Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. RESULTS: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. CONCLUSION: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry

Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.This work was supported by Cancer Research UK (C1094/A11728 to CMLW and NGB for the RAPPER study, C26900/A8740 to GCB, and C8197/A10865 to AMD), the Royal College of Radiologists (C26900/ A8740 to GCB), the National Institute for Health Research (GCB; no grant number), Addenbrooke's Charitable Trust (GCB; no grant number), Institute of Cancer Research (National Institute for Health Research) Biomedical Research Centre (C46/A2131 to DPD and SG), the National Institute for Health Research Cambridge Biomedical Research Centre (NGB; no grant number), UK Medical Research Council (RG70550 to LD), the Joseph Mitchell Trust (AMD; no grant number), the Experimental Cancer Medicine Centre (CMLW; no grant number), Cancer Research UK Program grant Section of Radiotherapy (C33589/ A19727 to SLG), the United States National Institutes of Health (1R01CA134444 to BSR and HO, 2P30CA014520-34 to SB, and 1K07CA187546-01A1 to SLK), the American Cancer Society (RSGT-05- 200-01-CCE to BSR), the U.S. Department of Defense (PC074201 to BSR and HO), Mount Sinai Tisch Cancer Institute Developmental Fund Award (BSR; no grant number), the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to AV and PI13/01136 to AC), Fondo Europeo de Desarrollo Regional (FEDER 2007–2013 to AV and AC; no grant number), Instituto de Salud Carlos III (FIS PI10/00164 and PI13/ 02030 to AV and PI13/01136 to AC), Xunta de Galicia and the European Social Fund (POS-A/2013/034 to LF), and the Alberta Cancer Board Research Initiative Program (103.0393.71760001404 to MP). AMD receives support from the REQUITE study, which is funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 601826. Laboratory infrastructure for the RAPPER study was funded by Cancer Research UK [C8197/A10123] and the Manchester Experimental Cancer Medicine Centre. The RAPPER cohort comprises individuals and data recruited into the RT01 and CHHiP UK radiotherapy trials. The RT01 trial was supported by the UK Medical Research Council. The CHHiP trial (CRUK/06/016) was supported by the Department of Health and Cancer Research UK (C8262/A7253); trial recruitment was facilitated within centers by the National Institute for Health Research Cancer Research Network. DPD and SLG acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ebiom.2016.07.02

Multiple Local and Recent Founder Effects of TGM1 in Spanish Families

<div><h3>Background</h3><p>Mutations in the <em>TGM1</em> gene encoding transglutaminase 1 are a major cause of autosomal recessive congenital ichthyosis. In the Galician (NW Spain) population, three mutations, c.2278C>T, c.1223_1227delACAC and c.984+1G>A, were observed at high frequency, representing ∼46%, ∼21% and ∼13% of all <em>TGM1</em> gene mutations, respectively. Moreover, these mutations were reported only once outside of Galicia, pointing to the existence of historical episodes of local severe genetic drift in this region.</p> <h3>Methodology/Principal Findings</h3><p>In order to determine whether these mutations were inherited from a common ancestor in the Galician population, and to estimate the number of generations since their initial appearance, we carried out a haplotype-based analysis by way of genotyping 21 SNPs within and flanking the <em>TGM1</em> gene and 10 flanking polymorphic microsatellite markers spanning a region of 12 Mb. Two linkage disequilibrium based methods were used to estimate the time to the most recent common ancestor (TMRCA), while a Bayesian-based procedure was used to estimate the age of the two mutations. Haplotype reconstruction from unphased genotypes of all members of the affected pedigrees indicated that all carriers for each of the two mutations harbored the same haplotypes, indicating common ancestry.</p> <h3>Conclusions/Significance</h3><p>In good agreement with the documentation record and the census, both mutations arose between 2,800–2,900 years ago (y.a.), but their TMRCA was in the range 600–1,290 y.a., pointing to the existence of historical bottlenecks in the region followed by population growth. This demographic scenario finds further support on a Bayesian Coalescent Analysis based on <em>TGM1</em> haplotypes that allowed estimating the occurrence of a dramatic reduction of effective population size around 900–4,500 y.a. (95% highest posterior density) followed by exponential growth.</p> </div

Mineralogical evolution of cement pastes at early ages based on thermogravimetric analysis (TGA)

[EN] Ordinary thermogravimetric analysis (TG) and high-resolution TG tests were carried out on three different Portland cement pastes to study the phases present during the first day of hydration. Tests were run at 1, 6, 12 and 24 h of hydration, in order to determine the phases at these ages. High-resolution TG tests were used to separate decompositions presented in the 100¿200 C interval. The non-evaporable water determined by TG was used to determine hydration degree for the different ages. The effect of particle size distribution (PSD) on mineralogical evolution was established, as well as the addition of calcite as mineralogical filler. Finer PSD and calcite addition accelerate the hydration process, increasing the hydration degree on the first day of eaction between water and cement. According to high-resolution TG results, it was demonstrated that ettringite was the only decomposed phase in the 100¿200 C interval during the first 6 h of hydration for all studied cements. C-S-H phase starts to appear in all cements after 12 h of hydration.Funding was provided by Colciencias (Grant No. Convocatoria 567-2012).Gaviria, X.; Borrachero Rosado, MV.; Paya Bernabeu, JJ.; Monzó Balbuena, JM.; Tobón, J. (2018). Mineralogical evolution of cement pastes at early ages based on thermogravimetric analysis (TGA). Journal of Thermal Analysis and Calorimetry. 132(1):39-46. https://doi.org/10.1007/s10973-017-6905-0S39461321Benboudjema F, Meftah JM, Torernti F. Interaction between drying, shrinkage, creep and cracking phenomena in concrete. Eng Struct. 2005;27:239–50.Holt E. Contribution of mixture design to chemical and autogenous shrinkage of concrete at early ages. Cem Concr Res. 2005;35:464–72.Darquennes A, Staquet S, Delplancke-Ogletree MP, Espion B. Effect of autogenous deformation on the cracking risk of slag cement concretes. Cem Concr Compos. 2011;33:368–79.Slowik V, Schmidt M, Fritzsch R. Capillary pressure in fresh cement-based materials and identification of the air entry value. Cem Concr Compos. 2008;30(7):557–65.Evju C, Hansen S. Expansive properties of ettringite in a mixture of calcium aluminate cement, Portland cement and ß-calcium sulfate hemihydrates. Cem Concr Res. 2001;31:257–61.Bentz DP, Jensen OM, Hansen KK. Olesen, Stang, H. Haecker, C.J. Influence of cement particle-size distribution on early age autogenous strain and stresses in cement-based materials. J Am Ceram Soc. 2001;84(1):129–35.Barcelo L, Moranville M, Clavaud B. Autogenous shrinkage of concrete: a balance between autogenous swelling and self-desiccation. Cem Concr Res. 2005;35(1):177–83.Bouasker M, Mounanga P, Turcry P, Loukili A, Khelidj A. Chemical shrinkage of cement pastes and mortars at very early age: effect of limestone filler and granular inclusions. Cem Concr Compos. 2008;30(1):13–22.Bentz DP. A review of early-age properties of cement-based materials. Cem Concr Res. 2008;38(2):196–204.Ozawa T. Controlled rate thermogravimetry. New usefulness of controlled rate thermogravimetry revealed by decomposition of polyimide. J Therm Anal Calorim. 2000;59:375–84.Ramachandran VS, Paroli RM, Beaudoin JJ, Delgado AH. Thermal analysis of construction materials. Building materials series. New York: Noyes Publications; 2003.Zanier A. High-resolution TG for the characterization of diesel fuel additives. J Therm Anal Calorim. 2001;64:377–84.Tobón JI, Payá J, Borrachero MV, Restrepo OJ. Mineralogical evolution of Portland cement blended with silica nanoparticles and its effect on mechanical strength. Constr Build Mater. 2012;36:736–42.Singh M, Waghmare S, Kumar V. Characterization of lime plasters used in 16th century Mughal Monument. J Archeol Sci. 2014;42:430–4.Majchrzak-Kuçeba I. Thermogravimetry applied to characterization of fly ash-based MCM-41 mesoporous materials. J Therm Anal Calorim. 2012;107:911–21.Silva ACM, Gálico DA, Guerra RB, Legendre AO, Rinaldo D, Galhiane MS, Bannach G. Study of some volatile compounds evolved from the thermal decomposition of atenolol. J Therm Anal Calorim. 2014;115:2517–20.Rios-Fachal M, Gracia-Fernández C, López-Beceiro J, Gómez-Barreiro S, Tarrío-Saavedra J, Ponton A, Artiaga R. Effect of nanotubes on the thermal stability of polystyrene. J Therm Anal Calorim. 2013;113:481–7.Yamarte L, Paxman D, Begum S, Sarkar P, Chambers A. TG measurement of reactivity of candidate oxygen carrier materials. J Therm Anal Calorim. 2014;116:1301–7.Borrachero MV, Payá J, Bonilla M, Monzó J. The use of thermogravimetric analysis technique for the characterization of construction materials. The gypsum case. J Therm Anal Calorim. 2008;91(2):503–9.Tobón JI, Payá J, Borrachero MV, Soriano L, Restrepo OJ. Determination of the optimum parameters in the high resolution thermogravimetric analysis (HRTG) for cementitious materials. J Therm Anal Calorim. 2012;107:233–9.Kuzielova E, Žemlička M, Másilko, J, Palou, M.T. Effect of additives on the performance of Dyckerhoff cement, Class G, submitted to simulated hydrothermal curing. J Therm Anal Calorim. Accepted 29 Oct 2017Genc M, Genc ZK. Microencapsulated myristic acid–fly ash with TiO2 shell as a novel phase change material for building application. J Therm Anal Calorim. Accepted 24 Oct 2017.Singh M, Kumar SV, Waghmare SA. The composition and technology of the 3–4th century CE decorative earthen plaster of Pithalkhora caves, India. J Archeol Sci. 2016;7:224–37.Liu L, Liu Q, Cao Y, Pan WP. The isothermal studies of char-CO2 gasification using the high-pressure thermo-gravimetric method. J Therm Anal Calorim. 2015;120:1877–82.Majchrzak-Kuce I, Bukalak-Gaik D. Regeneration performance of metal–organic frameworks TG-vacuum tests. J Therm Anal Calorim. 2016;125:1461–6.Ion RM, Radovici C, Fierascu RC, Fierascu I. Thermal and mineralogical investigations of iron archaeological Materials. J Therm Anal Calorim. 2015;121:1247–53.Rupasinghe M, San Nicolas R, Mendis P, Sofi M, Ngo T. Investigation of strength and hydration characteristics in nano-silica incorporated cement paste. Cem Concr Compos. 2017;80:17–30.Esteves PL. On the hydration of water-entrained cement–silica systems: combined SEM, XRD and thermal analysis in cement pastes. Thermochim Acta. 2011;518:27–35.Riesen R. Adjustment of heating rate for maximum resolution in TG and TMA (MaxRes). J Therm Anal. 1998;53:365–74.Lim S, Mondal P. Micro- and nano-scale characterization to study the thermal degradation of cement-based materials. Mater Charact. 2014;92:15–25.Gill PS, Sauerbrunn SR, Crowe BS. High resolution thermogravimetry. J Therm Anal. 1992;38:255–66.Mounanga P, Khelidj A, Loukili A, Baroghel-Bouny V. Predicting Ca(OH)2 content and chemical shrinkage of hydrating cement pastes using analytical approach. 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New challenges for BRCA testing:a view from the diagnostic laboratory

Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies

Background: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. Objective: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. Design, Setting, and Participants: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArrayH NT Cycler. Outcome Measurements and Statistical Analysis: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. Results and Limitations: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. Conclusion: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out

Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Biomarkers in anal cancer: from biological understanding to stratified treatment

Squamous cell carcinomas of the anus and anal canal represent a model of a cancer and perhaps the first where level 1 evidence supported primary chemoradiotherapy (CRT) in treating locoregional disease with curative intent. The majority of tumours are associated with infection with oncogenic subtypes of human papilloma virus and this plays a significant role in their sensitivity to treatment. However, not all tumours are cured with CRT and there remain opportunities to improve outcomes in terms of oncological control and also reducing late toxicities. Understanding the biology of ASCC promises to allow a more personalised approach to treatment, with the development and validation of a range of biomarkers and associated techniques that are the focus of this review