[Show abstract][Hide abstract] ABSTRACT: Background:
The human APOBEC protein family plays critical but distinct roles in host defense. Recent studies revealed that APOBECs mediate C-to-T mutagenesis in multiple cancers, including breast cancer. It is still unclear whether APOBEC gene family shows functional diversification involved in cancer mutagenesis.
We performed an integrated analysis to characterize the functional diversification of APOBEC gene family associated with breast cancer mutagenesis relative to estrogen receptor (ER) status. Among the APOBEC family, we found that both APOBEC3B and APOBEC3C mRNA levels were significantly higher in estrogen receptor negative (ER-) subtype compared with estrogen receptor positive (ER+) subtype (P < 2.2 × 10(-16) and P < 3.1 × 10(-5), respectively). Epigenomic data further reflected the distinct chromatin states of APOBEC3B and APOBEC3C relative to ER status. Notably, we observed the significantly positive correlation between the APOBEC3B-mediated mutagenesis and APOBEC3B expression levels in ER+ cancers but not in ER- cancers. In contrast, we discovered the negative correlation of APOBEC3C mRNA levels with base-substitution mutations in ER- tumors. Meanwhile, we observed that breast cancers in carriers of germline deletion of APOBEC3B gene harbor similar mutation patterns, but higher mutation rates in the TCW motif (W corresponds to A or T) than cancers in non-carriers, indicating additional factors may also induce carcinogenic mutagenesis.
These results suggest that functional potential of APOBEC3B and APOBEC3C involved in cancer mutagenesis is associated with ER status.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.
[Show abstract][Hide abstract] ABSTRACT: Background:
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.
The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).
Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
No preview · Article · Aug 2015 · Journal of the National Cancer Institute
[Show abstract][Hide abstract] ABSTRACT: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H1 IA gene; P = 8.82 x 10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P = 1.67 x 10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P= 4.25 x 10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P = 0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast
majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations
between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry,
followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the
KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women.
Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide
significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic
basis of obesity.
Full-text · Article · May 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: The APOBEC gene family was initially reported to play critical roles in virus restriction. We recently found that a common germline deletion in the APOBEC3B gene was strongly associated with breast cancer risk. It has been reported that the APOBEC3B gene may play a significant role in C-to-T mutations in breast cancer. However, it remain unknown how APOBEC3 family genes are regulated. In this study, we aimed at determining epigenetic profile of activation and inactivation of APOBEC family members in breast cancer cell lines through large-scale integrated analyses. All data were downloaded from the GEO/ENCODE databases. RNA-seq data were available from 12 cell lines, including three estrogen receptor negative (ER-), eight estrogen receptor positive (ER+) breast cancer cell lines as well as one normal breast epithelia cell line. Data of epigenetic markers based on ChIP-seq, including H3K4me3, H3K27ac, H3K4me1, H3K36me3, H3K9me3 and H3K27me3, were available from both ER+; and ER- breast cancer cell lines. DNA methyl-seq data were obtained only in one ER- cell line. RNA-seq data showed that among APOBEC genes, the APOBEC3B gene was the only one showing up-regulation compared with normal breast cell lines. Other APOBEC members, including APOBEC1, APOBEC2, APOBEC3A, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4 and AID were either not expressed or down-regulated in breast cancer cell lines with an exception of the constantly high expression of the APOBEC3C gene observed in ER- breast cancer cell lines but down-regulation in ER+; breast cancer cell lines. Activated epigenetic markers, including H3K4me3 and H3K27ac and H3K36me3, were observed in the APOBEC3B gene, in both ER+; and ER- breast cancer cell lines. The activated markers H3K4me3 and H3K36me3 were also observed in the APOBEC3C gene in the ER- cell lines. Except the APOBEC3B and APOBEC3C genes, all other APOBEC family members showed DNA hyper-methylation at their promoters in the ER- cell line, which may contribute to their no expression or down-regulation. In conclusion, our integrated epigenetic analysis showed that both histone modification and DNA methylation may regulate gene expression patterns in APOBEC family members in breast cancer cell lines.
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown.
In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.
No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81-0.94, p-value = 4.4x10-4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 (OR = 1.32, 95% CI 1.18-1.47, p-value = 1.1x10-6).
This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies. Impact: These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
No preview · Article · May 2013 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: Age at natural menopause (ANM) is a complex trait with high heritability and is associated with several major hormonal-related diseases. Recently, several genome-wide association studies (GWAS), conducted exclusively among women of European ancestry, have discovered dozens of genetic loci influencing ANM. No study has been conducted to evaluate whether these findings can be generalized to Chinese women.
We evaluated the index single nucleotide polymorphisms (SNPs) in 19 GWAS-identified genetic susceptibility loci for ANM among 3,533 Chinese women who had natural menopause. We also investigated 3 additional SNPs which were in LD with the index SNP in European-ancestry but not in Asian-ancestry populations. Two genetic risk scores (GRS) were calculated to summarize SNPs across multiple loci one for all SNPs tested (GRSall), and one for SNPs which showed association in our study (GRSsel). All 22 SNPs showed the same association direction as previously reported. Eight SNPs were nominally statistically significant with P≤0.05: rs4246511 (RHBDL2), rs12461110 (NLRP11), rs2307449 (POLG), rs12611091 (BRSK1), rs1172822 (BRSK1), rs365132 (UIMC1), rs2720044 (ASH2L), and rs7246479 (TMEM150B). Especially, SNPs rs4246511, rs365132, rs1172822, and rs7246479 remained significant even after Bonferroni correction. Significant associations were observed for GRS. Women in the highest quartile began menopause 0.7 years (P = 3.24×10(-9)) and 0.9 years (P = 4.61×10(-11)) later than those in the lowest quartile for GRSsel and GRSall, respectively.
Among the 22 investigated SNPs, eight showed associations with ANM (P<0.05) in our Chinese population. Results from this study extend some recent GWAS findings to the Asian-ancestry population and may guide future efforts to identify genetic determination of menopause.
[Show abstract][Hide abstract] ABSTRACT: Background
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.Methods
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.ResultsOf the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10(-4)) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10(-22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10(-24)).Conclusions
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
Full-text · Article · Feb 2013 · Journal of the National Cancer Institute
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION: Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? SUMMARY ANSWER: Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. PARTICIPANTS AND SETTING: We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. MAIN RESULTS: For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10(-6), binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. STUDY FUNDING/COMPETING INTERESTS: This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: As breast and ovarian cancers may have similar etiologies, this study aimed to evaluate the hypothesis that breast cancer shares common genetic susceptibility variants with ovarian cancer. METHODS: Ten genetic variants in 9 loci were previously identified to be associated with ovarian cancer risk among Caucasian women; an additional 353 variants in high linkage disequilibrium (r2≥0.6) among Han Chinese were identified. Data were available from the Affymetrix Genome Wide Array (6.0) or MACH imputation for 25 and 78 common genetic variants (minor allele frequency (MAF) ≥0.05), respectively. Associations with breast cancer risk were evaluated by additive logistic regression models among 2,918 breast cancer cases and 2,324 controls. RESULTS: No associations with breast cancer risk were evident for 103 ovarian cancer susceptibility variants in five loci. Four loci were not evaluated, as they included only rare variants (MAF<0.05). CONCLUSIONS: Ovarian cancer susceptibility variants identified in Caucasian women were not associated with breast cancer risk among 5,242 Chinese women. Impact: These findings suggest that breast and ovarian cancer may not share common susceptibility variants among Chinese women.
No preview · Article · Jan 2013 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS: To investigate this hypothesis, a two-stage study was carried out to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage 2, which consisted of ten additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS: Five of the 21 SNPs had significant allelic odds ratios and 95% confidence intervals as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
No preview · Article · Dec 2012 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) was 1.08 (95% CI: 1.06-1.09) for GRS1 and 1.15 (95% CI: 1.13-1.18) for GRS2. The OR for quintiles were 1.00, 1.26, 1.69, 1.95 and 2.18 (P<0.0001) for GRS1 and 1.00, 1.33, 1.60, 2.03 and 2.80 (P<0.001) for GRS2. Participants in the higher tertile of GRS1 and the higher BMI category had a higher risk of T2D compared to those on the lower tertiles of the GRS1 and of BMI (OR = 11.08; 95% CI: 7.39-16.62). We found similar results when we investigated joint effects between GRS1 and WHR terciles and exercise participation. We finally investigated the joint effect between tertiles of GRSs and a composite high risk score (no exercise participation and high BMI and WHR) on T2D risk. We found that compared to participants with low GRS1 and no high risk factors for T2D, those with high GRS1 and three high risk factors had a higher risk of T2D (OR = 13.06; 95% CI: 8.65-19.72) but the interaction factor was of marginal significance. The association was accentuated when we repeated analysis with the GRS2. In conclusion we found an association between GRS and lifestyle factors, alone and in combination, contributed to the risk of and T2D among middle age Chinese.