The Effect of Pre-Diagnostic Alcohol Consumption on Survival after Breast Cancer in Young Women.

Background: Alcohol consumption has been comprehensively investigated as an etiologic risk factor for breast cancer but has received little attention in terms of its impact on prognosis after breast cancer, particularly for young women. Methods: 1286 women diagnosed with invasive breast cancer at or before 45 years of age from two population-based case-control studies in the Seattle-Puget Sound region were followed from their diagnosis of breast cancer (between January 1983 and December 1992) for survival through June 2002, during which time 364 women had died. Cox proportional hazards modeling was used to assess the effect of pre-diagnostic alcohol consumption on the risk of dying. Results: After adjusting for age and diagnosis year, compared to non-drinkers, women who consumed alcohol in the 5 years prior to diagnosis had a decreased risk of death [>0 to <3 drinks per week: HR(hazard ratio) = 0.7 (95% CI: 0.6-0.95); 3 to <7 drinks per week: RR = 0.6 (95% CI: 0.4-0.8); ≥ 7 drinks per week: RR = 0.7 (95% CI: 0.5-0.9)]. This association was unchanged upon additional adjustment for potential confounders including most notably treatment, stage at diagnosis, and mammogram history. Conclusion: These results suggest that women who consume alcohol prior to a diagnosis of breast cancer have improved survival which does not appear to be attributable to differences in stage, screening or treatment

Geophysical surveys of the East Kirkton Limestone, Visean, West Lothian, Scotland

ABSTRACT: Magnetic and resistivity geophysical surveys conducted across the only known exposure of the East Kirkton Limestone have produced new information upon its extent. This is important to determine because of its unique faunal assemblage and possible hot spring deposition, suggesting a potential for precious metal mineralisation. Magnetic anomalies are attributed to basalts within the Bathgate Hills Volcanic Formation. Modelling of the magnetic data demonstrates a general dip to the west of about 25°, and the presence of significant local faulting. Modelling of vertical electrical sounding data shows the East Kirkton sequence (the limestone and associated beds) to be a low resistivity layer within the more highly resistive volcanic sequence. The East Kirkton sequence is seen to deepen to the west, and also to the north probably by faulting. Therefore the present exposure is the only near surface occurrence of the East Kirkton Limestone locally, but within the area of the survey no lateral limits to the formation are observed. KEY WORDS: Geophysics, hot springs, magnetic surveys, mineralisation, resistivity surveys, Lower Carboniferous. The East Kirkton quarry at Bathgate Bedding planes seen at outcrop dip at 15-25° to the W. Various hypotheses exist regarding the extent of the East Kirkton Limestone beyond the quarry: (1) it continues N beneath a thin glacial cover as shown on the one-inch geological map (Scotland Sheet 31); (2) subcrop to the N is limited due to faulting at the N end of the known exposure (Stephenson &amp; Monro 1986); or (3) the sequence was deposited in an isolated lagoon forming only a small lens of sediment (Geikie 1861). Magnetic and resistivity surveys were undertaken to determine the structure and extent of the EKS in the vicinity of the quarry. Exploration was undertaken mostly W (down dip) and to the N. Housing development prevented work to the S. The results are of use in future prospecting of the East Kirkton Limestone for precious metal mineralisation Geophysical approach Our aim was to determine the subsurface structure of the EKS using the East Kirkton quarry as a reference point. Given the presence of basaltic lavas and clastic volcanics above and below the sedimentary sequence, it was anticipated that there would be a strong contrast of magnetic and electrical resistivity properties between the EKS and volcanics. Borehole information was made available by the National Museums of Scotland, permitting calibration of the geophysical results but only to rather limited depths (typically 10 m, maximum 33 m). Magnetometer survey The total magnetic field intensity was measured along 12 E-W traverses across the quarry and its projected continuation along strike to the N. The contoured results are plotted in Magnetic susceptibility measurements of bore hole samples Using these values, a model profile across the East Kirkton quarry was determined using the GRA VMAG computer program. The model was constructed along line Z, a dip line crossing the anomaly immediately W of the quarry The one-inch geological map shows the EKS to be underlain by basalts Resistivity survey Four electrical resistivity vertical soundings were conducted using expanding Wenner arrays (VES1-VES3 of At East Kirkton we attribute generally low, but highly variable, resistivities modelled at surface to soils and/or boulder clay. At depth the main resistivity contrast was expected to be between the highly resistive volcanics of the Bathgate Hills Volcanic Formation and the low resistivity of the mixed sedimentary EKS. Resistivities of much less than 100 ohm-m modelled at depth can be correlated with the EKS. High resistivities (480 ohm-m) above the EKS on VES1 and VES2 are correlated with the lower of two basalts of the magnetic model. High resistivities (typically over 400 ohm-m) beneath the EKS are consistent with the presence of volcanic rocks. The following points arise from the resistivity results: (1) Comparison of VES1 and VES2 confirms the significant westward deepening of the EKS shown by.the magnetic interpretation. (2) VES1, VES3 and VES4 are located broadly along strike from each other, but show the sub-EKS volcanics to deepen northwards. This was confirmed by the constant separation traverse. Thus the EKS may thicken. The resolution of the resistivity data does not permit us to distinguish between a northward deepening due to folding or faulting

Risk Factors for Triple-Negative Breast Cancer in Women Under Age 45

Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use >/=1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (Pheterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (Pheterogeneity = 0.02 and 0.01, respectively). Among women /=1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women </=40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology

Genomewide gene expression profiles of HPV-positive and HPV-negative oropharyngeal cancer: potential implications for treatment choices.

OBJECTIVE: To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral cavity and oropharyngeal squamous cell carcinoma (OSCC). DESIGN: We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. The HPV DNA was detected using polymerase chain reaction followed by the Roche LINEAR ARRAY HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software, version 5.0. SETTING: Three medical centers affiliated with the University of Washington. PATIENTS: A total of 119 patients with primary OSCC and 35 patients without cancer, all of whom were treated at the setting institutions, provided tissues samples for the study. RESULTS: Human papillomavirus DNA was found in 41 of 119 tumors (34.5%) and 2 of 35 normal tissue samples (5.7%); 39 of the 43 HPV specimens were HPV-16. A higher prevalence of HPV DNA was found in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed in HPV-positive oropharyngeal cancer than in HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycling. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (eg, TYMS, STMN1, CCND1, and RBBP4) are involved in chemotherapy or radiation sensitivity. CONCLUSION: These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors

Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival

<p>Abstract</p> <p>Background</p> <p>Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.</p> <p>Results</p> <p>We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with <it>p </it>= 0.044 or 0.011, respectively).</p> <p>Conclusions</p> <p>Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.</p

An extended set of PRDM1/BLIMP1 target genes links binding motif type to dynamic repression

The transcriptional repressor B lymphocyte-induced maturation protein-1 (BLIMP1) regulates gene expression and cell fate. The DNA motif bound by BLIMP1 in vitro overlaps with that of interferon regulatory factors (IRFs), which respond to inflammatory/immune signals. At such sites, BLIMP1 and IRFs can antagonistically regulate promoter activity. In vitro motif selection predicts that only a subset of BLIMP1 or IRF sites is subject to antagonistic regulation, but the extent to which antagonism occurs is unknown, since an unbiased assessment of BLIMP1 occupancy in vivo is lacking. To address this, we identified an extended set of promoters occupied by BLIMP1. Motif discovery and enrichment analysis demonstrate that multiple motif variants are required to capture BLIMP1 binding specificity. These are differentially associated with CpG content, leading to the observation that BLIMP1 DNA-binding is methylation sensitive. In occupied promoters, only a subset of BLIMP1 motifs overlap with IRF motifs. Conversely, a distinct subset of IRF motifs is not enriched amongst occupied promoters. Genes linked to occupied promoters containing overlapping BLIMP1/IRF motifs (e.g. AIM2, SP110, BTN3A3) are shown to constitute a dynamic target set which is preferentially activated by BLIMP1 knock-down. These data confirm and extend the competitive model of BLIMP1 and IRF interaction

Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

Plasma cells (PCs) as effectors of humoral immunity produce Igs to match pathogenic insult. Emerging data suggest more diverse roles exist for PCs as regulators of immune and inflammatory responses via secretion of factors other than Igs. The extent to which such responses are preprogrammed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. In this study, we dissect the impact of IFNs on the regulatory networks of human PCs. We show that core PC programs are unaffected, whereas PCs respond to IFNs with distinctive transcriptional responses. The IFN-stimulated gene 15 (ISG15) system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active systemic lupus erythematosus. Thus, ISG15-secreting PCs represent a distinct proinflammatory PC subset providing an Ig-independent mechanism of PC action in human autoimmunity

Serum Organochlorine Pesticide Residues and Risk of Testicular Germ Cell Carcinoma: A Population-Based Case-Control Study

Testicular germ cell carcinoma (TGCC) is the most common malignancy among men aged 20-34. Although the pathogenesis of TGCC is poorly understood, sub-optimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess anti-androgenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p’-DDE, and whether the p,p-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor (AR) gene. We conducted a population-based case-control study among 18-44 year-old male residents of three Washington State counties. Cases (n=246) were diagnosed during 1999-2003 with a first, primary TGCC. Controls (n=630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatography-high resolution mass spectrometry analysis of organochlorine pesticide residues, and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p’-DDE was modified by AR CAG (<23 vs.23+ repeats) or GGN (<17 vs.17+ repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy

Frequency of CHEK2 mutations in a population based, case–control study of breast cancer in young women

INTRODUCTION: The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America. METHODS: We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington. RESULTS: There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09). CONCLUSION: The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA