Hongji Dai

An miR-502–Binding Site Single-Nucleotide Polymorphism in the 3′-Untranslated Region of the SET8 Gene Is Associated with Early Age of Breast Cancer Onset

Purpose: MicroRNAs regulate gene expression by binding to the 3′-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3′-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 single-nucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer. Experimental Design: We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls. Results: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels. Conclusions: These data suggest that the miR-502–binding site single-nucleotide polymorphism in the 3′-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings. (Clin Cancer Res 2009;15(19):6292–300)

Distribution of mammographic density and its influential factors among Chinese women

BACKGROUND Mammographic density (MD) has not been systematically investigated among Chinese women. Breast cancer screening programmes provided detailed information on MD in a large number of asymptomatic women. METHODS In the Multi-modality Independent Screening Trial (MIST), we estimated the association between MD and its influential factors using logistic regression, adjusting for age, body mass index (BMI) and study area. Differences between Chinese and other ethnic groups with respect to MD were also explored with adjustment for age and BMI. RESULTS A total of 28 388 women aged 45 to 65 years, who had been screened by mammography, were enrolled in the study. Of these, 49.2% were categorized as having dense breasts (BI-RADS density 3 and 4) and 50.8% as fatty breasts (BI-RADS density 1 and 2). Postmenopausal status [odds ratio (OR) = 0.66; 95% confidence interval (CI): 0.62-0.70] and higher number of live births (OR = 0.56; 95% CI: 0.46-0.68) were inversely associated with MD, whereas prior benign breast disease (OR = 1.48; 95% CI: 1.40-1.56) and later age at first birth (OR = 1.17; 95% CI: 1.08-1.27) were positively associated with MD. In comparison with the data from the Breast Cancer Surveillance Consortium, we found that women in MIST were more likely to have fatty breasts than Americans (from the Breast Cancer Surveillance Consortium) in the older age group (≥50 years) but more likely to have dense breasts in the younger age group (<50 years). CONCLUSIONS This study suggests that several risk factors for breast cancer were associated with breast density in Chinese women. Information on the determinants of mammographic density may provide valuable insights into breast cancer aetiology.

Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer.

Inference of the biological roles of lncRNAs in breast cancer development remains a challenge. Here, we analyzed RNA-seq data in tumor and normal breast tissue samples from 18 breast cancer patients and 18 healthy controls and constructed a functional lncRNA-mRNA co-expression network. We revealed two distinctive co-expression patterns associated with breast cancer, reflecting different underlying regulatory mechanisms: (1) 516 pairs of lncRNA-mRNAs have differential co-expression pattern, in which the correlation between lncRNA and mRNA expression differs in tumor and normal breast tissue; (2) 291 pairs have dose-response co-expression pattern, in which the correlation is similar, but the expression level of lncRNA or mRNA differs in the two tissue types. We further validated our findings in TCGA dataset and annotated lncRNAs using TANRIC. One novel lncRNA, AC145110.1 on 8p12, was found differentially co-expressed with 127 mRNAs (including TOX4 and MAEL) in tumor and normal breast tissue and also highly correlated with breast cancer clinical outcomes. Functional enrichment and pathway analyses identified distinct biological functions for different patterns of co-expression regulations. Our data suggested that lncRNAs might be involved in breast tumorigenesis through the modulation of gene expression in multiple pathologic pathways.

Urban-rural disparity of overweight/obesity distribution and its potential trend with breast cancer among Chinese women

Objective To evaluate the urban-rural disparity of overweight/obesity and explore its potential trend with breast cancer among Chinese women. Results The prevalence of overweight/obesity for Chinese rural women (35.2%, 29.2% for overweight and 6.0% for obesity) was significantly higher than that for Chinese urban women (33.4%, 27.7% for overweight and 5.7% for obesity) (P < 0.001). For either rural or urban women, the prevalence of overweight/obesity was highest in north region, followed by east region for rural women and north-east region for urban women. For rural women, higher prevalence of overweight/obesity was significantly positively associated with elder age, Han nationality, low level of education, no occupation, high family income, less number of family residents, insurance, and elder age at marriage. Similar positive associations were also found for urban women, except negative associations for high family income, less number of family residents, and elder age at marriage. A non-significant positive trend between overweight/obesity and breast cancer was found for rural women [odds ratio (OR): 1.06; 95% confidence interval (CI): 0.87–1.29], but a significant positive trend for urban women (OR: 1.55; 95% CI: 1.19–2.02). Materials and Methods A total of 1 210 762 participants were recruited from the Chinese National Breast Cancer Screening Program. Overweight and obesity were defined as body mass index (BMI) ranged 24.0–27.9 kg/m2 and BMI ≥ 28.0kg/m2, respectively. Conclusions There was an obvious urban-rural disparity of overweight/obesity distribution among Chinese women, which could also lead to an obvious disparity of breast cancer distribution.

Preliminary effectiveness of breast cancer screening among 1.22 million Chinese females and different cancer patterns between urban and rural women

To determine the preliminary effectiveness of breast cancer screening among Chinese females, 1226714 women aged 35–69 years first received clinical breast examinations. Urban women with suspected cancer received mammography followed by breast ultrasound (BUS), while rural suspected women underwent BUS followed by mammography. After one-year follow-up, 223 and 431 breast cancers were detected among urban and rural women (respectively), with overall detection rates of 0.56/1000 and 0.52/1000. Higher detection rates were significantly associated with older age at screening for both urban and rural women; additionally, urban women were at significantly higher risk if they had no job, no insurance, or were obese; additional risk factors specific to rural women included Han nationality, higher income, being unmarried, and having a family history of cancer (all P values < 0.05). Among screening-detected breast cancers in urban vs. rural women, 46.2% and 38.8% (respectively) were early stage, 62.5% and 66.3% were ≤2 centimeters, 38.0% and 47.3% included lymph-node involvement, and 14.0% and 6.0% were identified as carcinoma in situ. All abovementioned cancer characteristics were significantly better than clinic-detected cancers (all P values < 0.001). In conclusion, several important differences were found between urban and rural women in screening effectiveness and patterns of cancer distribution.

A survey of overall life satisfaction and its association with breast diseases in Chinese women

To investigate the association between overall life satisfaction and healthy lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast cancer and benign breast disease in Chinese women. In a multicentered breast disease screening program in China, we enrolled 33,057 women aged 45–65 years without prior diagnosis of breast cancer. After completing an epidemiological questionnaire, all participants were examined by clinical breast examination, breast ultrasound, and mammography independently. All breast cancer cases and a selected sample of benign breast diseases were confirmed pathologically. Univariate and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between life satisfaction and lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast diseases. Overall life satisfaction was positively associated with womens healthy lifestyle. Compared with less satisfied women, satisfied women were less likely to be smokers (OR = 0.54; 95% CI: 0.47–0.62), have more exercise (OR = 1.49; 95% CI: 1.26–1.75), eat less fried (OR = 0.60; 95% CI: 0.50–0.71), smoked (OR = 0.54, 95% CI: 0.47–0.63), pickled (OR = 0.66, 95% CI: 0.55–0.79), and grilled (OR = 0.63, 95% CI: 0.54–0.74) foods. Satisfied women were more likely to have knowledge of breast cancer (OR = 1.48, 95% CI: 1.29–1.70), and have regular physical examinations (OR = 1.11, 95% CI: 1.01–1.12). Compared to less satisfied women, we found significantly lower detection rate of benign breast diseases (OR = 0.90, 95% CI: 0.82–0.99), and lower but nonsignificant detection rate of breast cancer (OR = 0.66, 95% CI: 0.35–1.25) in satisfied women. Women with a higher overall life satisfaction are more likely to have healthy lifestyle, knowledge of breast cancer, and regular physical examination, thus resulting in a lower detection rate of breast diseases in screening.

Personal history of psoriasis and risk of incident cancer among women: a population-based cohort study.

DEAR EDITOR, Psoriasis is a chronic inflammatory skin disorder. The pathophysiology is characterized by T-cell-mediated keratinocytic hyperproliferation and inflammatory changes. Inflammation substantially contributes to the development and progression of cancers, with both local immune response and systemic inflammation playing dramatic roles. The chronic, inflammatory state induced by psoriasis may therefore be associated with neoplastic diseases. Most prior studies on psoriasis and cancer were based on moderate-to-severe psoriasis in clinical settings, and results for most cancers other than cutaneous squamous cell carcinoma (SCC) and Hodgkin lymphoma have been inconclusive (Appendix S1; see Supporting Information). We systematically examined the association between a personal history of psoriasis and risk of incident cancer (other than keratinocyte carcinoma, also known as nonmelanoma skin cancer, i.e. SCC and basal cell carcinoma), based on a prospective analysis of the Nurses’ Health Study (Appendix S1). In 2008 we queried Nurses’ Health Study participants as to whether they had physician-diagnosed psoriasis and if so the year of diagnosis (1997 or before, 1998–2001, 2002–5, 2006–7 or 2008). We confirmed self-reported psoriasis using the Psoriasis Screening Tool questionnaire, which was 99% sensitive and 94% specific for psoriasis in a hospitalbased pilot study. We asked about the involved body surface area (BSA) when psoriasis was at its worst, measured using the palm (i.e. the subject’s flat hand and thumb together, fingers not included). For cancer outcomes, only confirmed invasive cases after medical record review were included, except for breast cancer and bladder cancer, which included both invasive and in situ cases. Among participants with information on their history of psoriasis, we excluded cases of psoriasis that responded to the Psoriasis Screening Tool but were not verified, or cancers occurring in or before 1997 (Fig. S1; see Supporting Information). Person-years of follow-up were calculated from the return of the 1996 questionnaire to either the date of diagnosis of the first primary cancer, death, the last questionnaire response or June 2012, whichever came first. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of total cancer and major individual cancers, using Cox proportional hazards models, stratified by age and 2-year interval. Details of the covariates and other statistical analysis methods are given in Appendix S1. Among a total of 64 990 participants, 2182 (3 4%) cases of psoriasis were diagnosed as of 2008, and 1404 were confirmed. Of these, 1292 (92 0%) had mild psoriasis (≤ 2 palms’ involvement). Information on psoriasis and the characteristics of the participants in 1996 is provided in Appendix S1. During the follow-up (1996–2012), 8348 cases of cancer were identified (Table 1). We did not find an altered risk of total cancer associated with personal history of psoriasis (multivariate-adjusted HR 1 02, 95% CI 0 89–1 17). In the analysis of individual cancers, personal history of psoriasis was associated with an increased risk of melanoma (HR 1 95, 95% CI 1 21–3 13) and kidney cancer (HR 2 50, 95% CI 1 27–4 92) (Table 1). We conducted additional analyses by excluding cases of self-reported psoriasis that were not reached for validation or did not respond to the validation questionnaires. The associations appeared even stronger (Table 2). Subgroup analysis by psoriasis severity found that the associations were stronger among psoriasis with ≥ 1 palm’s involvement. There was a trend towards increased risk of melanoma (Ptrend = 0 003) and kidney cancer (Ptrend < 0 001) with increasing psoriasis severity (Table 2). In the analyses excluding all cases of moderate-to-severe psoriasis (> 2 palm areas’ involvement), the associations for melanoma and kidney cancer remained significant. The HR (95% CI) was 1 98 (1 22–3 23) for melanoma and 2 44 (1 19–5 00) for kidney cancer. We conducted a set of other sensitivity analyses and secondary analyses and did not find material change of the HRs (Appendix S1). Few studies have examined the association between psoriasis and risk of incident cancer based on a population-based cohort study. Several cohort studies based on registry datasets have examined the association. Four focused on one cancer type only, and a fifth evaluated total cancer but did not examine individual cancers. The sixth and seventh studies comprehensively examined the risk of individual cancers, but both adjusted for only a few confounders. Among these studies, three examined the association for melanoma but reported opposite associations. None examined kidney cancer specifically. Comparisons of our findings with these studies are shown in Appendix S1. Inflammation and oxidative stress might be the mechanisms underlying the associations with melanoma and kidney cancer,

Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma

An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single‐nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome‐wide association meta‐analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10−7 and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10−5) for the first time as independently related to BCC risk in meta‐analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10−18). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

Associations between benign cutaneous nevi and risk of Type 2 diabetes mellitus in men and women: results from two prospective cohort studies

To examine the association of cutaneous nevi with Type 2 diabetes risk.

Improved Performance of Adjunctive Ultrasonography After Mammography Screening for Breast Cancer Among Chinese Females

Micro‐Abstract This is the first study to investigate whether women other than those with dense breasts are suitable for adjunctive ultrasonography after negative mammography, and also the first study to determine whether all women with negative mammography are suitable for adjunctive ultrasonography. Introduction: Until now, no studies have investigated whether women other than those with dense breasts are suitable for adjunctive ultrasonography after negative mammography, and investigated whether all women with negative mammography are suitable for adjunctive ultrasonography. Methods: Based on the Multi‐modality Independent Screening Trial in China, a total of 31,918 women aged 45 to 65 years underwent both ultrasonography and mammography. Physicians performed ultrasonography and mammography separately and were blinded to each others findings until their interpretations had been recorded. For both ultrasonography and mammography, suspicious results and those highly suggestive of a malignancy were confirmed by pathologic examination, whereas other results were confirmed by 1‐year follow‐up after initial screening. Results: Based on Breast Imaging Reporting and Data System (BIRADS) assessments, 84 (84.8%) of 99 cancers were identified on mammography (detection rate, 2.6/1000), and 61 (61.6%) of 99 cancers were identified on ultrasonography (detection rate, 1.9/1000). Integrated mammography with ultrasonography identified 94 (95.0%) of 99 cancers, with an increment of 11.9% in cancer detection rate (from 2.6/1000 to 2.9/1000) (P < .05). Moreover, among women with BIRADS 3, adjunctive ultrasonography detected no cancers. All 10 additional cancers detected by adjunctive ultrasonography were from women with BIRADS 0 to 2, at a cost of 207 women with false positives. Additionally, dense breasts and benign breast disease were significantly associated with positive ultrasonography after BIRADS 0 to 2 (all P values < .05). Conclusions: After negative mammography, adjunctive ultrasonography should only be recommended for BIRADS 0 to 2 but not BIRADS 3, especially for women with dense breasts or benign breast disease.