Shou-Tung Chen

Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility.

Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case‐control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol‐O‐methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP‐glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species‐mediated oxidation during the conversion of CE‐semiquinone (CE‐SQ) to CE‐quinone (CE‐Q), and 2 of the glutathione S‐transferase superfamily, GSTM1 and GSTT1, involved in CE‐Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high‐risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (≥26 years) at first full‐term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high‐risk genotypes were not the same in women having experienced different menarche‐to‐FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (≥12 years) before FFTP. Furthermore, because CE‐Q can attack DNA, leading to the formation of double‐strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE‐metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE‐metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.

Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene Aurora-A/STK15/BTAK

Aneuploidy, an abnormal number of chromosomes, is relatively common and occurs early in breast cancer development. This observation supports a breast tumorigenic contribution of mechanisms responsible for maintaining chromosome number stability in which centrosomes play an essential role. We therefore speculated that the Aurora‐A/STK15/BTAK gene, implicated in the regulation of centrosome duplication, may be associated with breast tumorigenesis. To test this hypothesis, we conducted a case‐control study of 709 primary breast cancer patients and 1,972 healthy controls, examining single‐nucleotide polymorphisms (SNPs), including a suggested functional Phe31Ile SNP, in Aurora‐A. We were also interested in knowing whether any association between Aurora‐A and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that, since estrogen is known to promote breast cancer development via its mitogenic effect leading to malignant proliferation on breast epithelium and since Aurora‐A is involved in regulating mitosis, the discovery of a joint effect between the Aurora‐A genotype and reproductive risk factors on cancer risk might yield valuable clues to the association of breast tumorigenesis with estrogen. Support for this hypothesis came from the following observations. (i) Two SNPs in Aurora‐A were significantly associated with breast cancer risk (p < 0.05). (ii) Haplotype analyses, based on different combinations of multiple SNPs in Aurora‐A, revealed a strong association with breast cancer risk; interestingly, the genotypic distribution of the suggested functional Phe31Ile SNP was not significantly different between breast cancer patients and controls, but the specific haplotype containing the putative at‐risk Ile allele was more common in patients. (iii) This association between risk and putative high‐risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with a longer interval between menarche and first full‐term pregnancy. (iv) The protective effect conferred by a history of full‐term pregnancy was significant only in women with a putative low‐risk genotype of Aurora‐A. Our study provides new findings supporting the mutator role of Aurora‐A in breast cancer development, suggesting that breast cancer could be driven by genomic instability associated with variant Aurora‐A, the tumorigenic contribution of which could be enhanced as a result of increased mitosis due to estrogen exposure.

Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility

The role of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, in the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair suggests that the mechanisms involved in HR and DNA DSB repair are of etiological importance during breast tumorigenesis. Bloom (BLM) helicase directly interacts with RAD51 recombinase, which is involved in regulating HR, and it is thus of particular interest to examine whether this interaction is associated with breast cancer susceptibility. This single-nucleotide polymorphism (SNP)-based case-control study was performed to examine this hypothesis using specimens from 933 patients with breast cancer and 1539 healthy controls. The results showed that one SNP (rs2380165) in BLM and two (rs2412546 and rs4417527) in RAD51 were associated with breast cancer risk. Furthermore, haplotype and diplotype analyses based on combinations of five SNPs in RAD51 revealed a strong association between RAD51 polymorphisms and breast cancer risk (P < 0.05). Support for the interaction between BLM and RAD51 in determining breast cancer risk came from the finding that the association between cancer risk and at-risk genotypes/haplotype pairs of RAD51 was stronger and more significant in women harboring homozygous variant alleles of BLM (P for interaction < 0.05). Interestingly, not only the intronic SNP located within the region encoding the helicase domain of BLM but also those within the RAD51-interaction domain-encoding region showed an interaction with RAD51 polymorphisms in determining breast cancer susceptibility. Our results suggest a contribution of BLM and RAD51 to breast cancer development and provide support for the tumorigenic significance of the functional interaction between these two HR proteins.

Synergistic Effects of Polymorphisms in DNA Repair Genes and Endogenous Estrogen Exposure on Female Breast Cancer Risk

BackgroundEndogenous estrogen is suggested to initiate cell proliferation and cause oxidative DNA damage during breast tumorigenesis. Cells eliminate DNA damage by means of repair enzymes. Genotypic variants of DNA damage repair genes, participating in base excision repair (BER) and nucleotide excision repair (NER) pathways, may act as modifiers that affect the association between estrogen exposure and breast cancer.MethodsIn a hospital-based case–control study of female breast cancer, DNA samples were obtained from 401 cases and 533 enrolled healthy controls, all of whom were Chinese women in Taiwan. Genotyping of polymorphisms of XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys and Arg229Gln), ERCC2 Lys751Gln, ERCC4 Ser662Pro, and ERCC5His1104Asp was performed and used to evaluate breast cancer susceptibility.ResultsOf the nonsynonymous polymorphisms, the ERCC5 1104Asp variant was significantly associated with breast cancer (odds ratioxa0=xa01.42; 95% confidence intervalxa0=xa01.08–1.97), and this association was more pronounced in women with lengthy estrogen exposure. A trend toward an increased risk of developing breast cancer was observed in women who carried greater numbers of combined high-risk genotypes of BER and NER genes (Ptrendxa0=xa0.038). The synergistic effect of multiple genes on the increase of risk was significant in women with a longer period of estrogen exposure (>26xa0years), greater age at first full-term pregnancy (>26xa0years), a longer menarche-to-first full-term pregnancy interval (>11xa0years), and higher body mass index (>22) (all Pxa0<xa0.05).ConclusionsThis study demonstrates that genotype polymorphisms related to DNA damage repair confer greater susceptibility to endogenous estrogen in the development of breast cancer in women.

Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes.

Tumor levels of the cell cycle regulators cyclin E and p27 correlate strongly with survival in breast cancer patients and are specifically regulated by the ubiquitin ligases hCDC4 and SKP2. This study was to explore whether genetic susceptibility to breast cancer is associated with polymorphism of these genes and whether gene-gene and gene-risk factor [i.e. full-term pregnancy (FTP)] interactions are important in determining cancer risk. A two-stage case-control study based on single-nucleotide polymorphisms was performed. The first study (560 cases and 1122 controls) was to define the contribution of cell cycle and ubiquitin ligase genes to cancer susceptibility. The second study (926 cases and 923 controls) was to confirm the association identified in the first stage and to map the variant alleles. Increased breast cancer risk was associated with both polymorphism of hCDC4 and a joint effect of cyclin E and hCDC4. These associations were more significant in nulliparous women, and cancer risk associated with a lower number of FTPs was only seen in women with a higher number of high-risk genotypes, providing support for an effect of gene-risk factor interaction in determining susceptibility. Sequence variants of intron 2 in hCDC4 were found to be the most significant polymorphism and high-stage estrogen receptor (ER)-negative patients carrying the homozygous variant genotype manifested significantly poorer survival. This study concludes that polymorphism of hCDC4 is a risk factor for breast cancer development by interacting with either cyclin E or FTP and may also prove useful in predicting progression of patients with high-stage and ER-negative breast cancers.

Genetic Variation in the Premature Aging Gene WRN: A Case-Control Study on Breast Cancer Susceptibility

The high risk of developing cancer seen in human genetic diseases that resemble accelerated aging provides support for a tumorigenic contribution of the mechanisms and genes responsible for regulating life span and aging. We therefore speculated that the WRN gene (encoding RECQL2, a DNA helicase), the germline mutation of which causes the progeroid disorder Werner syndrome, may be associated with breast tumorigenesis. This hypothesis was tested in this case-control study of 935 primary breast cancer patients and 1,545 healthy controls by examining single-nucleotide polymorphisms (SNPs) in WRN. We were also interested in knowing whether any identified association between WRN and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that because estrogen is known to promote breast cancer development via its mitogenic effect leading to cell proliferation, and because WRN is an essential gene, as its suboptimal function leads to a severe decrease in proliferation, estrogen stimulation may have a protective effect on cells harboring variant WRN, allowing them to survive and proliferate for the prolonged period needed for tumor formation. Support for this hypothesis came from the following observations: (a) one SNP in WRN was significantly associated with breast cancer risk (P = 0.002); (b) haplotype and diplotype analyses, based on different combinations of multiple SNPs in WRN, revealed a strong association with breast cancer risk; (c) this association between risk and putative high-risk genotypes was stronger and more significant in women with a longer interval between menarche and first full-term pregnancy; and (d) the protective effect conferred by having a higher number of full-term pregnancy was only significant in women with homozygous or heterozygous wild-type WRN genotypes. This study provides support for the tumorigenic role of WRN in breast cancer development, suggesting that breast cancer can be driven by the aging associated with variant WRN, the tumorigenic contribution of which might be enhanced as a result of increased cell growth due to estrogen exposure. (Cancer Epidemiol Biomarkers Prev 2007;16(2):263–9)

Genetic variation in the genome-wide predicted estrogen response element-related sequences is associated with breast cancer development

IntroductionEstrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the promoter region of estrogen-responsive genes, regulates their transcription, and consequently mediates physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect the estrogen-ER-ERE interaction. In this study, we examined the hypothesis that genetic variations of EREs are associated with breast cancer development.MethodsThis case-control study involved 815 patients of Asian descent with incident breast cancer and 821 healthy female controls. A total of 13,737 ERE sites in the whole genome predicted by a genome-wide computational algorithm were blasted with single-nucleotide polymorphism (SNP) sequences. Twenty-one SNPs located within 2,000 bp upstream or within introns 1 and 2 of putative genes and with a minor allele frequency greater than 5% were identified and genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility.ResultsA significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for ER, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of lifetime estrogen exposure, supporting a hormonal etiology of this SNP in breast tumorigenesis.ConclusionsOur findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development.

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

Purpose: To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer. Patients and Methods: A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1–8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression. Results: SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction <0.05). One of these intron 1 SNPs was also significantly associated with low ERα expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer–specific survival rate of patients, but had opposite effects in ERα-negative and ERα-positive early-stage patients. Conclusions: Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERα in these two populations. Clin Cancer Res; 16(13); 3473–84. ©2010 AACR.

Comparison of the Diagnostic Accuracy of Magnetic Resonance Imaging with Sonography in the Prediction of Breast Cancer Tumor Size: A Concordance Analysis with Histopathologically Determined Tumor Size

AbstractBackgroundIn order to effectively treat patients with breast cancer, it is important to know the precise tumor size. We compared the rates of concordance of magnetic resonance imaging (MRI)-derived and sonography-derived breast cancer tumor size with histopathologically determined tumor size.MethodsAccuracy of MRI and sonography in establishing tumor size was evaluated by comparing preoperative images with postoperative pathologic findings. The accuracy of MRI and sonography was graded as concordance, underestimation, or overestimation and was compared in different subgroups.ResultsnA total of 682 patients comprised the study cohort. Mean tumor size was 3.64xa0±xa01.8xa0cm via MRI, 2.12xa0±xa01.0xa0cm via sonography, and 2.78xa0±xa01.7xa0cm via pathologic examination. The difference between breast sonography and MRI to pathologic tumor field size was −0.68xa0±xa01.4, and 0.85xa0±xa01.25xa0cm, respectively (Pxa0<xa00.001). Sonography had a concordance rate of 54.3xa0%, an overestimated rate of 9.8xa0%, and an underestimated rate of 35.9xa0%. For MRI, the concordance rate was 44.1xa0%, the overestimated rate was 52.5xa0%, and the underestimated rate was 3.4xa0%. In subgroup analysis, breast MRI had a higher concordance rate in patients with T3 (>5xa0cm) lesions. When the results of MRI and sonography were considered together, the concordance rate increased from 54.3 to 62.2xa0%.ConclusionMRI tends to overestimate the actual tumor size, while sonography frequently underestimates it. Combined sonography and MRI increases the accuracy of tumor size prediction.

Preoperative clinicopathologic factors and breast magnetic resonance imaging features can predict ductal carcinoma in situ with invasive components.

PURPOSEnDuctal carcinoma in situ (DCIS) is a non-invasive cancerous breast lesion; however, from 10% to 50% of patients with DCIS diagnosed by core needle biopsy (CNB) or vacuum-assisted core biopsy (VACB) are shown to have invasive carcinoma after surgical excision. In this study, we evaluated whether preoperative clinicopathologic factors and breast magnetic resonance image (MRI) features are predictive of DCIS with invasive components before surgery.nnnMATERIALS AND METHODSnPatients comprised 128 adult women with a diagnosis of DCIS as determined by pathological analysis of CNB or VACB specimens and positive MRI findings who underwent breast surgery during the period January 2011 to December 2013 at the Changhua Christian Hospital. Clinicopathologic and breast MRI factors were compared between patients with postoperative pathology indicative of true DCIS and those with postoperative pathology showing DCIS with invasive components.nnnRESULTSnOf the 128 patients with a preoperative diagnosis of DCIS, 73 (57.0%) had postoperative histopathologic evidence of true DCIS and 55 (43.0%) showed evidence of DCIS with invasive components. Results of statistical analyses revealed that MRI evidence of a mass-like lesion (P=0.025), nipple-areolar complex (NAC) invasion (P=0.029), larger tumor volume (P=0.010), larger maximum measurable apparent diffusion coefficient (ADC) area (P=0.039), heterogenous or rim enhancement pattern (P=0.010), as well as immunohistochemical evidence of human epidermal growth factor receptor 2 (HER-2) overexpression (P=0.010) were predictive of DCIS with an invasive component in postoperative surgical specimens.nnnCONCLUSIONnInvasive component should be considered in biopsy proven DCIS patients with preoperative MRI evidence of a mass-like lesion, nipple-areolar complex invasion, large tumor volume, a larger maximum measurable ADC area, or a rim or heterogenous enhancement pattern, as well as in patients with immunohistochemical evidence of HER-2 overexpression.