Lipoprotein lipase is frequently overexpressed or translocated in cervical squamous cell carcinoma and promotes invasiveness through the non-catalytic C terminus.

BACKGROUND: We studied the biological significance of genes involved in a novel t(8;12)(p21.3;p13.31) reciprocal translocation identified in cervical squamous cell carcinoma (SCC) cells. METHODS: The rearranged genes were identified by breakpoint mapping, long-range PCR and sequencing. We investigated gene expression in vivo using reverse-transcription PCR and tissue microarrays, and studied the phenotypic consequences of forced gene overexpression. RESULTS: The rearrangement involved lipoprotein lipase (LPL) and peroxisome biogenesis factor-5 (PEX5). Whereas LPL-PEX5 was expressed at low levels and contained a premature stop codon, PEX5-LPL was highly expressed and encoded a full-length chimeric protein (including the majority of the LPL coding region). Consistent with these findings, PEX5 was constitutively expressed in normal cervical squamous cells, whereas LPL expression was negligible. The LPL gene was rearranged in 1 out of 151 cervical SCCs, whereas wild-type LPL overexpression was common, being detected in 10 out of 28 tissue samples and 4 out of 10 cell lines. Forced overexpression of wild-type LPL and PEX5-LPL fusion transcripts resulted in increased invasiveness in cervical SCC cells, attributable to the C-terminal non-catalytic domain of LPL, which was retained in the fusion transcripts. CONCLUSION: This is the first demonstration of an expressed fusion gene in cervical SCC. Overexpressed wild-type or translocated LPL is a candidate for targeted therapy.

Malignant germ cell tumours of childhood: new associations of genomic imbalance.

Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p- (P=0.003), 3p+ (P=0.02), 4q- (P=0.07) and 6q- (P=0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5-16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P=0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities.

The effect of auditory stimulation on autobiographical recall in dementia.

Elderly individuals with mild-moderate ("high ability") or moderate ("low ability") dementia, answered autobiographical memory questions drawn from three life eras (remote, medium-remote, and recent), in familiar music, novel music, cafeteria noise or quiet. Recall was significantly better in the high-ability than the low-ability group, in sound than in quiet, and in music than in noise. Recall was significantly related to life era, declining from remote to recent memory. The superiority of recall in music compared with noise was apparent for recall from remote and medium-remote but not recent eras. The results are interpreted as favoring an explanation of the beneficial effect of auditory stimulation, predominantly in terms of enhanced arousal or attention deployment, with a possible subsidiary role for associative facilitation.

In vitro gibberellin a(4) binding to extracts of cucumber hypocotyls.

Cucumber hypocotyls were extracted and the extract centrifuged at 100,000g to yield a supernatant or cytosol fraction. Binding of [(3)H]-gibberellin(4) (GA(4)) to soluble macromolecular components present in the cytosol was demonstrated at 0 C by Sephadex chromatography. Binding assays performed with cytosol that had been preheated or incubated with protease, DNase, RNase, or phospholipase A or C indicated that heat and protease treatments disrupted the binding, which suggests that binding occurred to a protein. Equilibrium dialysis of a protein-enriched fraction prepared by ammonium sulfate precipitation also indicated binding of [(3)H]GA(4) to macromolecular components. [(3)H]GA(4) binding was pH-sensitive, saturable, reversible, and significantly affected by biologically active gibberellins, but not by inactive gibberellins or other plant hormones such as indoleacetic acid, abscisic acid, or kinetin. Thin layer chromatography indicated that [(3)H]GA(4), and not a metabolite, was the species bound. A kinetic analysis indicated that specific binding of [(3)H]GA(4) was due to a single class of binding sites having an estimated K(d) of 10(-7) molar and a concentration of 0.8 x 10(-12) moles gram(-1) fresh weight or 0.4 x 10(-12) moles milligram(-1) soluble protein.

No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer.

Endogenous hormone exposure is known to alter breast cancer susceptibility and genes responsive to such hormones are plausible candidates for predisposition genes. We have examined polymorphisms in genes for two members of the nuclear receptor superfamily which are expressed in breast tissue and known to moderate rates of cell proliferation in a case-control association study: the androgen receptor (AR) and the vitamin D receptor (VDR). We have used two series of Caucasian female breast cancer cases, one incident and one prevalent, and compared both with two sets of matched controls from the East Anglian region of Britain. Since the results are similar in the two series we have combined them. The AR poly[Gly](n) and poly[Gln](n) tracts were genotyped in a total of 508 female breast cancer cases and 426 controls. The VDR TaqI polymorphism was analysed in 951 cases and 627 controls drawn from the same population series. There were no significant differences between cases and controls for either the AR or VDR polymorphisms. Compared with individuals with two short alleles (<22 repeats) of the AR poly[Gln](n) tract, the odds ratios and 95% confidence intervals (95% CI) for individuals with one or two long alleles were 0.82 (95% CI 0.62-1.09) and 1.31 (95% CI 0.87-1.97), respectively. Heterozygotes and homozygotes for the VDR TaqI cutting site had odds ratios of 1.01 (95% CI 0.81-1.27) and 0.97 (95% CI 0.71-1.32), respectively. None of the AR or VDR polymorphisms investigated has a major effect on risk of breast cancer in the British population.

No association between a polymorphism in the steroid metabolism gene CYP17 and risk of breast cancer.

A recent study showed an association between a single base substitution, T-->C, in the promotor region of the CYP17 gene, the risk of breast cancer and age at menarche in Asian, African-American and Latino women from California and Hawaii. The C allele was associated with increased risk of breast cancer, significantly so for patients presenting with advanced disease, whereas the TT genotype was associated with later age at menarche in control subjects. We attempted to confirm these findings in a large case-control study in East Anglia, England (835 cases and 591 control subjects). We found no evidence of an increased risk of breast cancer [odds ratio (OR) 1.10, confidence interval (CI) 0.89-1.37] or advanced breast cancer (OR 0.88, CI 0.38-2.01) in C allele carriers, nor any association between age at menarche and genotype. We conclude that these alleles do not significantly alter breast cancer risk in the English population.