Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.
BACKGROUND
One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.


METHODS
We used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward's hierarchical clustering method was used to classify the methylation status of the X chromosome.


RESULTS
We grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1-2.5, two copies of active X group: HR 1.4, 95% CI 1.0-1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.


CONCLUSIONS
Loss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.
Department of Hospital Pathology, Inchun St. Mary's hospital, College of Medicine, The Catholic University of Korea, Inchun, Republic of Korea.
Jun
J
Kang
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Hee Jin
HJ
Lee
Department of Hospital Pathology, Inchun St. Mary's hospital, College of Medicine, The Catholic University of Korea, Inchun, Republic of Korea.
Jiyoung
J
Kim
Department of Hospital Pathology, Inchun St. Mary's hospital, College of Medicine, The Catholic University of Korea, Inchun, Republic of Korea.
Jae Jun
JJ
Lee
Department of Hospital Pathology, Inchun St. Mary's hospital, College of Medicine, The Catholic University of Korea, Inchun, Republic of Korea.
Lee-so
LS
Maeng
D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D016208:Databases, Factual; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D015854:Up-Regulation; D049951:X Chromosome Inactivation
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; C505905:ZDHHC15 protein, human