Inherited Variants in Regulatory T Cell Genes and Outcome of Ovarian Cancer

<div><p>Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10⁻⁵), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10⁻⁴, and rs3753348, p = 9.0×10⁻⁴, respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10⁻⁴). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10⁻⁴) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.</p> </div

Regulatory T Cell SNPs Associated with Overall Survival (p<0.001).

<p>Adjusted for study site (MAY+MAC, RPCI, POL, UKO+UKR, TBO, NCO, RMH, SEA), age at diagnosis (<50 years, 50–69 years, >70 years), tumor stage (I or II, III or IV, unknown), race (white, non-white, unknown), and tumor grade (low, high, unknown); linkage disequilibrium reduced to r²<0.95; MAF, minor allele frequency.</p

Distributions of Ovarian Cancer Clinical Characteristics by Study.

<p>Distributions of Ovarian Cancer Clinical Characteristics by Study.</p

<i>CD80</i> rs13071247 Genotype and Tumor Expression.

<p>Among N = 54 MAY+MAC invasive ovarian cancer cases, Agilent whole human genome 4×44 K expression array probe A_24_P155632; CD80 log₂ ratios of tumor versus reference RNA expression (y-axis) versus genotype (x-axis); dashes indicate median; each symbol represents a unique patient; data points are jittered so all data are visible.</p