Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Shalaka S. Hampras, Moffitt Cancer Center
Lara E. Sucheston-Campbell, The Ohio State University
Rikki Cannioto, Roswell Park Cancer Institute
Jenny Chang-Claude, German Cancer Research Center
Francesmary Modugno, University of Pittsburgh
Thilo Dörk, Medizinische Hochschule Hannover (MHH)
Peter Hillemanns, Medizinische Hochschule Hannover (MHH)
Leah Preus, Roswell Park Cancer Institute
Keith L. Knutson, Mayo Clinic
Paul K. Wallace, Roswell Park Cancer Institute
Chi Chen Hong, Roswell Park Cancer Institute
Grace Friel, Roswell Park Cancer Institute
Warren Davis, Roswell Park Cancer Institute
Mary Nesline, Roswell Park Cancer Institute
Celeste L. Pearce, Keck School of Medicine of USC
Linda E. Kelemen, Alberta Health Services
Marc T. Goodman, Cedars-Sinai Medical Center
Elisa V. Bandera, Rutgers Cancer Institute of New Jersey
Kathryn L. Terry, Brigham and Women's Hospital
Nils Schoof, Karolinska Institutet
Kevin H. Eng, Roswell Park Cancer Institute


Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.