Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers

In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the NEIL2 gene previously identified as "cancer risk modifier" for BRCA2 mutation carriers. To that end, we studied the role of this SNP (rs804271) on NEIL2 transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six BRCA1 and BRCA2 mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on NEIL2 gene expression and oxidative DNA damage accumulation. The second was a set of twenty lymphoblastoid cell lines (LCLs), thirteen BRCA1 mutation carriers and seven non-carriers control, that were used to analyze the correlation between NEIL2 mRNA and/or protein levels, the oxidative and the double stranded break (DSB) DNA damage levels. Our results suggest that an excessive production of NEIL2 enzyme, associated with the SNP, may have a deleterious effect modifying cancer risk susceptibility in BRCA2 mutation carriers. We hypothesize that due to the SNP impact on NEIL2 transcriptional upregulation, a cascade of events may converge in the accumulation of oxidative DNA damage and its posterior conversion into DSBs for this specific group of patients.We thank Alicia Barroso her technical assistance. Also to Dr. Thomas Helleday, (Karolinska Institutet, Stockholm, Sweden) that kindly provided NEIL2 and UNG purified enzymes. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170),Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) were funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from: [insert, where appropriate] the GTEx Portal on 01/12/2015 and/or dbGaP accession number phs000424.v7.p2 on 01/10/2017.S

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

A Comprehensive Framework for Uncovering Non-Linearity and Chaos in Financial Markets: Empirical Evidence for Four Major Stock Market Indices

The presence of chaos in the financial markets has been the subject of a great number of studies, but the results have been contradictory and inconclusive. This research tests for the existence of nonlinear patterns and chaotic nature in four major stock market indices: namely Dow Jones Industrial Average, Ibex 35, Nasdaq-100 and Nikkei 225. To this end, a comprehensive framework has been adopted encompassing a wide range of techniques and the most suitable methods for the analysis of noisy time series. By using daily closing values from January 1992 to July 2013, this study employs twelve techniques and tools of which five are specific to detecting chaos. The findings show no clear evidence of chaos, suggesting that the behavior of financial markets is nonlinear and stochastic

Molecular insights into the OGG1 gene, a cancer risk modifier in BRCA1 and BRCA2 mutations carriers.

We have recently shown that rs2304277 variant in the OGG1 glycosidase gene of the Base Excision Repair pathway can increase ovarian cancer risk in BRCA1 mutation carriers. In the present study, we aimed to explore the role of this genetic variant on different genome instability hallmarks to explain its association with cancer risk.We have evaluated the effect of this polymorphism on OGG1 transcriptional regulation and its contribution to telomere shortening and DNA damage accumulation. For that, we have used a series of 89 BRCA1 and BRCA2 mutation carriers, 74 BRCAX cases, 60 non-carrier controls and 23 lymphoblastoid cell lines (LCL) derived from BRCA1 mutation carriers and non-carriers.We have identified that this SNP is associated to a significant OGG1 transcriptional down regulation independently of the BRCA mutational status and that the variant may exert a synergistic effect together with BRCA1 or BRCA2 mutations on DNA damage and telomere shortening.These results suggest that this variant, could be associated to a higher cancer risk in BRCA1 mutation carriers, due to an OGG1 transcriptional down regulation and its effect on genome instability.J.B.'s laboratory is partially funded by the Spanish Ministry of Health PI12/00070 supported by FEDER funds, and the Spanish Research Network on Rare diseases (CIBERER). C.B-B is granted by the PI12/00070. M.A.B.'s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA#232854, the Korber Foundation, Fundacion Botin and Fundacion Lilly. MU is supported by the Spanish Ministry of Health PI14/00459 with FEDER funds.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 in mother-daughter pairs with unaffected BRCA1/2 carrier daughters.

<p>Data from the mother-daughter pairs from familial breast cancer families showing the age of breast cancer diagnosis, or age at interview of unaffected daughters, and the age-adjusted telomere length.</p><p>BR: Breast cancer, BR Bi: Bilateral Breast cancer, OV: Ovarian cancer.</p

Comparison of telomere length, adjusted for age, in control women and hereditary and sporadic breast cancer.

<p>Age-adjusted telomere length (calculated as the difference between the observed and the predicted values; see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002182#s4" target="_blank">Materials and Methods</a> section) distribution in peripheral blood leukocytes of control women (n = 267); familial breast cancer groups BRCA1 (n = 48), BRCA2 (n = 45), and BRCAX (n = 105); and sporadic breast cancer (n = 71). Bilateral <i>t</i>-tests were performed to compare telomeres of breast cancer groups with the controls and the respective <i>p</i>-values are represented. Significantly shorter telomeres were found in all hereditary breast cancer groups whereas no significant differences appeared between controls and sporadic breast cancer cases.</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