Hu, Nan

Abstract Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Extensive mammographic density (MD), a well‐established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low‐risk population but with high prevalence of dense breasts. Diagnostic pre‐treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI‐RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2, span [μm], and acini count/TDLU) in benign tissues.Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI‐RADS, c‐d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08–63.1; ptrend < 0.0001) compared to those with non‐dense breasts (BI‐RADS, a‐b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of “at‐risk” epithelium.

Abstract Introduction: Terminal duct lobular unit (TDLU) involution, an age-related physiological process, is characterized by the reduction of size and numbers. Reduced involution is associated with higher mammographic density, a strong breast cancer risk factor. Both factors predict risk of developing breast cancer among women with benign disease. Given that prior studies have been conducted mainly in White women, we compared the extent of TDLU involution among Western and Asian breast cancer cases to describe potential racial heterogeneity in breast cancer etiology. Method: We obtained three TDLU involution metrics (count/100 mm2, mean span, and mean acini count/TDLU; all inversely correlated with TDLU involution) measured in benign breast tissue sections from 379 Chinese (254 luminal A and 125 core basal phenotype [CBP] cases) and 476 Polish (407 luminal A and 69 CBP) breast cancer cases. Polytomous logistic regression was performed using tertiles of TDLU measures as ordinal dependent variable and race as an independent variable. Covariates included age, body mass index, and parity. Analyses were performed separately by age group (&lt;50, ≥50) and subtype (luminal A and CBP). Results: Among luminal A cases, Chinese had significantly greater TDLU count compared with Polish in both age groups (ORtrend= 11.0; 95% CI=2.80-43.2; Ptrend=0.001 for age&lt;50; ORtrend= 12.1; 95% CI=5.12-28.7; Ptrend=1E-08 for age≥50). In addition, Chinese were more likely to have greater mean span and acini count among younger cases (ORtrend=2.5; 95% CI=1.44-4.28; Ptrend=0.001 for mean span and ORtrend=7.4; 95% CI=4.13-13.4; Ptrend=3E-11 for acini count) but not among older cases. Among CBP cases, Chinese were more likely to have greater acini count compared to Polish only among younger women (ORtrend=2.6; 95% CI=1.12-6.95; Ptrend=0.03 for age&lt;50). Conclusion: We found Chinese were more likely to have reduced TDLU involution compared to Polish cases after accounting for potential confounders, with greater differences for luminal A and younger women. Studies of TDLU involution in diverse populations are needed to confirm and understand whether population difference in TDLU involution metrics are related to age at breast cancer onset and risks for specific tumor subtypes. Citation Format: Hyuna Sung, Changyuan Guo, Jennifer Guida, Shan Zheng, Erni Li, Jing Li, Nan Hu, Joseph Deng, Montserrat Garcia-Closas, Jonine Figueroa, Mark Sherman, Gretchen Gierach, Ning Lu, Xiaohong R. Yang. Racial variation in terminal duct lobular unit (TDLU) involution in Chinese and Polish breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2017-5290