TP53 mutation p.R337H in gastric cancer tissues of a 12-year-old male child - evidence for chimerism involving a common mutant founder haplotype: case report

<p>Abstract</p> <p>Background</p> <p>Gastric adenocarcinoma is rare in children and adolescents, with about 17 cases under age 21 in the world's literature. We report a case of invasive well-differentiated metastatic gastric cancer in a Brazilian 12-year-old boy without documented familial history of cancer.</p> <p>Case presentation</p> <p>The patient, diagnosed with metastatic disease, died seven months after surgery. DNA from intra-surgical specimens revealed a <it>TP53 </it>mutation at codon 337 (p.R337H) in samples with neoplastic cells (dysplasia, tumor and metastasis) but not in non-transformed cells (incomplete intestinal metaplasia and non-involved celiac lymph node). In all mutation-positive tissues, p.R337H occurred on the same background, a founder allele identified by a specific haplotype previously described in Brazilian Li-Fraumeni syndrome patients. The same mutant haplotype, corresponding to a founder mutation present in 0.3% of the general population in Southern Brazil, was found in the genome of the father. Presence of this inherited haplotype in the tumor as well as in the father's germline, suggests a rare case of microchimerism in this patient, who may have harbored a small number of mutant cells originating in another individual, perhaps a dizygotic twin that died early in gestation.</p> <p>Conclusion</p> <p>This case represents one of the earliest ages at diagnosis of gastric cancer ever reported. It shows that cancer inheritance can occur in the absence of an obvious germline mutation, calling for caution in assessing early cancers in populations with common founder mutations such as p.R337H in Southern Brazil.</p

Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.</p> <p>Methods</p> <p>Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.</p> <p>Results</p> <p>Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.</p> <p>Conclusions</p> <p>Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.</p

Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) founder mutation : clues from haplotyping of short tandem repeats on Chromosome 17p

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial his- tory. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Ibe- ric origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenera- tional distance) and thus pre-dating European migration to Brazil. So far, the founder p. Arg337His haplotype has not been detected outside Brazil, with the exception of two resi- dents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.This study was funded by grant # 478430/2012-4 from CNPq (RFA MCT/CNPq - No 14/2012; Universal), Brazil.We would like to thank UFRGS, UFPA, AC Camargo, HC Barretos and University of Minho for their support during this work

Using dual-detector helical CT angiography to detect deep venous thrombosis in patients with suspicion of pulmonary embolism: diagnostic value and additional findings.

OBJECTIVE: The purpose of this study was to assess the value of dual-slice helical CT angiography in detecting deep venous thrombosis in patients in whom acute pulmonary embolism was suspected and to describe the additional extrathoracic findings. SUBJECTS AND METHODS: Sixty-five consecutive patients were examined for suspected pulmonary embolism using helical CT of the chest (2.7-mm collimation; table speed, 7.5 mm/sec; 100-140 mL of contrast medium injected at a rate of 3 mL/sec) followed by CT of the lower limbs (6.5-mm collimation; table speed, 10 mm/sec) without any additional contrast medium injection. Sequential scanning of the abdomen was performed using 10-mm collimation and an interval of 40 mm. Color Doppler sonography of the lower limbs was done within 24 hr of CT by two radiologists who were unaware of CT findings. Results of CT venography were compared with those of Doppler sonography and with phlebography or repeated focalized sonography in cases of discrepancy. RESULTS: Twenty-two patients had pulmonary embolism revealed on chest CT. Sixteen patients had a deep venous thrombosis. Thirteen patients with pulmonary embolism had a deep venous thrombosis. Three patients with deep venous thrombosis had no pulmonary embolism. Sensitivity and specificity for diagnosing deep venous thrombosis with CT was 93% and 97%, respectively (kappa = 0.88). Additional extrathoracic findings were observed in four patients. CONCLUSION: Combined CT venography with dual-slice scanning is an accurate method to diagnose deep venous thrombosis that may reveal additional imaging findings in some patients with possible pulmonary embolism

G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms

The tumor suppressor gene TP53, encoding p53, is expressed as several transcripts. The fully spliced p53 (FSp53) transcript encodes the canonical p53 protein. The alternatively spliced p53I2 transcript retains intron 2 and encodes D40p53 (or DNp53), an isoform lacking first 39 N-terminal residues corresponding to the main transactivation domain. We demonstrate the formation of G-quadruplex structures (G4) in a GC-rich region of intron 3 that modulates the splicing of intron 2. First, we show the formation of G4 in synthetic RNAs encompassing intron 3 sequences by ultraviolet melting, thermal difference spectra and circular dichroism spectroscopy. These observations are confirmed by detection of G4-induced reverse transcriptase elongation stops in synthetic RNA of intron 3. In this region, p53 pre-messenger RNA (mRNA) contains a succession of short exons (exons 2 and 3) and introns (introns 2 and 4) covering a total of 333 bp. Site-directed mutagenesis of Gtracts putatively involved in G4 formation decreased by $30% the excision of intron 2 in a green fluorescent protein-reporter splicing assay. Moreover, treatment of lymphoblastoid cells with 360A, a synthetic ligand that binds to single-strand G4 structures, increases the formation of FSp53 mRNA and decreases p53I2 mRNA expression. These results indicate that G4 structures in intron 3 regulate the splicing of intron 2, leading to differential expression of transcripts encoding distinct p53 isoforms

ESO & NOT photometric monitoring of the Cloverleaf quasar

The Cloverleaf quasar, H1413+117, has been photometrically monitored at ESO (La Silla, Chile) and with the NOT (La Palma, Spain) during the period 1987--1994. All good quality CCD frames have been successfully analysed using two independent methods (i.e. an automatic image decomposition technique and an interactive CLEAN algorithm). The photometric results from the two methods are found to be very similar, and they show that the four lensed QSO images vary significantly in brightness (by up to 0.45 mag), nearly in parallel. The lightcurve of the $D$ component presents some slight departures from the general trend which are very likely caused by micro-lensing effects. Upper limits, at the 99% confidence level, of 150 days on the absolute value for the time delays between the photometric lightcurves of this quadruply imaged variable QSO, are derived. This is unfortunately too large to constrain the lens model but there is little doubt that a better sampling of the lightcurves should allow to accurately derive these time delays. Pending a direct detection of the lensing galaxy (position and redshift), this system thus constitutes another good candidate for a direct and independent determination of the Hubble parameter. Based on observations collected at the European Southern Observatory (La Silla, Chile) and with the Nordic Optical Telescope (La Palma, Spain). Table 1. Logbook for the ESO and NOT observations together with photometric results for the Cloverleaf quasar. This long table can be accessed on the WWW at the URL address: http://vela.astro.ulg.ac.be/grav_lens/glp_homepage.html

ESO key programme, gravitational lensing: quasars and radio galaxies; a status report

The scientific background and objectives of our ESO Key Programme are first recalled. A brief account of our research activities (observing runs at ESO and elsewhere, meetings, etc.) is then given. Preliminary scientific results are presented concerning 1) our observational database for highly luminous quasars and distant powerful radiogalaxies; 2) speckle observations of highly luminous quasars; 3) the photometric monitoring and 4) detailed studies of several known gravitational lenses; 5) optical observations of 3C and 4C radio galaxies and 6) of the well known Einstein ring MG 1131+0456