A regional ground motion excitation/attenuation model for the San Francisco region

By using small-to-moderate-sized earthquakes located within ~200 km of San Francisco, we characterize the scaling of the ground motions for frequencies ranging between 0.25 and 20 Hz, obtaining results for geometric spreading, Q(f), and site parameters using the methods of Mayeda et al. (2005) and Malagnini et al. (2004). The results of the analysis show that, throughout the Bay Area, the average regional attenuation of the ground motion can be modeled with a bilinear geometric spreading function with a 30 km crossover distance, coupled to an anelastic function exp(-pi*f*r/V*Q(f)) , where: Q(f)=180f^0.42. A body-wave geometric spreading, g(r)= r^-1.0, is used at short hypocentral distances (r < 30 km), whereas g(r)= r^-0.6 fits the attenuation of the spectral amplitudes at hypocentral distances beyond the crossover. The frequency-dependent site effects at 12 of the Berkeley Digital Seismic Network (BDSN) stations were evaluated in an absolute sense using coda-derived source spectra. Our results show: i) the absolute site response for frequencies ranging between 0.3 Hz and 2.0 Hz correlate with independent estimates of the local magnitude residuals (dML) for each of the stations; ii) moment-magnitudes (MW) derived from our path and site-corrected spectra are in excellent agreement with those independently derived using full-waveform modeling as well as coda-derived source spectra; iii) we use our weak-motion-based relationships to predict motions region wide for the Loma Prieta earthquake, well above the maximum magnitude spanned by our data set, on a completely different set of stations. Results compare well with measurements taken at specific NEHRP site classes; iv) an empirical, magnitude-dependent scaling was necessary for the Brune stress parameter in order to match the large magnitude spectral accelerations and peak ground velocities with our weak-motion-based model

A Regional Ground Motion Excitation attenuation Model for the San Francisco Region

By using small-to-moderate-sized earthquakes located within ~200 km of San Francisco, we characterize the scaling of the ground motions for frequencies ranging between 0.25 and 20 Hz, obtaining results for geometric spreading, Q(f), and site parameters using the methods of Mayeda et al. (2005) and Malagnini et al. (2004). The results of the analysis show that, throughout the Bay Area, the average regional attenuation of the ground motion can be modeled with a bilinear geometric spreading function with a 30 km crossover distance, coupled to an anelastic function ! exp " #fr $Q( f ) % & ' ( ) * , where: Q(f)=180 f 0.42. A body-wave geometric spreading, g(r)= r -1.0, is used at short hypocentral distances (r < 30 km), whereas g(r)= r -0.6 fits the attenuation of the spectral amplitudes at hypocentral distances beyond the crossover. The frequency-dependent site effects at 12 of the Berkeley Digital Seismic Network (BDSN) stations were evaluated in an absolute sense using coda-derived source spectra. Our results show: i) the absolute site response for frequencies ranging between 0.3 Hz and 2.0 Hz correlate with independent estimates of the local magnitude residuals (dML) for each of the stations; ii) moment-magnitudes (MW) derived from our path and sitecorrected spectra are in excellent agreement with those independently derived using fullwaveform modeling as well as coda-derived source spectra; iii) we use our weak-motionbased relationships to predict motions region wide for the Loma Prieta earthquake, well above the maximum magnitude spanned by our data set, on a completely different set of stations. Results compare well with measurements taken at specific NEHRP site classes; iv) an empirical, magnitude-dependent scaling was necessary for the Brune stress parameter in order to match the large magnitude spectral accelerations and peak ground velocities with our weak-motion-based model

California Integrated Seismic Network (CISN) Local Magnitude Determination in California and Vicinity

Determining local magnitude (M_L) in a manner that is uniform and internally consistent for earthquakes throughout California and the vicinity is an important component of the California Integrated Seismic Network (CISN). We present a new local magnitude attenuation function and corresponding station adjustments that are valid throughout California. The new attenuation function is an analytic function of the radial hypocentral distance between 1 and 500 km. Associated station adjustments are also available for 1185 horizontal seismometer and accelerometer channels from five seismic networks operating in California. The new attenuation function and adjustments provide several advantages to CISN. They allow a more robust M_L computation, the M_Ls are more consistent between northern and southern California than they have been in the past, and because adjustments are now available for more station-network-channel-location codes (SNCLs), M_Ls can be computed for small earthquakes in more locations than was previously possible. In addition to describing our method for calibrating the new CISN M_L, we also present a tool for adding adjustments for new or upgraded stations

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations

Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa

BACKGROUND: Carbonic anhydrase (CA) isozymes may have an important role in cancer development. Some isozymes control pH homeostasis in tumors that appears to modulate the behaviour of cancer cells. CA XIII is the newest member of the CA gene family. It is a cytosolic isozyme which is expressed in a number of normal tissues. The present study was designed to investigate CA XIII expression in prospectively collected colorectal tumor samples. METHODS: Both neoplastic and normal tissue specimens were obtained from the same patients. The analyses were performed using CA XIII-specific antibodies and an immunohistochemical staining method. For comparison, the tissue sections were immunostained for other cytosolic isozymes, CA I and II. RESULTS: The results indicated that the expression of CA XIII is down-regulated in tumor cells compared to the normal tissue. The lowest signal was detected in carcinoma samples. This pattern of expression was quite parallel for CA I and II. CONCLUSION: The down-regulation of cytosolic CA I, II and XIII in colorectal cancer may result from reduced levels of a common transcription factor or loss of closely linked CA1, CA2 and CA13 alleles on chromosome 8. Their possible role as tumor suppressors should be further evaluated

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P &lt; 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat