The genetic audiogenic seizure hamster from Salamanca: The GASH:Sal

Producción CientíficaGASH:Sal hamster strain and the control Syrian hamsters. The GASH:Sal constitutes an experimental model of reflex epilepsy of audiogenic origin derived from an autosomal recessive disorder. Thus, the GASH:Sal exhibits generalized tonic–clonic seizures, characterized by a short latency period after auditory stimulation, followed by wild running, a convulsive phase, and finally stupor, with origin in the brainstem. The seizure profile of the GASH:Sal is similar to those exhibited by other models of inherited AGS susceptibility, which decreases after six months of age, but the proneness across generations is maintained. The GASH:Sal can be considered a reliable model of audiogenic seizures, suitable to investigate current antiepileptic pharmaceutical treatments as well as novel therapeutic drugs

Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer

There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer

MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression

Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation.We thank all members of the Human Cancer Genetics Programme of the Spanish National Cancer Research Centre for all their support. We want to particularly acknowledge the patients, the INCLIVA BioBank (PT13/0010/0004) integrated in the Spanish National Biobanks Network, and Pablo Isidro Marrón, coordinator of Biobanco del Principado de Asturias, for their collaboration. This work has been funded by grants from the Spanish Ministry of Economy and Competitiveness (INNPRONTA LIFE project) and FIS PI11/01059 (BM-D).S

Telomere length in affected BRCA1/2 mutation carriers and corresponding non-carrier sisters.

<p>Comparison of age-adjusted telomere length between <i>BRCA1/2</i> mutation carriers (n = 19) and healthy non-carrier sisters (n = 22) from 19 different families (8 BRCA1, 11 BRCA2) is represented through box-plots showing the median and interquartile distance for each group. Age-adjusted telomere length was calculated for each sample as the difference between the actual and the predicted value using the line of best fit from controls (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002182#s4" target="_blank">Materials and Methods</a>). Atypical (circles) and extreme (asterisks) values are also shown. Mann-Whitney U tests between the groups were performed, and significantly shorter telomeres were found in mutation carriers versus non-carriers. The non-carrier sisters from affected families do not show differences in telomere length with the control women.</p

Telomere length distribution in control, familial breast cancer, and sporadic breast cancer cases.

<p>Telomere length distribution in peripheral blood leukocytes as a function of age for the control women population (n = 267, grey circles) and for breast cancer cases (black circles). Controls show the expected telomere length erosion with increasing age. Regression line for controls is drawn (y = −0.0146x+1.585, R² = 0.144). Comparison between control telomere length distribution and telomeres from 48 BRCA1 (A), 44 BRCA2 (B), 105 BRCAX (C), and 71 sporadic breast cancer cases (D) is represented.</p

Age-adjusted telomere length and anticipation in the age of diagnosis in mother-daughter pairs.

<p>Data from the mother-daughter pairs with familial breast cancer showing the age of breast cancer diagnosis and the age-adjusted telomere length.</p><p>BR: Breast cancer, BR Bi: Bilateral Breast cancer, OV: Ovarian cancer, Leu: Leukemia, Mel: Melanoma</p>a<p>Families not showing anticipation in the age of onset.</p

Anticipation effect in the age of breast cancer onset in the familial breast cancer genetic subgroups.

<p>Kaplan–Meier curves showing the differences in age of onset of familial breast cancer in mothers and daughters in BRCA1 (left panel), BRCA2 (middle panel), and BRCAX (right panel) families. Log-rank test <i>p-</i>values are represented for each group.</p

Difference in the age of onset of breast cancer between mothers and daughters in hereditary breast cancer.

<p>Mean age of cancer development in mothers and daughters in the three groups, BRCA1, BRCA2 and BRCAX, of hereditary breast cancer. Statistical significance of the difference between mothers and daughters was estimated by t-tests.</p><p>s.d. Standard deviation. Bilateral <i>t</i>-test was performed to assess the significance of the differences between mothers and daughters. Values for the <i>t</i>-statistic and the <i>p</i>-value for the <i>t</i>-test are indicated.</p

Changes in telomere length between mother-daughter pairs.

<p>(A) Box-plots representing telomere length distribution in mothers and daughters affected with breast cancer, affected mothers and daughters unaffected but carrying <i>BRCA1/2</i> mutations, and control mothers and daughters. Significant differences were found in mother-daughter pairs from familial breast cancer families with a decrease in the telomere length in both affected and unaffected, mutation-carrying daughters, but not in controls. (B) Generational changes in telomere length in mother-daughter pairs with familial breast cancer (n = 19) compared to control mother-daughter pairs (n = 16). Differences between age-adjusted telomere length in daughters and age-adjusted telomere length of the corresponding mother were obtained for affected and control groups. Median value is drawn as a horizontal line for each group. Telomeres of affected daughters were significantly shorter than those of their mothers, compared to the changes observed in control mother-daughter pairs (Mann-Whitney U, p-value = 0.003).</p