriam F Moffatt Journal: Sci Rep Date: 2021-06-14 Impact factor: 4.379