Browsing by Subject "MESSENGER-RNA DECAY"

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  • Patel, V.L.; Busch, E.L.; Friebel, T.M.; Cronin, A.; Leslie, G.; McGuffog, L.; Adlard, J.; Agata, S.; Agnarsson, B.A.; Ahmed, M.; Aittomäki, K.; Alducci, E.; Andrulis, I.L.; Arason, A.; Arnold, N.; Artioli, G.; Arver, B.; Auber, B.; Azzollini, J.; Balmaña, J.; Barkardottir, R.B.; Barnes, D.R.; Barroso, A.; Barrowdale, D.; Belotti, M.; Benitez, J.; Bertelsen, B.; Blok, M.J.; Bodrogi, I.; Bonadona, V.; Bonanni, B.; Bondavalli, D.; Boonen, S.E.; Borde, J.; Borg, A.; Bradbury, A.R.; Brady, A.; Brewer, C.; Brunet, J.; Buecher, B.; Buys, S.S.; Cabezas-Camarero, S.; Caldes, T.; Caliebe, A.; Caligo, M.A.; Calvello, M.; Campbell, I.G.; Carnevali, I.; Carrasco, E.; Chan, T.L.; Chu, A.T.W.; Chung, W.K.; Claes, K.B.M.; Cook, J.; Cortesi, L.; Couch, F.J.; Daly, M.B.; Damante, G.; Darder, E.; Davidson, R.; De La Hoya, M.; Della Puppa, L.; Dennis, J.; Díez, O.; Ding, Y.C.; Ditsch, N.; Domchek, S.M.; Donaldson, A.; Dworniczak, B.; Easton, D.F.; Eccles, D.M.; Eeles, R.A.; Ehrencrona, H.; Ejlertsen, B.; Engel, C.; Evans, D.G.; Faivre, L.; Faust, U.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Fountzilas, G.; Frost, D.; García-Barberan, V.; Garre, P.; Gauthier-Villars, M.; Geczi, L.; Gehrig, A.; Gerdes, A.-M.; Gesta, P.; Giannini, G.; Glendon, G.; Godwin, A.K.; Goldgar, D.E.; Greene, M.H.; Gutierrez-Barrera, A.M.; Hahnen, E.; Hamann, U.; Hauke, J.; Herold, N.; Hogervorst, F.B.L.; Honisch, E.; Hopper, J.L.; Hulick, P.J.; Izatt, L.; Jager, A.; James, P.; Janavicius, R.; Jensen, U.B.; Jensen, T.D.; Johannsson, O.Th.; John, E.M.; Joseph, V.; Kang, E.; Kast, K.; Kiiski, J.I.; Kim, S.-W.; Kim, Z.; Ko, K.-P.; Konstantopoulou, I.; Kramer, G.; Krogh, L.; Kruse, T.A.; Kwong, A.; Larsen, M.; Lasset, C.; Lautrup, C.; Lazaro, C.; Lee, J.; Lee, J.W.; Lee, M.H.; Lemke, J.; Lesueur, F.; Liljegren, A.; Lindblom, A.; Llovet, P.; Lopez-Fernandez, A.; Lopez-Perolio, I.; Lorca, V.; Loud, J.T.; Ma, E.S.K.; Mai, P.L.; Manoukian, S.; Mari, V.; Martin, L.; Matricardi, L.; Mebirouk, N.; Medici, V.; Meijers-Heijboer, H.E.J.; Meindl, A.; Mensenkamp, A.R.; Miller, C.; Gomes, D.M.; Montagna, M.; Mooij, T.M.; Moserle, L.; Mouret-Fourme, E.; Mulligan, A.M.; Nathanson, K.L.; Navratilova, M.; Nevanlinna, H.; Niederacher, D.; Cilius Nielsen, F.C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O.I.; Ong, K.-R.; Osorio, A.; Ott, C.-E.; Palli, D.; Park, S.K.; Parsons, M.T.; Pedersen, I.S.; Peissel, B.; Peixoto, A.; Perez-Segura, P.; Peterlongo, P.; Petersen, A.H.; Porteous, M.E.; Pujana, M.A.; Radice, P.; Ramser, J.; Rantala, J.; Rashid, M.U.; Rhiem, K.; Rizzolo, P.; Robson, M.E.; Rookus, M.A.; Rossing, C.M.; Ruddy, K.J.; Santos, C.; Saule, C.; Scarpitta, R.; Schmutzler, R.K.; Schuster, H.; Senter, L.; Seynaeve, C.M.; Shah, P.D.; Sharma, P.; Shin, V.Y.; Silvestri, V.; Simard, J.; Singer, C.F.; Skytte, A.-B.; Snape, K.; Solano, A.R.; Soucy, P.; Southey, M.C.; Spurdle, A.B.; Steele, L.; Steinemann, D.; Stoppa-Lyonnet, D.; Stradella, A.; Sunde, L.; Sutter, C.; Tan, Y.Y.; Teixeira, M.R.; Teo, S.H.; Thomassen, M.; Tibiletti, M.G.; Tischkowitz, M.; Tognazzo, S.; Toland, A.E.; Tommasi, S.; Torres, D.; Toss, A.; Trainer, A.H.; Tung, N.; Van Asperen, C.J.; Van Der Baan, F.H.; Van Der Kolk, L.E.; Van Der Luijt, R.B.; Van Hest, L.P.; Varesco, L.; Varon-Mateeva, R.; Viel, A.; Vierstrate, J.; Villa, R.; Von Wachenfeldt, A.; Wagner, P.; Wang-Gohrke, S.; Wappenschmidt, B.; Weitzel, J.N.; Wieme, G.; Yadav, S.; Yannoukakos, D.; Yoon, S.-Y.; Zanzottera, C.; Zorn, K.K.; D’Amico, A.V.; Freedman, M.L.; Pomerantz, M.M.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.L.; Ottini, L.; Nielsen, H.R.; Rebbeck, T.R. (2020)
    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
  • Rebbeck, Timothy R.; Mitra, Nandita; Wan, Fei; Sinilnikova, Olga M.; Healey, Sue; McGuffog, Lesley; Mazoyer, Sylvie; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.; Nathanson, Katherine L.; CIMBA Consortium; Nevanlinna, Heli; Aittomäki, Kristiina (2015)
    IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317(12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682(6%) with ovarian cancer, 272(2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% Cl, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RH R = 1.34; 95% Cl, 1.01-1.78; P =.04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% Cl, 1.22-1.55; P = 6 x 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% Cl, 0.56-0.70; P = 9 x 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% Cl, 1.06-2.78; P =.03), c.772 to c.1806 (BCCRI; RHR = 1.63; 95% Cl, 1.10-2.40; P =.01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% Cl, 1.69-3.16; P =.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% Cl, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% Cl, 0.41-0.80; P =.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
  • Lagus, Heli; Klaas, Mariliis; Juteau, Susanna; Elomaa, Outi; Kere, Juha; Vuola, Jyrki; Jaks, Viljar; Kankuri, Esko (2019)
    Because molecular memories of past inflammatory events can persist in epidermal cells, we evaluated the long-term epidermal protein expression landscapes after dermal regeneration and in psoriatic inflammation. We first characterized the effects of two dermal regeneration strategies on transplants of indicator split-thickness skin grafts (STSGs) in ten adult patients with deep burns covering more than 20% of their body surface area. After fascial excision, three adjacent areas within the wound were randomized to receive a permanent dermal matrix, a temporary granulation-tissue-inducing dressing or no dermal component as control. Control areas were covered with STSG immediately, and treated areas after two-weeks of dermis formation. Epidermis-dermis-targeted proteomics of one-year-follow-up samples were performed for protein expression profiling. Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Given the dermal inflammatory component found in our dermal regeneration samples as well as in early psoriatic lesions, we hypothesized that DNAH10 protein expression also would be affected in psoriatic skin samples. We discovered increased DNAH10 expression in inflammatory lesions when compared to unaffected skin. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. This study (ISRCTN14499986) was funded by the Finnish Ministry of Defense and by government subsidies for medical research.
  • Tervaniemi, Mari H.; Katayama, Shintaro; Skoog, Tiina; Siitonen, H. Annika; Vuola, Jyrki; Nuutila, Kristo; Tammimies, Kristiina; Suomela, Sari; Kankuri, Esko; Kere, Juha; Elomaa, Outi (2018)
    Background: CCHCR1 (Coiled Coil alpha-Helical Rod protein 1) is a putative psoriasis candidate gene with the risk alleles CCHCR1*WWCC and *Iso3, the latter inhibiting the translation of isoform 1. CCHCR1 was recently shown to be a centiosomal piotein, as well as a component of cytoplasmic piocessmg bodies (P-bodies) that regulate mRNA turnovel. The function of CCHCR1 has remained unsettled, partly because of the inconsistent findings, it has been shown to play a wide variety of roles in divergent processes, e.g., cell proliferation and steroidogenesis. Here we utilized RNA sequencing (RNAseq) using HEK293 cells overexpressing isoforms 1 or 3 (Iso1, Iso3 cells), in combination with the coding non-risk or risk (*WWCC haplotype of CCHCR1. Our aim was to study the overall role of CCHCR1 and the effects of its variants. Results: The overexpression of CCHCR1 variants in HEK293 cells resulted in cell line-specific expression profiles though seveial similarities were observable. Overall the Iso1 and Iso3 cells showed a clear isoform-specific clustering as two separate groups, and the Non-risk and Risk cells often exhibited opposite effects. The RNAseq supported a role for CCHCR1 in the centrosomes and P-bodies; the most highlighted pathways included regulation of cytoskeleton, adherens and tight junctions, mRNA surveillance and RNA transport. Interestingly, both the RNAseq and immunofluorescent localization revealed variant-specific differences for CCHCR1 within the P-bodies. Conclusions: CCHCR1 influenced a wide variety of signaling pathways, which could reflect its active role in the P-bodies and centrosomes that both are linked to the cytoskeleton; as a centrosomal P-body protein CCHCR1 may regulate diverse cytoskeleton-mediated functions, such as cell adhesion and division. The piesent findings may explain the previous inconsistent obseivations about the functions of CCHCR1.
  • Mattila, Henna; Schindler, Martin; Isotalo, Jarkko; Ikonen, Tarja; Vihinen, Mauno; Oja, Hannu; Tammela, Teuvo L. J.; Wahlfors, Tiina; Schleutker, Johanna (2011)