Cancer Susceptibility In Women Research Articles

Impact of WNT1-inducible signaling pathway protein-1 (WISP-1) genetic polymorphisms and clinical aspects of breast cancer.

Breast cancer is the most common diagnosed malignancy in women. This study genotyped blood samples from 236 Han Chinese women with breast cancer and 128 healthy controls for single nucleotide polymorphisms (SNPs) rs2977537, rs2929970, rs2929973, rs2977530, and rs62514004, to determine whether these WNT1-inducible signaling pathway protein 1 (WISP-1) genetic polymorphisms increase the risk of developing breast cancer. Compared with wild-type (AA) carriers, those carrying the WISP1 rs62514004 AG or AG + GG genetic variants had a greater risk of developing breast cancer. In an evaluation of the association between clinicopathological aspects and the WISP1 SNP rs62514004 in the breast cancer cohort, patients with the GG genotype were less likely than those with the AA genotype to develop stage III/IV disease. Patients carrying the WISP1 rs2929973 GG + TT variant were almost twice as likely as those carrying the GT genotype to have estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors, while those with the WISP1 rs62514004 AG + GG genetic variants were around twice as likely as those with the AA genotype to have HER2-positive tumors. This study details risk associations between WISP1 SNPs and breast cancer susceptibility in women of Han Chinese ethnicity.

Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Striking life events associated with primary breast cancer susceptibility in women: a meta-analysis study

PurposeThe association between striking life events, an important stress and acute anxiety disorder, and the occurrence of primary breast cancer is unclear. The current meta-analysis was designed to assess the relationship between striking life events and primary breast cancer incidence in women.MethodsSystematic computerized searching of the PubMed, ScienceDirect, Embase, and BMJ databases with the combinations of controlled descriptors from Mesh, including breast cancer, breast tumor, cancer of breast, mammary carcinoma, life events, life change events, case–control studies, case-base studies, cohort study, and cohort analysis and identified a total of 307 papers published from January 1995 to April 2012. Following evaluation of methodological quality with the Downs & Black criteria, seven case–control or cohort studies were selected and the association between striking life events and primary breast cancer incidence in women was measured using random effect or fixed-effect odds ratios combined with 95% confidence interval.ResultsThe seven studies included in the final meta-analysis included 99,807 women. A meta-analysis showed that the pooled OR for striking life events and breast cancer was 1.51 (95% CI 1.15 - 1.97, P = 0.003), indicating that women with striking life events were at 1.5-fold greater risk of developing breast cancer. The pooled OR for severe striking life events and breast cancer was 2.07 (95% CI 1.06 - 4.03), indicating that women with severe striking life events were at 2-fold greater risk of developing breast cancer.ConclusionsThe current meta-analysis showed significant evidence for a positive association between striking life events and primary breast cancer incidence in women.

No Association of Matrix Metalloproteinase [MMP]-2 (−735C > T) and Tissue Inhibitor of Metalloproteinase [TIMP]-2 (−418G > C) Gene Polymorphisms with Cervical Cancer Susceptibility

Matrix metalloproteinase [MMP]-2 and tissue inhibitor of metalloproteinase [TIMP]-2 are emerging as pivotal players in inflammation and carcinogenesis. The present study aimed to evaluate the role of MMP-2 (-735C>T) [rs 2285053] and TIMP-2 (-418G>C) [rs 8179090] gene polymorphisms in cervical cancer susceptibility in Indian women. We recruited 200 cervical cancer patients from North India and 200 unrelated, age-matched, cancer-free healthy female controls of similar ethnicity. Genomic DNA extraction from peripheral blood samples, collected from the study subjects, was carried out using salting-out method. MMP-2 and TIMP-2 genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism. Our findings demonstrated no significant association between MMP-2 (-735C>T) and TIMP-2 (-418G>C) gene polymorphisms and the risk of developing cervical cancer in the study population. Further stratified analysis using a case-only study approach revealed that there was no effect of MMP-2/TIMP-2 polymorphisms on early and advanced stages of cervical cancer. Further MMP-2 and TIMP-2 polymorphisms did not modulate the risk in cervical cancer patients who smoked tobacco/cigarettes. Overall, the present study demonstrated a lack of association between MMP-2 and TIMP-2 gene polymorphisms and cervical cancer susceptibility in women of Northern India.

Abstract 2606: Absence of association between common genetic polymorphisms in the TERT-CLPTM1L locus and breast cancer risk in women of African descent

Abstract Recent genome wide association studies (GWAS) provided evidence that common low-penetrance single nucleotide polymorphisms (SNPs) contribute to breast cancer development. Common SNPs in the TERT (telomerase reverse transcriptase)-CLPTM1L (cleft lip and palate transmembrane 1 like) locus have been reported to be associated with several types of cancer, such as lung cancer/adenocarcinoma, glioma, bladder cancer, prostate cancer, and pancreatic cancer. Researchers also hypothesized that common SNPs in the TERT gene could play a role in breast cancer susceptibility. However, findings are inconsistent, and most studies included Caucasians only. In the present study, we sought to investigate whether common genetic variants in the TERT-CLPTM1L locus could contribute to breast cancer susceptibility in women of African ancestry. A total 2,892 women of African ancestry were participated in the present study, consisting of 1,509 breast cancer cases and 1,383 controls collected from Nigeria, Barbados, and the United States. Eleven SNPs in the TERT-CLPTM1L locus that were previously shown to be associated with cancers were selected and genotyped using the Illumina GoldenGate Genotyping platform, together with 30 ancestry informative markers (AIMs). Test for HWE suggested that the genotypes for all the SNPs were in Hardy-Weinberg proportions and there was no deviation from HWE. We performed unconditional multiple logistic regression to estimate the association between the TERT-CLPTM1L genetic variants and breast cancer risk, adjusting for age, study site, and estimated genetic ancestry. Overall we did not observe any P value < 0.05 after permutation in the analyses of allelic and genotypic models. We also conducted haplotype analysis for a five-SNP LD block, rs4975616-rs3816659-rs402710-rs401681-rs31489 but again failed to obtain significant association in the present study. Our findings do not support an effect of the tested genetic variants in the TERT-CLPTM1L locus on breast cancer susceptibility in women of African ancestry. However, it is worth noting that our current study did not apply a fine-mapping strategy; other genetic variants in LD with previously reported cancer susceptibility polymorphisms might be bona fide causal variants contributing to the risk of breast cancer. Larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2606. doi:1538-7445.AM2012-2606

Enhanced Mammary Progesterone Receptor-A Isoform Activity in the Promotion of Mammary Tumor Progression by Dietary Soy in Rats

Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-methyl-N-nitrosourea, dietary intake of soy protein isolate (SPI) reduced mammary tumor occurrence but increased incidence of more invasive tumors in tumored rats, relative to the control diet casein. Here we evaluated whether mammary tumor progression in tumor-bearing rats lifetime exposed to SPI is associated with deregulated progesterone receptor (PR) isoform expression. In histologically normal mammary glands of rats with invasive ductal carcinoma lesions, PR-A protein levels were higher for SPI- than casein-fed rats, whereas PR-B was undetectable for both groups. Increased mammary PR-A expression was associated with higher transforming growth factor-β1, stanniocalcin-1, and CD44 transcript levels; lower E-cadherin and estrogen receptor-α expression; and reduced apoptotic status in ductal epithelium. Serum progesterone (ng/ml) (CAS: 25.94 ± 3.81; SPI: 13.19 ± 2.32) and estradiol (pg/ml) (CAS: 27.9 ± 4.49; SPI: 68.48 ± 23.87) levels differed with diet. However, sera from rats of both diet groups displayed comparable mammosphere-forming efficiency in human MCF-7 cells. Thus, soy-rich diets may influence the development of more aggressive tumors by enhancing PR-A-dependent signaling in premalignant breast tissues.

Estrogen Receptor α Gene Polymorphism and Breast Cancer

Estrogen and estrogen receptors play important roles in the proliferation and development of breast cancer. Several genetic alterations identified in the estrogen receptor alpha gene (ESR1) are thought to influence the expression or function of this protein, and many have been evaluated for their role in breast cancer predisposition. The aim of this study was to evaluate the role of the C325G single nucleotide polymorphism (SNP) in the ESR1 in predisposition to breast cancer. The candidate SNP C325G in ESR1, exon 4 was genotyped in breast cancer patients and in healthy controls that were age and sex matched. Genotyping was performed using both single-stranded conformational polymorphism (SSCP) and a higher throughput allelic discrimination method using real-time PCR. Data on clinical features and demographic details were collected. Significant association of breast cancer risk was shown in the subgroup of women 50 years and younger who had the C allele (OR: 2.28, 95% CI: 1.10-4.72) (P= 0.03). However, the overall susceptibility to breast cancer was not significant, although all estimates were in the direction of a higher risk in women with CC genotypes. This study found significant evidence that polymorphism within the low penetrance ESR1 is associated with breast cancer susceptibility in women of 50 years or younger. There is also an indication that G allele is protective (compared to C allele).

Is telomere length in peripheral blood lymphocytes correlated with cancer susceptibility or radiosensitivity?

Mean terminal restriction fragment (TRF) lengths in white blood cells (WBCs) have been previously found to be associated with breast cancer. To assess whether this marker could be used as a test for breast cancer susceptibility in women, TRF length was measured in 72 treated female breast cancer patients and 1696 unaffected female controls between the ages of 45 and 77 from the Twin Research Unit at St Thomas' Hospital, as well as 140 newly diagnosed breast cancer cases and 108 mammographically screened unaffected controls from Guy's Hospital. Mean TRF was also tested for correlation with chromosome radiosensitivity and apoptotic response in the Guy's Hospital patients. After adjusting for age, smoking and body mass index, there was no significant difference in TRF lengths between the treated breast cancer patients and unaffected controls (P=0.71). A positive correlation between age-adjusted apoptotic response and mean TRF in newly diagnosed untreated breast cancer patients (P=0.008) was identified but no significant difference in TRF lengths between breast cancer patients and unaffected controls was detected (P=0.53). This suggests that TRF lengths in WBC, is not a marker of breast cancer susceptibility and does not vary significantly between affected women before and after treatment.

Psychological Impact of Genetic Testing for Breast Cancer Susceptibility in Women of Ashkenazi Jewish Background: A Prospective Study

The recognition that the prevalence of three founder mutations in the BRCA1 and BRCA2 genes is over 2% in Ashkenazi Jews has resulted in numerous epidemiological research studies of this ethno-religious group. To determine the effects of incorporating research into clinical practice, a psychological impact study of women participating in an epidemiological study was conducted. Sixty women of Ashkenazi Jewish background who underwent genetic testing for founder mutations were assessed using mailed, self-administered questionnaires with validated measures of psychological outcome. Forty-three women elected to learn their results and 17 women declined to do so. Women who elected to learn their results were also assessed 7-10 days, 4 months, and 12 months after results disclosure. Women who chose to learn their results had significantly higher baseline breast cancer anxiety, compared to those who elected not to learn their results (z = -2.27; p = 0.023). Unaffected women who elected to learn their results showed a significant decrease in breast cancer anxiety 4 months (z = -2.37, p = 0.018) and 12 months (z = -3.06, p = 0.002) post-notification compared to baseline. Genetic testing for mutations common in Ashkenazi Jewish women with result disclosure does not lead to adverse psychological outcomes.

Host Genetic Polymorphism Analysis in Cervical Cancer

The natural history of cervical cancer comprises a latency period that probably involves long-term immunologic tolerance of human papillomavirus infection. Identifying host determinants of viral persistence may help to better understand the mechanisms of tolerance and may lead to the development of tests that can allow more focused follow-up of high-risk individuals. Genotypic frequencies of 12 polymorphic loci in four candidate genes from 127 cervical cancer patients were compared with a control group of 108 female blood donors. Genotypes were determined by PCR amplification and direct sequencing of isolated genomic DNA. The tumor necrosis factor-alpha (TNFalpha) -238 polymorphism was significantly underrepresented in cervical cancer patients [heterozygotes (HETs), odds ratio (OR) = 0.33; 95% confidence interval (CI), 0.11-0.96], as was the TNFalpha -376 polymorphism (P = 0.02; 0% for any variant genotype in cases vs 4.7% in controls). The NRAMP1 3' untranslated region STP+86 polymorphism also appeared to be inversely associated with cervical cancer, but this result did not reach statistical significance (HET, OR = 0.57; 95% CI, 0.32-1.02). The p53 codon 72 arginine allele showed a suggestive negative association with cervical cancer (HET, OR = 0.49; 95% CI, 0.14-1.63; homozygotes, OR = 0.35; 95% CI, 0.11-1.17). The remaining alleles tested showed no association with cervical cancer. We identified host genetic polymorphisms that may be associated with cervical cancer risk, some of which have been linked to potential functional effects on cellular immune responses or antigen processing. We failed to confirm earlier reports of increased cervical cancer susceptibility in women who harbor the p53 P72R allele. Although our findings support the general hypothesis that host immunogenetic determinants other than class II MHC may be important in the development of cervical cancer, further analysis of the HLA gene cluster comprising the implicated TNFalpha single-nucleotide polymorphisms will be required to determine whether their association is linkage independent.

Ethnic differences in knowledge and attitudes about BRCA1 testing in women at increased risk

Informed consent for BRCA1 mutation testing will require adequate knowledge of patterns of inheritance of cancer and the benefits, limitations, and risks of DNA testing. This study examined knowledge about the inheritance of breast cancer and attitudes about genetic testing for breast–ovarian cancer susceptibility in women at increased risk. Knowledge and attitudes were measured in 407 African American and Caucasian women aged 18–75 who had at least one first-degree relative (FDR) with breast and/or ovarian cancer. The average knowledge score was 6.0 out of a total of 11 (S.D.=2.15). Compared to Caucasian women, African American women had lower levels of knowledge and had more positive attitudes about the benefits of genetic testing. There were no significant ethnic differences in attitudes about the limitations and risks of testing, however, income was negatively associated with this outcome. Ethnic differences in knowledge and attitudes about genetic testing for breast–ovarian cancer risk may be attributable to differences in exposure to genetic information and referral by health care providers.