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  • Palviainen, Mari J; Junnikkala, Sami; Raekallio, Marja; Meri, Seppo; Vainio, Outi (BioMed Central, 2015)
    Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory pain in humans and animals. An overdose of an NSAID is nephrotoxic and can lead to acute kidney injury (AKI). Complement activation occurs in several types of renal disorders with proteinuria. The aim of this study was to investigate whether complement system becomes activated in kidneys after a high dose of NSAID. Kidney tissue and urine samples were collected from six sheep with ketoprofen-induced AKI and from six healthy control sheep. The localization of complement proteins in kidney tissue was carried out using immunohistochemical stainings, and excretion of C3 was tested by immunoblotting. Results The complement system was found to become activated in the kidney tissue as demonstrated by positive immunostaining for C1q, C3c, C4c, C5, C9 and factor H and by Western blotting analysis of C3 activation products in urine samples in sheep with AKI. Conclusions Our results thus suggest that the alternative complement pathway is activated, and it may contribute to the acute tubular injury seen in the kidneys of NSAID-induced AKI sheep. Inhibition of complement activation may serve as potential therapeutic target for intervention in drug-induced AKI.
  • Kovalchuk, Andriy; Raffaello, Tommaso; Jaber, Emad; Keriö, Susanna; Ghimire, Rajendra; Lorenz, W W; Dean, Jeffrey F; Holopainen, Jarmo K; Asiegbu, Fred O (BioMed Central, 2015)
    Abstract Background During their lifetime, conifer trees are exposed to numerous herbivorous insects. To protect themselves against pests, trees have developed a broad repertoire of protective mechanisms. Many of the plant’s defence reactions are activated upon an insect attack, and the underlying regulatory mechanisms are not entirely understood yet, in particular in conifer trees. Here, we present the results of our studies on the transcriptional response and the volatile compounds production of Scots pine (Pinus sylvestris) upon the large pine weevil (Hylobius abietis) feeding. Results Transcriptional response of Scots pine to the weevil attack was investigated using a novel customised 36.4 K Pinus taeda microarray. The weevil feeding caused large-scale changes in the pine transcriptome. In total, 774 genes were significantly up-regulated more than 4-fold (p ≤ 0.05), whereas 64 genes were significantly down-regulated more than 4-fold. Among the up-regulated genes, we could identify genes involved in signal perception, signalling pathways, transcriptional regulation, plant hormone homeostasis, secondary metabolism and defence responses. The weevil feeding on stem bark of pine significantly increased the total emission of volatile organic compounds from the undamaged stem bark area. The emission levels of monoterpenes and sesquiterpenes were also increased. Interestingly, we could not observe any correlation between the increased production of the terpenoid compounds and expression levels of the terpene synthase-encoding genes. Conclusions The obtained data provide an important insight into the transcriptional response of conifer trees to insect herbivory and illustrate the massive changes in the host transcriptome upon insect attacks. Moreover, many of the induced pathways are common between conifers and angiosperms. The presented results are the first ones obtained by the use of a microarray platform with an extended coverage of pine transcriptome (36.4 K cDNA elements). The platform will further facilitate the identification of resistance markers with the direct relevance for conifer tree breeding.
  • Chong, Sun-Li; Derba-Maceluch, Marta; Koutaniemi, Sanna; Gómez, Leonardo D; McQueen-Mason, Simon J; Tenkanen, Maija; Mellerowicz, Ewa J (BioMed Central, 2015)
    Abstract Background Expressing microbial polysaccharide-modifying enzymes in plants is an attractive approach to custom tailor plant lignocellulose and to study the importance of wall structures to plant development. Expression of α-glucuronidases in plants to modify the structures of glucuronoxylans has not been yet attempted. Glycoside hydrolase (GH) family 115 α-glucuronidases cleave the internal α-D-(4-O-methyl)glucopyranosyluronic acid ((Me)GlcA) from xylans or xylooligosaccharides. In this work, a GH115 α-glucuronidase from Schizophyllum commune, ScAGU115, was expressed in Arabidopsis thaliana and targeted to apoplast. The transgene effects on native xylans’ structures, plant development, and lignocellulose saccharification were evaluated and compared to those of knocked out glucuronyltransferases AtGUX1 and AtGUX2. Results The ScAGU115 extracted from cell walls of Arabidopsis was active on the internally substituted aldopentaouronic acid (XUXX). The transgenic plants did not show any change in growth or in lignocellulose saccharification. The cell wall (Me)GlcA and other non-cellulosic sugars, as well as the lignin content, remained unchanged. In contrast, the gux1gux2 double mutant showed a 70% decrease in (Me)GlcA to xylose molar ratio, and, interestingly, a 60% increase in the xylose content. Whereas ScAGU115-expressing plants exhibited a decreased signal in native secondary walls from the monoclonal antibody UX1 that recognizes (Me)GlcA on non-acetylated xylan, the signal was not affected after wall deacetylation. In contrast, gux1gux2 mutant was lacking UX1 signals in both native and deacetylated cell walls. This indicates that acetyl substitution on the xylopyranosyl residue carrying (Me)GlcA or on the neighboring xylopyranosyl residues may restrict post-synthetic modification of xylans by ScAGU115 in planta. Conclusions Active GH115 α-glucuronidase has been produced for the first time in plants. The cell wall–targeted ScAGU115 was shown to affect those glucuronate substitutions of xylan, which are accessible to UX1 antibody and constitute a small fraction in Arabidopsis, whereas majority of (Me)GlcA substitutions were resistant, most likely due to the shielding by acetyl groups. Plants expressing ScAGU115 did not show any defects under laboratory conditions indicating that the UX1 epitope of xylan is not essential under these conditions. Moreover the removal of the UX1 xylan epitope does not affect lignocellulose saccharification.
  • Acevedo, Nathalie; Reinius, Lovisa E; Vitezic, Morana; Fortino, Vittorio; Söderhäll, Cilla; Honkanen, Hanna; Veijola, Riitta; Simell, Olli; Toppari, Jorma; Ilonen, Jorma; Knip, Mikael; Scheynius, Annika; Hyöty, Heikki; Greco, Dario; Kere, Juha (BioMed Central, 2015)
    Abstract Background Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
  • Stenroos, Antti J; Handolin, Lauri E (BioMed Central Ltd, 2014)
    Abstract Background Alpine skiing is one of the most popular winter sports in the world. Nevertheless, it has always been associated with a high risk of injury. There are however, only a few studies that have examined the risk of injury of competitive skiers, especially of the junior ski racers. Methods The inclusion criterion was an injury in alpine skiing resulting in a pause in training longer than one week. Athletes of all ages were included. The study period was from the start of the season of 2008&#8211;2009 to end of the season of 2009&#8211;2010 (two years). Results The average annual number of ski racers in Finland was 661. There were 61 injuries (36 males with a median age of 14&#160;years, 25 females with a median age of 14) fulfilling the inclusion criteria. Ligamentous knee injury was the most frequent (17) and lower leg fracture the second common (16) injury, respectively. There was a female dominance in the ACL injuries. Only one major abdominal injury and no major head injuries were observed. The overall training pause was 26&#160;weeks after the ACL injury and 17&#160;weeks after the lower leg fracture, respectively. Conclusion The most common and most disabling injuries affect the knee and the lower leg. The high number of lower leg and ACL injuries is alarming. A continuous and careful monitoring of injuries needs to be established to assess this trend. A systematic review of injuries is the appropriate way to monitor the effects of changes made in terms of safety. The present retrospective two-year pilot study forms a base for a continuous alpine ski injury survey in Finland.
  • Tudor-Locke, Catrine; Mire, Emily F; Dentro, Kara N; Barreira, Tiago V; Schuna, John M; Zhao, Pei; Tremblay, Mark S; Standage, Martyn; Sarmiento, Olga L; Onywera, Vincent; Olds, Tim; Matsudo, Victor; Maia, José; Maher, Carol; Lambert, Estelle V; Kurpad, Anura; Kuriyan, Rebecca; Hu, Gang; Fogelholm, Mikael; Chaput, Jean-Philippe; Church, Timothy S; Katzmarzyk, Peter T (BioMed Central, 2015)
    Abstract Background We present a model for reporting accelerometer paradata (process-related data produced from survey administration) collected in the International Study of Childhood Obesity Lifestyle and the Environment (ISCOLE), a multi-national investigation of >7000 children (averaging 10.5 years of age) sampled from 12 different developed and developing countries and five continents. Methods ISCOLE employed a 24-hr waist worn 7-day protocol using the ActiGraph GT3X+. Checklists, flow charts, and systematic data queries documented accelerometer paradata from enrollment to data collection and treatment. Paradata included counts of consented and eligible participants, accelerometers distributed for initial and additional monitoring (site specific decisions in the face of initial monitoring failure), inadequate data (e.g., lost/malfunction, insufficient wear time), and averages for waking wear time, valid days of data, participants with valid data (≥4 valid days of data, including 1 weekend day), and minutes with implausibly high values (≥20,000 activity counts/min). Results Of 7806 consented participants, 7372 were deemed eligible to participate, 7314 accelerometers were distributed for initial monitoring and another 106 for additional monitoring. 414 accelerometer data files were inadequate (primarily due to insufficient wear time). Only 29 accelerometers were lost during the implementation of ISCOLE worldwide. The final locked data file consisted of 6553 participant files (90.0% relative to number of participants who completed monitoring) with valid waking wear time, averaging 6.5 valid days and 888.4 minutes/day (14.8 hours). We documented 4762 minutes with implausibly high activity count values from 695 unique participants (9.4% of eligible participants and <0.01% of all minutes). Conclusions Detailed accelerometer paradata is useful for standardizing communication, facilitating study management, improving the representative qualities of surveys, tracking study endpoint attainment, comparing studies, and ultimately anticipating and controlling costs. Trial registration ClinicalTrials.gov: NCT01722500
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Rafiq, Sajjad; Behrens, Sabine; Goode, Ellen L; Pharoah, Paul P; Seibold, Petra; Fasching, Peter A; Andrulis, Irene L; Kristensen, Vessela N; Couch, Fergus J; Hamann, Ute; Hooning, Maartje J; Nevanlinna, Heli; Eilber, Ursula; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Lindblom, Annika; Mannermaa, Arto; Lambrechts, Diether; García-Closas, Montserrat; Hall, Per; Chenevix-Trench, Georgia; Shah, Mitul; Luben, Robert; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Alnæs, Grethe I G; Borresen-Dale, Anne-Lise; Nord, Silje; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Torres, Diana; Ulmer, Hans-Ulrich; Rüdiger, Thomas; Jager, Agnes; van Deurzen, Carolien H; Tilanus-Linthorst, Madeleine M; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Margolin, Sara; Kosma, Veli-Matti; Hartikainen, Jaana M; Kataja, Vesa; Hatse, Sigrid; Wildiers, Hans; Smeets, Ann; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Li, Jingmei; Humphreys, Keith; Phillips, Kelly-Anne; Linn, Sabine; Cornelissen, Sten; van den Broek, Sandra A J; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Shen, Chen-Yang; Teo, Soo H; Taib, Nur A M; Yip, Cheng H; Ho, Gwo F; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Dunning, Alison M; Benitez, Javier; Czene, Kamila; Sucheston, Lara E; Maishman, Tom; Tapper, William J; Eccles, Diana; Easton, Douglas F; Schmidt, Marjanka K; Chang-Claude, Jenny (BioMed Central, 2015)
    Abstract Introduction Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). Methods We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. Results Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10−3) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10−4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10−3). Two SNPs in IL12B (r2 = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10−4). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10−5) without study heterogeneity. Conclusions TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
  • Arponen, Heidi; Mäkitie, Outi; Waltimo-Sirén, Janna (BioMed Central, 2014)
    Abstract Background Joint hypermobility is a common clinical characteristic of patients with Osteogenesis imperfecta (OI), a disorder with serious comorbidities of scoliosis and cranial base anomalies. This study aimed at evaluating how prevalent joint hypermobility is in paediatric OI patients, and to find out whether it serves as a potential predictive marker of the different spinal complications; scoliosis and craniovertebral anomalies (basilar impression and basilar invagination). Methods In this cross-sectional one-center study we analysed retrospectively clinical patient records and radiographs of 47 OI patients, aged 1–19 years, some of whom were treated with bisphosphonates. Presence of joint hypermobility, scoliosis, and craniovertebral anomalies was recorded and possible connections between the phenomena were explored with correlation analysis. Results Joint hypermobility was found in 70% of the patients. Scoliosis and cranial base anomalies had developed in 26%. The presence of spinal complications was independent of the bisphosphonate treatment status and joint hypermobility. Conclusions Scoliosis and craniovertebral anomalies are strongly associated in paediatric OI patients. Joint hypermobility that is much more common appears, however, to be a poor predictor.
  • Arponen, Heidi; Mäkitie, Outi; Waltimo-Sirén, Janna (BioMed Central Ltd, 2014)
    Abstract Background Joint hypermobility is a common clinical characteristic of patients with Osteogenesis imperfecta (OI), a disorder with serious comorbidities of scoliosis and cranial base anomalies. This study aimed at evaluating how prevalent joint hypermobility is in paediatric OI patients, and to find out whether it serves as a potential predictive marker of the different spinal complications; scoliosis and craniovertebral anomalies (basilar impression and basilar invagination). Methods In this cross-sectional one-center study we analysed retrospectively clinical patient records and radiographs of 47 OI patients, aged 1&#8211;19 years, some of whom were treated with bisphosphonates. Presence of joint hypermobility, scoliosis, and craniovertebral anomalies was recorded and possible connections between the phenomena were explored with correlation analysis. Results Joint hypermobility was found in 70% of the patients. Scoliosis and cranial base anomalies had developed in 26%. The presence of spinal complications was independent of the bisphosphonate treatment status and joint hypermobility. Conclusions Scoliosis and craniovertebral anomalies are strongly associated in paediatric OI patients. Joint hypermobility that is much more common appears, however, to be a poor predictor.
  • Ma, Li; Piirainen, Sami; Kulesskaya, Natalia; Rauvala, Heikki; Tian, Li (BioMed Central, 2015)
    Abstract Background Social deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far. Methods To decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors. Results A group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice. Conclusions Our study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.
  • Kuchenbaecker, Karoline B; Neuhausen, Susan L; Robson, Mark; Barrowdale, Daniel; McGuffog, Lesley; Mulligan, Anna M; Andrulis, Irene L; Spurdle, Amanda B; Schmidt, Marjanka K; Schmutzler, Rita K; Engel, Christoph; Wappenschmidt, Barbara; Nevanlinna, Heli; Thomassen, Mads; Southey, Melissa; Radice, Paolo; Ramus, Susan J; Domchek, Susan M; Nathanson, Katherine L; Lee, Andrew; Healey, Sue; Nussbaum, Robert L; Rebbeck, Timothy R; Arun, Banu K; James, Paul; Karlan, Beth Y; Lester, Jenny; Cass, Ilana; Registry, Breast C F; Terry, Mary B; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; v O Hansen, Thomas; Ejlertsen, Bent; Gerdes, Anne-Marie; Nielsen, Finn C; Dennis, Joe; Cunningham, Julie; Hart, Steven; Slager, Susan; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N; Tafur, Isaac; Hander, Mary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Roversi, Gaia; Scuvera, Giulietta; Bonanni, Bernardo; Mariani, Paolo; Volorio, Sara; Dolcetti, Riccardo; Varesco, Liliana; Papi, Laura; Tibiletti, Maria G; Giannini, Giuseppe; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D G; Frost, Debra; Eccles, Diana; Douglas, Fiona; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Ong, Kai-ren; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M J; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Godwin, Andrew K; Rhiem, Kerstin; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Steinemann, Doris; Bogdanova-Markov, Nadja; Kast, Karin; Varon-Mateeva, Raymonda; Wang-Gohrke, Shan; Gehrig, Andrea; Markiefka, Birgid; Buecher, Bruno; Lefol, Cédrick; Stoppa-Lyonnet, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Barjhoux, Laure; Faivre, Laurence; Longy, Michel; Sevenet, Nicolas; Sinilnikova, Olga M; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Isaacs, Claudine; Van Maerken, Tom; Claes, Kathleen; Piedmonte, Marion; Andrews, Lesley; Hays, John; Rodriguez, Gustavo C; Caldes, Trinidad; de la Hoya, Miguel; Khan, Sofia; Hogervorst, Frans B; Aalfs, Cora M; de Lange, JL; Meijers-Heijboer, Hanne E; van der Hout, Annemarie H; Wijnen, Juul T; van Roozendaal, KEP; Mensenkamp, Arjen R; van den Ouweland, Ans M; van Deurzen, Carolien H; van der Luijt, Rob B; Olah, Edith; Diez, Orland; Lazaro, Conxi; Blanco, Ignacio; Teulé, Alex; Menendez, Mireia; Jakubowska, Anna; Lubinski, Jan; Cybulski, Cezary; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Arason, Adalgeir; Maugard, Christine; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Olswold, Curtis; Lindor, Noralane; Pankratz, Vernon S; Hallberg, Emily; Wang, Xianshu; Szabo, Csilla I; Vijai, Joseph; Jacobs, Lauren; Corines, Marina; Lincoln, Anne; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne G; Pfeiler, Georg; Tea, Muy-Kheng; Phelan, Catherine M; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Imyanitov, Evgeny N; Glendon, Gord; Toland, Amanda E; Bojesen, Anders; Pedersen, Inge S; Jensen, Uffe B; Caligo, Maria A; Friedman, Eitan; Berger, Raanan; Laitman, Yael; Rantala, Johanna; Arver, Brita; Loman, Niklas; Borg, Ake; Ehrencrona, Hans; Olopade, Olufunmilayo I; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Antoniou, Antonis C (BioMed Central, 2014)
    Abstract Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
  • Huusko, Johanna M; Karjalainen, Minna K; Mahlman, Mari; Haataja, Ritva; Kari, M A; Andersson, Sture; Toldi, Gergely; Tammela, Outi; Rämet, Mika; Lavoie, Pascal M; Hallman, Mikko; on behalf of Gen-BPD Study Group (BioMed Central Ltd, 2014)
    Abstract Background Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with very preterm birth. The major risk factors include lung inflammation and lung immaturity. In addition, genetic factors play an important role in susceptibility to moderate-to-severe BPD. In this study, the aim was to investigate whether common polymorphisms of specific genes that are involved in inflammation or differentiation of the lung have influence on BPD susceptibility. Methods Genes encoding interleukin-6 (IL6) and its receptors (IL6R and IL6ST), IL-10 (IL10), tumor necrosis factor (TNF), and glucocorticoid receptor (NR3C1) were assessed for associations with moderate-to-severe BPD susceptibility. Five IL6, nine IL6R, four IL6ST, one IL10, two TNF, and 23 NR3C1 single nucleotide polymorphisms (SNPs) were analyzed in very preterm infants born in northern Finland (56 cases and 197 controls) and Canada (58 cases and 68 controls). IL-6, TNF and gp130 contents in umbilical cord blood, collected from very preterm infants, were studied for associations with the polymorphisms. Epistasis (i.e., interactions between SNPs in BPD susceptibility) was also examined. SNPs showing suggestive associations were analyzed in additional replication populations from Finland (39 cases and 188 controls) and Hungary (29 cases and 40 controls). Results None of the studied SNPs were associated with BPD nor were the IL6, TNF or IL6ST SNPs associated with cord blood IL-6, TNF and gp130, respectively. However, epistasis analysis suggested that SNPs in IL6ST and IL10 were associated interactively with risk of BPD in the northern Finnish population; however, this finding did not remain significant after correction for multiple testing and the finding was not replicated in the other populations. Conclusions We conclude that the analyzed SNPs within IL6, IL6R, IL6ST, IL10, TNF, and NR3C1 were not associated with BPD. Furthermore, there was no evidence that the studied SNPs directly contribute to the cord blood protein contents.
  • Arnulfo, Gabriele; Narizzano, Massimo; Cardinale, Francesco; Fato, Marco M; Palva, Jaakko M (BioMed Central, 2015)
    Abstract Background Invasive monitoring of brain activity by means of intracerebral electrodes is widely practiced to improve pre-surgical seizure onset zone localization in patients with medically refractory seizures. Stereo-Electroencephalography (SEEG) is mainly used to localize the epileptogenic zone and a precise knowledge of the location of the electrodes is expected to facilitate the recordings interpretation and the planning of resective surgery. However, the localization of intracerebral electrodes on post-implant acquisitions is usually time-consuming (i.e., manual segmentation), it requires advanced 3D visualization tools, and it needs the supervision of trained medical doctors in order to minimize the errors. In this paper we propose an automated segmentation algorithm specifically designed to segment SEEG contacts from a thresholded post-implant Cone-Beam CT volume (0.4 mm, 0.4 mm, 0.8 mm). The algorithm relies on the planned position of target and entry points for each electrode as a first estimation of electrode axis. We implemented the proposed algorithm into DEETO, an open source C++ prototype based on ITK library. Results We tested our implementation on a cohort of 28 subjects in total. The experimental analysis, carried out over a subset of 12 subjects (35 multilead electrodes; 200 contacts) manually segmented by experts, show that the algorithm: (i) is faster than manual segmentation (i.e., less than 1s/subject versus a few hours) (ii) is reliable, with an error of 0.5 mm ± 0.06 mm, and (iii) it accurately maps SEEG implants to their anatomical regions improving the interpretability of electrophysiological traces for both clinical and research studies. Moreover, using the 28-subject cohort we show here that the algorithm is also robust (error < 0.005 mm) against deep-brain displacements (< 12 mm) of the implanted electrode shaft from those planned before surgery. Conclusions Our method represents, to the best of our knowledge, the first automatic algorithm for the segmentation of SEEG electrodes. The method can be used to accurately identify the neuroanatomical loci of SEEG electrode contacts by a non-expert in a fast and reliable manner.
  • Malmström, Kristiina; Lehto, Maili; Majuri, Marja-Leena; Paavonen, Timo; Sarna, Seppo; Pelkonen, Anna S; Malmberg, L P; Lindahl, Harry; Kajosaari, Merja; Saglani, Sejal; Alenius, Harri; Mäkelä, Mika J (BioMed Central, 2014)
    Abstract Background Few data are available about the inflammatory cytokine profile of bronchoalveolar lavage (BAL) from young children with frequent wheeze. The first aim was to investigate the BAL cellular and cytokine profiles in infants with recurrent lower respiratory symptoms in whom bronchoscopy was indicated for clinical symptom evaluation. The second aim was to relate the BAL results with the histological findings of the endobronchial carina biopsies. Methods Thirty-nine infants (median age 0.9 years) underwent lung function testing by whole-body plethysmography prior to the bronchoscopy. The BAL differential cell counts and cytokine levels were quantified. These findings were compared with the histological findings of the endobronchial carina biopsies. Results The differential cytology reflected mainly that described for healthy infants with lymphocyte counts at the upper range level. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement membrane was found. Detectable levels of pro-inflammatory cytokine proteins IL-1β, IL-17A, IL-18, IL-23, and IL-33 were found, whereas levels of Th2-type cytokine proteins were low. Frequent wheeze was the only clinical characteristic significantly related to detectable combined pro-inflammatory cytokine profile. Lung function did not correlate with any cytokine. Conclusions A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement thickness was found. Detectable production of pro-inflammatory cytokines associated positively with frequent wheeze.
  • Vered, Marilena; Lehtonen, Meri; Hotakainen, Lari; Pirilä, Emma; Teppo, Susanna; Nyberg, Pia; Sormunen, Raija; Zlotogorski-Hurvitz, Ayelet; Salo, Tuula; Dayan, Dan (BioMed Central Ltd, 2015)
    Abstract Background Caveolin-1 (CAV1) may be upregulated by hypoxia and acts in a tumor-dependent manner. We investigated CAV1 in tongue squamous cell carcinoma (TSCC) and its association with clinical outcomes, and studied in vitro possible ways for CAV1 accumulation in the tumor microenvironment (TME). Methods TSCC cases (N&#8201;=&#8201;64) were immunohistochemically stained for CAV1. Scores were separately assessed in the tumor and TME and plotted for association with recurrence and survival (univariate analysis with log-rank test). In vitro studies were performed on a 3D myoma organotypic model, a mimicker of TME. Prior to monoculturing HSC-3 tongue cancer cells, the model underwent modifications in oxygenation level (1%O2 hypoxia to upregulate CAV1) and/or in the amount of natural soluble factors [deleted by 14-day rinsing (rinsed myoma, RM), to allow only HSC-3-derived factors to act]. Controls included normoxia (21%O2) and naturally occurring soluble factors (intact myoma, IM). HSC-3 cells were also co-cultured with CaDEC12 cells (fibroblasts exposed to human tongue cancer). CAV1 expression and cellular distribution were examined in different cellular components in hypoxic and rinsed myoma assays. Twist served as a marker for the process of epithelial-mesenchymal transition (EMT). Exosomes isolated from HSC-3 media were investigated for containing CAV1. Results Expression of CAV1 in TSCC had a higher score in TME than in the tumor cells and a negative impact on recurrence (p&#8201;=&#8201;0.01) and survival (p&#8201;=&#8201;0.003). Monocultures of HSC-3 revealed expression of CAV1 mainly in the TME-like myoma assay, similar to TSCC. CAV1+, alpha-smooth muscle actin (&#945;SMA)&#8201;+&#8201;and Twist&#8201;+&#8201;CAF-like cells were observed surrounding the invading HSC-3, possibly reflecting EMT. RM findings were similar to IM, inferring action of HSC-3 derived factors, and no differences were seen when hypoxia was induced. HSC-3-CaDEC12 co-cultures revealed CAV1+, &#945;SMA+ and cytokeratin-negative CAF-like cells, raising the possibility of CaDEC12 cells gaining a CAF phenotype. HSC-3-derived exosomes were loaded with CAV1. Conclusions Accumulation of CAV1-TME in TSCC had a negative prognostic value. In vitro studies showed the presence of CAV1 in cancer cells undergoing EMT and in fibroblasts undergoing trans-differentiation to CAFs. CAV1 delivery to the TME involved cancer cell-derived exosomes.
  • Lienemann, Taru; Kyyhkynen, Aino; Halkilahti, Jani; Haukka, Kaisa; Siitonen, Anja (BioMed Central, 2015)
    Abstract Background Salmonella enterica spp. enterica serotype Typhimurium (STM) is the most common agent of domestically acquired salmonellosis in Finland. Subtyping methods which allow the characterization of STM are essential for effective laboratory-based STM surveillance and for recognition of outbreaks. This study describes the diversity of Finnish STM isolates using phage typing, antimicrobial susceptible testing, pulsed-field gel electrophoresis (PFGE) and multilocus variable-number tandem repeat analysis (MLVA), and compares the discriminatory power and the concordance of these methods. Results A total of 375 sporadic STM isolates were analysed. The isolates were divided into 31 definite phage (DT) types, dominated by DT1 (47 % of the isolates), U277 (9 % of the isolates) and DT104 (8 % of the isolates). Of all the isolates, 62 % were susceptible to all the 12 antimicrobials tested and 11 % were multidrug resistant. Subtyping resulted in 83 different XbaI-PFGE profiles and 111 MLVA types. The three most common XbaI-PFGE profiles (STYM1, STYM7 and STYM8) and one MLVA profile with three single locus variants accounted for 56 % and 49 % of the STM isolates, respectively. The studied isolates showed a genetic similarity of more than 70 % by XbaI-PFGE. In MLVA, 71 % of the isolates lacked STTR6 and 77 % missed STTR10p loci. Nevertheless, the calculated Simpson’s diversity index for XbaI-PFGE was 0.829 (95 % CI 0.792−0.865) and for MLVA 0.867 (95 % CI 0.835−0.898). However, the discriminatory power of the 5-loci MLVA varied among the phage types. The highest concordance of the results was found between XbaI-PFGE and phage typing (adjusted Wallace coefficient was 0.833 and adjusted Rand coefficient was 0.627). Conclusions In general, the calculated discriminatory power was higher for genotyping methods (MLVA and XbaI-PFGE) than for phenotyping methods (phage typing). Overall, comparable diversity indices were calculated for PFGE and MLVA (both DI > 0.8). However, MLVA was phage type dependent providing better discrimination of the most common phage types. Furthermore, 5-loci MLVA was a less laborious method and easier to interpret than XbaI-PFGE. Thus, the laboratory-based surveillance of the Finnish human STM infections has been conducted with a combination of phage typing, antimicrobial susceptibility testing and 5-loci MLVA since January 2014.
  • Itkonen, Jaakko M; Urtti, Arto; Bird, Louise E; Sarkhel, Sanjay (BioMed Central Ltd, 2014)
    Abstract Background Neurotrophic factors influence survival, differentiation, proliferation and death of neuronal cells within the central nervous system. Human ciliary neurotrophic factor (hCNTF) has neuroprotective properties and is also known to influence energy balance. Consequently, hCNTF has potential therapeutic applications in neurodegenerative, obesity and diabetes related disorders. Clinical and biological applications of hCNTF necessitate a recombinant expression system to produce large amounts of functional protein in soluble form. Earlier attempts to express hCNTF in Escherichia coli (E. coli) were limited by low amounts and the need to refold from inclusion bodies. Results In this report, we describe a strategy to effectively identify constructs and conditions for soluble expression of hCNTF in E. coli. Small-scale expression screening with soluble fusion tags identified many conditions that yielded soluble expression. Codon optimized 6-His-hCNTF construct showed soluble expression in all the conditions tested. Large-scale culture of the 6-His-hCNTF construct yielded high (10 &#8211; 20 fold) soluble expression (8 &#8211; 9 fold) as compared to earlier published reports. Functional activity of recombinant 6-His-hCNTF produced was confirmed by its binding to hCNTF receptor (hCNTFR&#945;) with an EC50&#8201;=&#8201;36 nM. Conclusion Our results highlight the combination of codon optimization and screening soluble fusion tags as a successful strategy for high yielding soluble expression of hCNTF in E. coli. Codon optimization of the hCNTF sequence seems to be sufficient for soluble expression of hCNTF. The combined approach of codon optimization and soluble fusion tag screen can be an effective strategy for soluble expression of pharmaceutical proteins in E. coli.
  • Caburet, Sandrine; Anttonen, Mikko; Todeschini, Anne-Laure; Unkila-Kallio, Leila; Mestivier, Denis; Butzow, Ralf; Veitia, Reiner A (BioMed Central, 2015)
    Abstract Background Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression. Methods We have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes. Results Our results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related. Conclusions Our combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.
  • Mulligan, Anna M; Couch, Fergus J; Barrowdale, Daniel; Domchek, Susan M; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J; Robson, Mark; Sherman, Mark; Spurdle, Amanda B; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M; Janavicius, Ramunas; Hansen, Thomas vO; Nielsen, Finn C; Ejlertsen, Bent; Osorio, Ana; Muñoz-Repeto, Iván; Durán, Mercedes; Godino, Javier; Pertesi, Maroulio; Benítez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne EJ; Wijnen, Juul; Gómez García, Encarna B; Nelen, Marcel R; Kets, C Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine MA; van der Luijt, Rob B; Os, Theo; Rookus, Matti; Frost, Debra; Jones, J Louise; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K; Schmutzler, Rita K; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schäfer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Hardouin, Agnès; Berthet, Pascaline; Muller, Danièle; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo I; Weitzel, Jeffrey N; Lynch, Henry T; Ganz, Patricia A; Tomlinson, Gail E; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Lindor, Noralane M; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L; Greene, Mark H; Imyanitov, Evgeny; O'Malley, Frances P; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe B; Skytte, Anne-Bine; Caligo, Maria A; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan C; Neuhausen, Susan L; Beattie, Mary; Pharoah, Paul DP; Moysich, Kirsten B; Nathanson, Katherine L; Karlan, Beth Y; Gross, Jenny; John, Esther M; Daly, Mary B; Buys, Saundra M; Southey, Melissa C; Hopper, John L; Terry, Mary B; Chung, Wendy; Miron, Alexander F; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F; Andrulis, Irene L; Antoniou, Antonis C; Breast Cancer Family Registry; EMBRACE; GEMO Study Collaborators; HEBON; kConFab Investigators; Ontario Cancer Genetics Network; SWE-BRCA; CIMBA (BioMed Central Ltd, 2011)
    Abstract Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 &#215; 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.