Deletion of Chromosomes 13q and 14q Is a Common Feature of Tumors with BRCA2 Mutations

Introduction

Germline BRCA1 or BRCA2 mutations account for 20–30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low.

Methods

To develop more efficient approaches to screening we have compared the gene expression and genomic profiles of BRCA2-mutant breast tumors with those of breast tumors lacking BRCA1 or BRCA2 mutations.

Results

We identified a group of 66 genes showing differential expression in our training set of 7 BRCA2-mutant tumors and in an independent validation set of 19 BRCA2-mutant tumors. The differentially expressed genes include a prominent cluster of genes from chromosomes 13 and 14 whose expression is reduced. Gene set enrichment analysis confirmed that genes in specific bands on 13q and 14q showed significantly reduced expression, suggesting that the affected bands may be preferentially deleted in BRCA2-mutant tumors. Genomic profiling showed that the BRCA2-mutant tumors indeed harbor deletions on chromosomes 13q and 14q. To exploit this information we have created a simple fluorescence in situ hybridization (FISH) test and shown that it detects tumors with deletions on chromosomes 13q and 14q.

Conclusion

Together with previous reports, this establishes that deletions on chromosomes 13q and 14q are a hallmark of BRCA2-mutant tumors. We propose that FISH to detect these deletions would be an efficient and cost-effective first screening step to identify potential BRCA2-mutation carriers among breast cancer patients without a family history of breast cancer.     

Synthesis and evaluation of cholecystokinin trimers: A multivalent approach to pancreatic cancer detection and treatment

In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling the potential for early detection. There is a lack of tools for early detection of pancreatic cancer, one of the deadliest forms of cancer, but CCK2-R overexpression on pancreatic cancer cells makes CCK based multimers potential markers for these cells. In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R.     

The role of the Spemann organizer in anterior-posterior patterning of the trunk

The formation of the vertebrate body axis during gastrulation strongly depends on a dorsal signaling centre, the Spemann organizer as it is called in amphibians. This organizer affects embryonic development by self-differentiation, regulation of morphogenesis and secretion of inducing signals. Whereas many molecular signals and mechanisms of the organizer have been clarified, its function in anterior-posterior pattern formation remains unclear. We dissected the organizer functions by generally blocking organizer formation and then restoring a single function. In experiments using a dominant inhibitory BMP receptor construct (tBr) we find evidence that neural activation by antagonism of the BMP pathway is the organizer function that enables the establishment of a detailed anterior-posterior pattern along the trunk. Conversely, the exclusive inhibition of neural activation by expressing a constitutive active BMP receptor (hAlk-6) in the ectoderm prohibits the establishment of an anterior-posterior pattern, even though the organizer itself is still intact. Thus, apart from the formerly described separation into a head and a trunk/tail organizer, the organizer does not deliver positional information for anterior-posterior patterning. Rather, by inducing neurectoderm, it makes ectodermal cells competent to receive patterning signals from the non-organizer mesoderm and thereby enable the formation of a complete and stable AP pattern along the trunk.     

Structure of protein phosphatase methyltransferase 1 (PPM1), a leucine carboxyl methyltransferase involved in the regulation of protein phosphatase 2A activity

The important role of the serine/threonine protein phosphatase 2A (PP2A) in various cellular processes requires a precise and dynamic regulation of PP2A activity, localization, and substrate specificity. The regulation of the function of PP2A involves the reversible methylation of the COOH group of the C-terminal leucine of the catalytic subunit, which, in turn, controls the enzyme's heteromultimeric composition and confers different protein recognition and substrate specificity. We have determined the structure of PPM1, the yeast methyltransferase responsible for methylation of PP2A. The structure of PPM1 reveals a common S-adenosyl-l-methionine-dependent methyltransferase fold, with several insertions conferring the specific function and substrate recognition. The complexes with the S-adenosyl-l-methionine methyl donor and the S-adenosyl-l-homocysteine product and inhibitor unambiguously revealed the co-substrate binding site and provided a convincing hypothesis for the PP2A C-terminal peptide binding site. The structure of PPM1 in a second crystal form provides clues to the dynamic nature of the PPM1/PP2A interaction.     

Genome analysis at different ploidy levels allows cloning of the powdery mildew resistance gene Pm3b from hexaploid wheat

In wheat, race-specific resistance to the fungal pathogen powdery mildew (Blumeria graminis f. sp. tritici) is controlled by the Pm genes. There are 10 alleles conferring resistance at the Pm3 locus (Pm3a to Pm3j) on chromosome 1AS of hexaploid bread wheat (Triticum aestivum L.). The genome of hexaploid wheat has a size of 1.6 x 1010 bp and contains more than 80% of repetitive sequences, making positional cloning difficult. Here, we demonstrate that the combined analysis of genomes from wheat species with different ploidy levels can be exploited for positional cloning in bread wheat. We have mapped the Pm3b gene in hexaploid wheat to a genetic interval of 0.97 centimorgan (cM). The diploid T. monococcum and the tetraploid T. turgidum ssp. durum provided models for the A genome of hexaploid wheat and allowed to establish a physical contig spanning the Pm3 locus. Although the haplotypes at the Pm3 locus differed markedly between the three species, a large resistance gene-like family specific to wheat group 1 chromosomes was consistently found at the Pm3 locus. A candidate gene for Pm3b was identified using partial sequence conservation between resistant line Chul and T. monococcum cv. DV92. A susceptible Pm3b mutant, carrying a single-base pair deletion in the coding region of the candidate gene was isolated. When tested in a single cell transformation assay, the Pm3b candidate gene conferred race-specific resistance to powdery mildew. These results demonstrate that the candidate gene, a member of the coiled-coil nucleotide binding site leucine-rich repeat (NBS-LRR) type of disease resistance genes, is the Pm3b gene.     

Impact of different levels of cinnamyl alcohol dehydrogenase down-regulation on lignins of transgenic tobacco plants

The effects of cinnamyl alcohol dehydrogenase (CAD, EC.1.1.1.195) down-regulation on lignin profiles of plants were analysed in four selected transgenic lines of tobacco (Nicotiana tabacum L. cv. Samsun) exhibiting different levels of CAD activity (8–56% of the control). A significant decrease in thioacidolysis yields (i.e. yield of β-O-4 linked monomers) and in the ratio of syringyl to guaiacyl monomers (S/G) was observed for three transgenic lines and the most drastic reduction (up to 50%) was correlated with the lowest level of CAD activity. Higher lignin extractability by mild alkali treatment was confirmed, and, in addition to a tenfold increase in C₆-C₁ aldehydes, coniferyl aldehyde was detected by high-performance liquid chromatography in the alkali extracts from the xylem of transgenic plants. In-situ polymerisation of cinnamyl aldehydes in stem sections of untransformed tobacco gave a xylem cell wall coloration strikingly similar to the reddish-brown coloration of the xylem of antisense CAD-down-regulated plants. Overall, these data provide new arguments for the involvement of polymerised cinnamyl aldehydes in the formation of the red-coloured xylem of CAD-down-regulated plants. Received: 24 January 1997 / Accepted: 14 May 1997     

The Silk Road Health Project: How Mobility and Migration Status Influence HIV Risks among Male Migrant Workers in Central Asia

Objectives

We examined whether mobility, migrant status, and risk environments are associated with sexually transmitted infections (STIs) and HIV risk behaviors (e.g. sex trading, multiple partners, and unprotected sex).

Methods

We used Respondent Driven Sampling (RDS) to recruit external male migrant market vendors from Kyrgyzstan, Uzbekistan, and Tajikistan as well internal migrant and non-migrant market vendors from Kazakhstan. We conducted multivariate logistic regressions to examine the effects of mobility combined with the interaction between mobility and migration status on STIs and sexual risk behaviors, when controlling for risk environment characteristics.

Results

Mobility was associated with increased risk for biologically-confirmed STIs, sex trading, and unprotected sex among non-migrants, but not among internal or external migrants. Condom use rates were low among all three groups, particularly external migrants. Risk environment factors of low-income status, debt, homelessness, and limited access to medical care were associated with unprotected sex among external migrants.

Conclusion

Study findings underscore the role mobility and risk environments play in shaping HIV/STI risks. They highlight the need to consider mobility in the context of migration status and other risk environment factors in developing effective prevention strategies for this population.