Abstract A126: Risk factors for epithelial ovarian cancer by tumor dominance, a surrogate for cell of origin
Authors: Kotsopoulos Joanne , Gates Margaret A. , Hecht Jonathan L. , Rosner Bernard A. , Crum Christopher C. , Tworoger Shelley S. 
Published: May 2012

Abstract
Ovarian tumors traditionally are thought to arise from the ovarian surface epithelium (OSE); however recent studies suggest that some tumors may originate in the distal fallopian tube. Differences in the risk factors for tumors of ovarian versus tubal origin may help to explain inconsistent associations observed across studies for some exposures. To determine cell of origin in cancer resections, it is necessary to conduct detailed sectioning of fallopian tubes and ovaries, which is impractical in large epidemiologic studies. However a prior study suggested that tumor dominance, determined from pathology reports, may be an acceptable surrogate for cell of origin, such that tumors arising in the OSE are more likely to involve only one ovary or to show one involved ovary exceeding the other in dimension by more than two-fold (DOM+), while tumors of tubal origin show symmetric ovarian involvement or an even distribution across the peritoneal cavity (DOM−). Therefore, to explore risk factor associations by cell of origin, we prospectively investigated the relationship of both reproductive/hormonal and non-reproductive exposures with risk of DOM+ versus DOM− tumors among 403 incident invasive cases of confirmed epithelial ovarian cancer from the Nurses' Health Study (NHS) and NHSII. Cox proportional hazards regression, stratified by dominance and time period, was used to examine the associations. For each exposure, we calculated the P-value for heterogeneity using a likelihood ratio test comparing models with separate estimates for the two subtypes versus a single estimate across subtypes. There were 281 DOM+ and 122 DOM− cases diagnosed between 1976 and 2006. In analyses of reproductive/hormonal exposures, there was no significant heterogeneity across the two subtypes for the associations with age, age at natural menopause, breastfeeding, parity, oral contraceptive use, estrogen use, and hysterectomy (P-heterogeneity ≥ 0.40). However, the association with tubal ligation was significantly stronger for DOM+ (RR=0.51; 95%CI=0.34–0.75) versus DOM− tumors (RR=0.95; 95%CI=0.58–1.56; P-heterogeneity=0.05). While associations with several non-reproductive exposures (e.g., BMI, physical activity, talc use) did not vary by subtype (P-heterogeneity ≥ 0.11), the association with family history of ovarian cancer was stronger for DOM− (RR=3.32; 95% CI=1.52–7.25) versus DOM+ tumors (RR=0.95; 95%CI=0.39–2.32; P-heterogeneity=0.04). The results were similar when we limited our analysis to 228 cases with serous invasive or poorly differentiated histology. Although limited by small case numbers, our results suggest that tubal ligation may be more strongly associated with tumors of ovarian origin, while family history of ovarian cancer primarily increases risk of tumors of tubal origin. Characterizing risk factor relationships by tumor dominance may elucidate how these exposures alter risk and help to improve prevention efforts.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A126.