Germán Rodríguez

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population‐based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p = 0.002, Fishers exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p = 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single‐base substitutions, p = 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p = 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p = 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1–13.1], p = 0.034, log‐rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor‐suppressor gene; and (iii) the clinical condition and behavior of the patients.

Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer.

The human androgen receptor (AR) gene possesses 2 trinucleotide repeats of CAG and GGN in exon 1. The CAG repeat corresponds to a polyglutamine tract in the N‐terminal region of the receptor, that affects its transcriptional efficiency. The GGN repeat codifies for a polyglycine tract, and affects the amount of the AR protein transcribed. The endometrium contains ARs and the androgens have antiproliferative properties in cultured endometrial cancer (EC) cells. Larger CAG repeats of the AR gene give rise to a weaker transcriptional activity and have been found to be associated with endometrial carcinogenesis. The possible involvement of CAG and GGN tracts in the progression of EC is unknown. To study that possibility, we have genotyped both CAG and GGN polymorphisms of the AR gene in tumor tissue genomic DNA from a series of 204 consecutive patients with EC, and analyzed the results with regard to the pathological features and clinical outcome of patients. We classified the alleles as S (short ≤ median; S‐CAG ≤21 repeats; S‐GGN ≤22 repeats) or L (long > median). The genotype with both S‐CAG repeat alleles (SS‐CAG) was more common in patients diagnosed at an early stage (41.6% SS‐CAG vs 22.6% SL‐ and LL‐CAG together, p = 0.048) and in tumors that did not invade the vascular space (43.0% SS‐CAG vs 26.4% SL‐ and LL‐CAG together, p = 0.034). The genotype with SS‐GGN alleles was more common in well‐differentiated tumors (41.2% SS‐GGN vs 25.2% LS‐ and LL‐GGN together, p = 0.017) and in endometrioid histological subtype tumors (35.3% SS‐GGN vs 13.0% SL‐ and LL‐GGN together, p = 0.034). When the genotypes of both repeats coexisting in each tumor specimen were taken into consideration, the relationship between the SS‐CAG genotype and early stage remained only in the presence of the SS‐GGN genotype (43.9% vs 0%, p = 0.01). No other associations were observed. In univariate survival analysis, patients with short alleles of both repeats (SS‐CAG and SS‐GGN genotypes simultaneously) had a lower risk of cancer‐specific death (p = 0.032, mean follow‐up: 63 months). Our data suggests that short CAG or GGN repeats of the AR gene are associated with a more benign condition of traditional prognostic variables in EC.

A criterion for the automatic identification of multimodal sea wave spectra

A simple and efficient procedure to automatically distinguish between uni-modal and multi-modal scalar spectra, which is consistent with the random nature of the spectral density estimations, is proposed. The suggested methodology is based on the logarithmic transformation of the spectral estimations. Examples that demonstrate the procedure are presented.

Uncertainty in the estimation of the slope of the high frequency tail of wave spectra

Abstract The uncertainty of the high frequency tail slope of wave spectra, as a result of the intrinsically random variability of wind generated waves and the estimation procedures of the wave spectra, is examined by using simulated and field measured wave records. It is shown that considerable uncertainty on the ‘true’ value of the slope exists due to the statistical variability of the spectral estimates. Furthermore, significant uncertainties are introduced both by the choice of the method of spectral estimation and by varying the number of degrees of freedom. The identification of these different sources of uncertainty and the quantification of their values in some representative cases are important for the correct interpretation of results from measurements programs aiming at establishing the correct slope of the high frequency tail of wave spectra.

Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer

AIM DNA double strand break (DSB) repair is a central cellular mechanism of the DNA damage response to maintain genomic stability. DSB components are frequently mutated in colorectal cancer with microsatellite instability (MSI). We investigated whether DSB repair is involved in endometrial cancer (EC) with MSI. METHODS Mononucleotide microsatellite tracts of 14 genes of the DSB repair system were analysed in a series of 41 EC with MSI. Among these genes, the microcephalin 1 (MCPH1/BRIT1) has never been tested as target of MSI in tumour series. RESULTS The most frequently mutated gene was DNAPKcs (n=14, 34%) followed by RAD50 (n=7, 17%), MRE11, ATR and BRCA1 (n=6, 15%), and by CtIP and MCPH1 (n=5, 12%). While DSB biallelic mutations were infrequent, a high proportion of tumours (n=30, 73%) presented mutations at some component of the DSB repair pathway, and almost half of them showed alterations at two or more components. Tumours with mutations in two or more genes were significantly associated with advanced grade (p=0.03) and vascular invasion (p=0.02) and marginally associated with advanced stage (p=0.07). CONCLUSIONS Our results suggest that in EC, the DSB repair is a relatively common mutational target of MSI and might contribute to tumour progression, and also that MCHP1 may be a novel target gene of MSI.

Microsatellite Instability Predicts Clinical Outcome in Radiation-Treated Endometrioid Endometrial Cancer

PURPOSE To elucidate whether microsatellite instability (MSI) predicts clinical outcome in radiation-treated endometrioid endometrial cancer (EEC). METHODS AND MATERIALS A consecutive series of 93 patients with EEC treated with extrafascial hysterectomy and postoperative radiotherapy was studied. The median clinical follow-up of patients was 138 months, with a maximum of 232 months. Five quasimonomorphic mononucleotide markers (BAT-25, BAT-26, NR21, NR24, and NR27) were used for MSI classification. RESULTS Twenty-five patients (22%) were classified as MSI. Both in the whole series and in early stages (I and II), univariate analysis showed a significant association between MSI and poorer 10-year local disease-free survival, disease-free survival, and cancer-specific survival. In multivariate analysis, MSI was excluded from the final regression model in the whole series, but in early stages MSI provided additional significant predictive information independent of traditional prognostic and predictive factors (age, stage, grade, and vascular invasion) for disease-free survival (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.01-10.49; p = 0.048) and cancer-specific survival (HR 4.20, 95% CI 1.23-14.35; p = 0.022) and was marginally significant for local disease-free survival (HR 3.54, 95% CI 0.93-13.46; p = 0.064). CONCLUSIONS These results suggest that MSI may predict radiotherapy response in early-stage EEC.

Correlation between successive wave heights and periods in mixed sea states

Abstract The degree of dependence between successive wave heights and periods is examined for sea states resulting from the combination of a remotely generated wave field and a locally generated wave system, based on simulated wave records. The sea states analysed represent situations that are swell dominated, wind–sea dominated or they have equivalent energy in the wind–sea and swell components. Results of the analysis of the simulated data have been compared with those expected from the theories for the joint distributions of consecutive wave heights and periods and with the results from a Pierson–Moskowitz target spectrum.

Uncertainty of the sea state parameters resulting from the methods of spectral estimation

The uncertainty of some commonly used spectral wave parameters resulting from the spectral estimation procedure is assessed. It is observed that the methods of spectral estimation produce a significant uncertainty for all parameters examined, but this is of considerable importance only for the peak period, which is one of the most important parameters to model the wave climate.

Experimental evidence of the transition between power law models in the high frequency range of the gravity wave spectrum

Abstract The existence of a transition in the slope of the wind-generated gravity wave spectrum from a f−4 to a f−5 power law, at a given frequency in the high frequency range, is examined. Evidence of its existence and of the non-uniqueness of the wave spectrum slope in the equilibrium range is presented. Furthermore, it is demonstrated that the statistical variability of the spectral estimates makes it difficult to obtain reliable results from limited sets of finite length wave records.

Analysis and simulation of wave records through fast Hartley transform

The Hartley transform, a real-valued alternative to the complex Fourier transform, is presented as an efficient tool for the analysis and synthesis of ocean surface wave records. Basic theoretical properties of this real-valued transform are briefly reviewed. Similarities and differences between Fourier and Hartley integral transforms, as well as computational benefits and disadvantages between numerical algorithms used to evaluate their discrete versions, are presented. The fast Hartley transform algorithm is used to simulate stationary Gaussian time series of the sea surface elevation and to estimate the spectral density function, the Hilbert transform and the envelope function of wave records.