Triple negative breast carcinoma is a prognostic factor in Taiwanese women

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Gene expression analyses in breast cancer epidemiology: the Norwegian Women and Cancer postgenome cohort study

Introduction The introduction of high-throughput technologies, also called -omics technologies, into epidemiology has raised the need for high-quality observational studies to reduce several sources of error and bias. Methods The Norwegian Women and Cancer (NOWAC) postgenome cohort study consists of approximately 50,000 women born between 1943 and 1957 who gave blood samples between 2003 and 2006 and filled out a two-page questionnaire. Blood was collected in such a way that RNA is preserved and can be used for gene expression analyses. The women are part of the NOWAC study consisting of 172,471 women 30 to 70 years of age at recruitment from 1991 to 2006 who answered one to three questionnaires on diet, medication use, and lifestyle. In collaboration with the Norwegian Breast Cancer Group, every NOWAC participant born between 1943 and 1957 who is admitted to a collaborating hospital for a diagnostic biopsy or for surgery of breast cancer will be asked to donate a tumor biopsy and two blood samples. In parallel, at least three controls are approached for each breast cancer case in order to obtain blood samples from at least two controls per case. The controls are drawn at random from NOWAC matched by time of follow-up and age. In addition, 400 normal breast tissues as well as blood samples will be collected among healthy women participating at the Norwegian Mammography Screening program at the Breast Imaging Center at the University Hospital of North-Norway, Tromsø. Results The NOWAC postgenome cohort offers a unique opportunity (a) to study blood-derived gene expression profiles as a diagnostic test for breast cancer in a nested case-control design with adjustment for confounding factors related to different exposures, (b) to improve the reliability and accuracy of this approach by adjusting for an individual's genotype (for example, variants in genes coding for hormone and drug-metabolizing and detoxifying enzymes), (c) to study gene expression profiles from peripheral blood as surrogate tissue to biomonitor defined exposure (for example, hormone) and its association with disease risk (that is, breast cancer), and (d) to study gene variants (single nucleotide polymorphisms and copy number variations) and environmental exposure (endogenous and exogenous hormones) and their influence on the incidence of different molecular subtypes of breast cancer. Conclusion The NOWAC postgenome cohort combining a valid epidemiological approach with richness of biological samples should make an important contribution to the study of the etiology and system biology of breast cancer

BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers

BACKGROUND: Epithelial ovarian cancer is one of the most lethal malignancies, and has a high recurrence rate. Thus, prognostic markers for recurrence are crucial for the care of ovarian cancer. As ovarian cancers frequently exhibit chromosome instability, we aimed at assessing the prognostic significance of two key mitotic kinases, BubR1 and Aurora A. METHODS: We analysed paraffin-embedded tissue sections from 160 ovarian cancer patients whose clinical outcomes had been tracked after first-line treatment. RESULTS: The median recurrence-free survival in patients with a positive and negative expression of BubR1 was 27 and 83 months, respectively (Po0.001). A positive BubR1 expression was also associated with advanced stage, serous histology and high grade. In contrast, Aurora A immunostaining did not correlate with any of the clinical parameters analysed. CONCLUSION: BubR1, but not Aurora A, is a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.Research in the H Lee laboratory is funded by the National Research Laboratory Program from the Korean ministry of Education and Science (ROA-2008-000-20023-0). This work was also supported by the Seoul National University Hospital Grant (0420080450), the 21C Frontier Functional Genome Project (FG06- 2-14) of the Korean ministry of Education and Science, Korea Research Foundation (KRF-2005-C00097), and the National R&D Program for Cancer Control (0620070) from the Korean ministry of Health welfare and Family Affairs. Imaging facilities in the H Lee laboratory are funded by RCFC (R11-2005-009-04003-0) of the SRC program from KOSEF

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

Processed pseudogenes acquired somatically during cancer development

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context