Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes.
BACKGROUND
Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single-nucleotide polymorphism (SNP) individually may not be well suited to detect small effects of multiple SNPs, such as those operating within the same biologic pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes.


METHODS
To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWAS (N cases = 2,813, N deaths = 1,116), with a novel Principal Component-Gamma GSA method. Analysis was completed for all cases and then separately for high-grade serous histologic subtype.


RESULTS
Analysis of the high-grade serous subjects resulted in 43 gene sets with P < 0.005 (1.7%); of these, 21 gene sets had P < 0.10 in both GWAS, including intracellular signaling pathway (P = 7.3 × 10(-5)) and macrolide binding (P = 6.2 × 10(-4)) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (P = 6.3 × 10(-4)) and macrolide binding (P = 1.0 × 10(-3)). Of 18 gene sets with P < 0.005 (0.7%), eight had P < 0.10 in both GWAS.


CONCLUSIONS
This research detected novel gene sets associated with EOC survival.


CONCLUSIONS
Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies.
Departments of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. fridley.brooke@mayo.edu
Brooke L
BL
Fridley
Gregory D
GD
Jenkins
Ya-Yu
YY
Tsai
Honglin
H
Song
Kelly L
KL
Bolton
David
D
Fenstermacher
Jonathan
J
Tyrer
Susan J
SJ
Ramus
Julie M
JM
Cunningham
Robert A
RA
Vierkant
Zhihua
Z
Chen
Y Ann
YA
Chen
Ed
E
Iversen
Usha
U
Menon
Aleksandra
A
Gentry-Maharaj
Joellen
J
Schildkraut
Rebecca
R
Sutphen
Simon A
SA
Gayther
Lynn C
LC
Hartmann
Paul D P
PD
Pharoah
Thomas A
TA
Sellers
Ellen L
EL
Goode
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004198:Disease Susceptibility; D016889:Endometrial Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D025341:Principal Component Analysis; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D015996:Survival Rate
D014408:Biomarkers, Tumor