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Supplementary Table from Associations between Preserved Foods and Breast Cancer Risk in Hong Kong Chinese Women

Age-related DNA methylation is a potential mechanism contributing to breast cancer development. Studies of primarily Caucasian women have identified many CpG sites of age-related methylation in non-diseased breast tissue possibly driving cancer development over time. There is a paucity of studies involving Asian women whose ages at breast cancer onset are usually younger than Caucasians. We identified the 181 most consistent age-related methylation events in non-diseased breast tissue across published studies. Age-related methylation events were measured in adjacent normal and breast tumour tissue in an exclusively Asian population at the previously identified age-related methylation sites. Age-related methylation was found in 118 probes in adjacent normal breast tissue. Methylation of 99% of these sites was increased with age and predominantly located on CpG islands in promoter regions. To ascertain biological relevance to breast cancer, we focused on the 37 sites with overall higher methylation in tumour compared to adjacent normal samples. Some sites positively related to age, including AQP5 and CORO6, inversely correlated with gene expression. Several others have known involvement in suppression of carcinogenesis including GPC5 and SST, suggesting that perturbation of epigenetic regulation at these sites due to ageing may contribute to the progression of carcinogenesis. This study highlights an age-related methylation landscape in non-tumour tissue, consistent not just across studies, but also across different populations. We present candidate age-related methylation sites warranting further investigation as potential epigenetic drivers of breast cancer. They may serve as potential targets of site-specific demethylation intervention strategies for the prevention of age-related breast cancer.

Preserved food such as cured foods may contain nitrate and nitrite that may contribute to the breast cancer development. Evidence on the associations between these preserved food intakes and risk of breast cancer is sparse. This study aimed to examine the associations between preserved foods (i.e., cured meat, pickled vegetables, canned meat, and canned fruit/vegetables) and breast cancer risk in Hong Kong Chinese women. A total of 1,307 breast cancer cases and 1,050 age-matched controls were recruited from three hospitals during November 2011 through January 2018. We used a standardized questionnaire to collect information on dietary factors, including preserved foods. Unconditional multiple logistic regression was performed to calculate the adjusted odds ratio (AOR) of breast cancer in relation to preserved food with adjustment of potential confounders. We further performed stratified analysis according to the breast cancer biology subtypes. We found that cured meat consumption was significantly associated with the risk of breast cancer [AOR, 1.32; 95% confidence interval 95% (CI), 1.06–1.64]. Compared with no cured meat consumption, cured meat intake ≥ once per week was associated with an AOR of 2.66 (95% CI, 1.38–5.35). Women with canned fruit/vegetable ≥ consumption once per week had a higher risk of breast cancer (OR, 1.19; 95% CI, 1.00–1.41), particularly for the HER2-positive subtypes, but it became borderline after adjustment of confounders. Our study reveals a positive association between consumption of cured meat and breast cancer risk in Chinese population. Cured meat intake might be a potential novel risk factor for breast cancer but this would have to be confirmed by large prospective cohort studies. Prevention Relevance: The main finding of this case–control study, an association between cured meat intake and a higher risk of breast cancer in Hong Kong Chinese women, contributes to the growing evidence for population-level health benefits of reducing cured meat consumption.

Coffee contains caffeine and diterpenes that were associated with decreased breast cancer risk, but results remained inconsistent. The study purpose was to investigate the associations between coffee products and breast cancer risk among Hong Kong Chinese women. We conducted a hospital-based case-control study in three public hospitals. 2169 Chinese women aged 24–84 years old were interviewed using a standardized questionnaire with questions asking types, cups and duration on coffee drinking. We used unconditional multivariate logistic regression to calculate the adjusted odds ratio (AOR) and 95% confidence interval (95% CI) for breast cancer risk with different coffee products. 238 (20.6%) cases and 179 (17.7%) controls are habitual coffee drinkers. No association was found between overall coffee drinking and breast cancer risk. Compared to the non-habitual coffee drinkers, women who consumed instant coffee (AOR = 1.50, 95% CI = 1.10–2.03) were significantly associated with an increased breast cancer risk. Women who drank brewed coffee (AOR = 0.48, 95% CI = 0.28–0.82) were negatively associated with breast cancer risk. A positive association between instant coffee and breast cancer risk was observed, contradicted to the outcomes of drinking brewed coffee. Larger studies are warranted to ascertain the role of different types of coffee products in breast cancer risk.

BACKGROUND: Previous studies reported heterogeneous associations between obesity and reproductive-related breast cancer risk factors and breast cancer intrinsic subtypes, however, few studies have been conducted in Asian populations. Here, we aimed to examine whether risks associated with established breast cancer risk factors varied by breast cancer subtypes in Chinese women. METHODS: We conducted a hospital-based case-control study in Hong Kong, including a total of 2169 Chinese women. Unconditional polytomous logistic regression models were used to calculate adjusted odds ratios(AORs) and 95% confidence intervals(95%CIs) to estimate relative risks associated with examined risk factors in case-control analyses and to test for heterogeneity across breast cancer subtypes in case-case analyses. RESULTS: In case-case analyses, compared with luminal A patients, luminal B(AOR= 1.76, 95% CI=1.07–2.88), HER2 overexpressing(AOR= 3.40, 95% CI=1.56–7.39) and triple negative(TNBC, AOR= 2.39, 95% CI=1.18–4.82) patients were more likely to be postmenopausal. In case-control analyses, reduced risks associated with parity and younger age at first birth were only seen for luminal A and B cases especially among postmenopausal women, whereas having ≥3 children was associated with increased risk for HER2 overexpressing and TNBC among premenopausal women. Obesity was associated with increased risk for all subtypes. CONCLUSIONS: We found heterogeneous associations between parity-related risk factors by menopausal status and breast cancer subtypes among Chinese patients, which is similar to those observed in Western populations. Interestingly, obesity was associated with increased breast cancer risk regardless of menopausal status or subtypes, except for premenopausal luminal patients, which appears to be unique in Asian populations.

Summary: Recent genomic studies suggest that Asian breast cancer (BC) may have distinct somatic features; however, most comparisons of BC genomic features across populations did not account for differences in age, subtype, and sequencing methods. In this study, we analyzed whole-exome sequencing (WES) data to characterize somatic copy number alterations (SCNAs) and mutation profiles in 98 Hong Kong BC (HKBC) patients and compared with those from The Cancer Genome Atlas of European ancestry (TCGA-EA, N = 686), which had similar distributions of age at diagnosis and PAM50 subtypes as in HKBC. We developed a two-sample Poisson model to compare driver gene selection pressure, which reflects the effect sizes of cancer driver genes, while accounting for differences in sample size, sequencing platforms, depths, and mutation calling methods. We found that somatic mutation and SCNA profiles were overall very similar between HKBC and TCGA-EA. The selection pressure for small insertions and deletions (indels) in GATA3 (false discovery rate (FDR) corrected p < 0.01) and single-nucleotide variants (SNVs) in TP53 (nominal p = 0.02, FDR corrected p = 0.28) was lower in HKBC than in TCGA-EA. Among the 13 signatures of single-base substitutions (SBS) that are common in BC, we found a suggestively higher contribution of SBS18 and a lower contribution of SBS1 in HKBC than in TCGA-EA, while the two APOBEC-induced signatures showed similar prevalence. Our results suggest that the genomic landscape of BC was largely very similar between HKBC and TCGA-EA, despite suggestive differences in some driver genes and mutational signatures that warrant future investigations in large and diverse Asian populations.

Background: Epigenetic age, captured by DNA methylation changes, is thought to be more informative with respect to disease risk and progression, than chronological age. A few studies have associated epigenetic age acceleration (EAA), the difference between DNA methylation age (DNAm age) and chronological age, with BC risk and subtypes. However, most of these studies were conducted in Western populations. In this study, we examined EAA in an Asian population, in which BC incidence rate is lower and age at BC onset is younger compared to most Western populations. Methods: We performed genome-wide DNA methylation profiling of 97 tumor and 89 paired distant normal tissue samples collected from BC patients in Hong Kong (HK) using an Illumina MethylationEPIC array. Two independent datasets were used to compare results: The Cancer Genome Atlas (TCGA, n=525 tumor and n=88 adjacent normal) and healthy women from the Komen tissue bank (n=59). DNAm age was calculated using Horvath's model based on 353 CpGs. The significance of EAA was tested using a simple linear regression model. We also used a multivariate regression model to test for equality of slopes (EAA rates) among different BC subtypes or datasets, considering interaction terms between age and subtype/dataset. Results: The average age at BC diagnosis was 58 years old (range: 33-81) and the distribution of the molecular subtype based on PAM50 was 43.0%, 29.1%, and 27.9% for luminal A, luminal B, and HER2-enriched/basal tumors, respectively. As expected, DNAm age showed a stronger correlation with chronological age in normal tissue (r=0.78, p Conclusion: Consistent with previous studies, we found that EAA in tumor samples varied across tumor subtypes. We also found that HK BC patients' epigenetic age accelerated at a different rate compared to predominantly white TCGA and Komen women, suggesting a potential racial biological difference. Large studies in other Asian populations are warranted to confirm our findings, which may provide biological insight into racial heterogeneity of BC, especially with regard to age at onset. Citation Format: Hela Koka, Bin Zhu, Shelly Lap Ah Tse, Difei Wang, Maeve Kiely, Jennifer Lyn Guida, Priscilla Lee, Feng Wang, Cherry Wu, Koon Ho Tsang, Wing-cheong Chan, Sze Hong Law, Eric Karlins, Bin Zhu, Amy Hutchinson, Belynda Hicks, Xiaohong R. Yang. DNA methylation age of paired tumor-normal breast tissue in Chinese women with breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 146.

Background: Coffee contains caffeine and polyphenols that were reported to be able to low breast cancer risk, but the evidence from epidemiological studies remains inconsistent. Coffee products (i....

Associations between nighttime eating and breast cancer stratified by ER status. (DOCX 14 kb)

Associations between nighttime eating and breast cancer stratified by menopausal status. (DOCX 14 kb)

Nighttime eating exposure assessment. (DOCX 13 kb)

Distribution of dietary factors among breast cancer cases and controls in Hong Kong Chinese women, 2012â 15. (DOCX 32 kb)

Supplemental Digital Content is available in the text, No risk assessment tool is available for identifying high risk population of breast cancer (BCa) in Hong Kong. A case–control study including 918 BCa cases and 923 controls was used to develop the risk assessment model among Hong Kong Chinese women. Each participant received an in-depth interview to obtain their lifestyle and environmental risk factors. Least absolute shrinkage and selection operator (LASSO) selection model was used to select the optimal risk factors (LASSO-model). A risk score system was constructed to evaluate the cumulative effects of selected factors. Bootstrap simulation was used to test the internal validation of the model. Model performance was evaluated by receiver-operator characteristic curves and the area under the curve (AUC). Age, number of parity, number of BCa cases in 1st-degree relatives, exposure to light at night, and sleep quality were the common risk factors for all women. Alcohol drinking was included for premenopausal women; body mass index, age at menarche, age at 1st give birth, breast feeding, using of oral contraceptive, hormone replacement treatment, and history of benign breast diseases were included for postmenopausal women. The AUCs were 0.640 (95% CI, 0.598–0.681) and 0.655 (95% CI, 0.621–0.653) for pre- and postmenopausal women, respectively. Further subgroup evaluation revealed that the model performance was better for women aged 50 to 70 years or ER-positive. This BCa risk assessment tool in Hong Kong Chinese women based on LASSO selection is promising, which shows a slightly higher discriminative accuracy than those developed in other populations.

Breast cancer incidence rates, clinical features, and risk factors are known to vary significantly by race/ethnicity. Recently, tumor sequencing and profiling analyses have improved molecular classification and refined existing breast cancer subtypes. However, detailed genomic analyses are limited in Asian populations. The goal of this study was to profile fresh frozen breast tumors and paired normal tissue in breast cancer cases who had surgeries at two hospitals in Hong Kong. Only tumors containing 50% or more tumor cells were included for sequencing. RNA sequencing (RNASeq), whole exome sequencing, and SNP array were conducted in ~100 tumors. In 92 tumors with RNASeq data, the unsupervised clustering analysis based on 2000 most variable genes identified two subgroups in patients with luminal tumors (defined by PAM50). The most significantly differentially expressed genes between the two luminal subgroups were enriched in immune and inflammation pathways. We further conducted the clustering analysis within 72 luminal tumors (luminal A + luminal B) using 700 immune genes, which again classified the patients into two subgroups (high-immune luminal [HILum] and low-immune luminal [LILum]). Three computational algorithms, CIBERSORT, MCP-counter, and ESTIMATE, were used to infer the fraction or abundance of immune cell populations in each tumor using RNASeq data. We found significant differences in the abundance of most immune cell populations between the two luminal subgroups. The HILum group, which consisted of 53% of all luminal tumors, had a higher overall immune score as well as a higher score for each immune cell subpopulation measured by MCP-counter, at levels similar to those in patients with HER2-positive or basal-like tumors. HILum tumors also expressed significantly higher levels of immune checkpoint genes such as PD1, PDL1, and CTLA4 compared with LILum tumors. Interestingly, HILum was also associated with lower ESR1 expression, earlier age onset, higher level of ploidy and loss-of-heterozygosity, and higher proportions of APOBEC signatures (mutation signatures 2 and 13 in COSMIC) and lower occurrence of the defective DNA mismatch repair signature (signature 6) compared with LILum. The HILum subtype is not specific to Hong Kong since similar results were seen in both TCGA white and Asian breast cancer patients. In summary, we identified a group of luminal patients who had higher levels of immune cell infiltration and immune checkpoint gene expression and are associated with distinct genomic features. These patients may potentially benefit from the immune checkpoint inhibitor therapies. Citation Format: Xiaohong (Rose) Yang, Bin Zhu, Difei Wang, Hela Koka, Tongwu Zhang, Feng Wang, Cherry Wu, Koon Ho Tsang, Wing-cheong Chan, Sze Hong Law, Priscilla Lee, Mengjie Li, Wentao Li, Suyang Wu, Zhiguang Liu, Mingyi Wang, Kristine Jones, Amy Hutchinson, Belynda Hicks, Jianxin Shi, Shelly Lap Ah Tse. Identification of a luminal subtype with high immune abundance among breast cancer patients in Hong Kong, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-165.