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53. Identification of nine new susceptibility loci for endometrial cancer

Author

O'Mara, T, Glubb, D, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, P, Beckmann, M, Black, A, Humphreys, M, Brauch, H, Brenner, H, Brinton, L, Buchanan, D, Burwinkel, B, Chang-Claude, J, Chanock, S, Chen, C, Chen, M, Cheng, T, Clarke, C, Clendenning, M, Cook, L, Couch, F, Cox, A, Crous-Bou, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, S, Dürst, M, Ekici, A, Fasching, P, Fridley, B, Friedenreich, C, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, M, Giles, G, Goode, E, Gorman, M, Haiman, C, Hall, P, Hankinson, S, Healey, C, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, E, Holliday, E, Hopper, J, Hunter, D, Jones, A, Krakstad, C, Kristensen, V, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, A, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, R, Mints, M, Montgomery, G, Nassir, R, Olsson, H, Orlow, I, Sacerdote, G, Sarto, G, Schumacher, F, Scott, R, Setiawan, VW, Shah, M, Sheng, M, Shu, X-O, Southey, M, Swerdlow, A, Tham, E, Trovik, J, Wolk, A, Xia, L, Xiang, YB, Yang, H, Yu, H, Zheng, W, Pharoah, P, Dunning, A, Kraft, P, De Vivo, I, Tomlinson, I, Easton, D, Spurdle, A, and Thompson, D

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018

57. Identification of nine new susceptibility loci for endometrial cancer.

Author

Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., Michailidou K., Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., and Michailidou K.

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.Copyright © 2018, The Author(s).

Published
2018

58. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Author

Moller, P, Seppala, TT, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, RH, Jeffries, J, Vasen, HFA, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, JT, Jenkins, MA, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Valentin, MD, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Genuardi, M, Mecklin, J-P, Moeslein, G, Sampson, JR, Capella, G, Moller, P, Seppala, TT, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, RH, Jeffries, J, Vasen, HFA, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, JT, Jenkins, MA, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Valentin, MD, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Genuardi, M, Mecklin, J-P, Moeslein, G, Sampson, JR, and Capella, G

Abstract

BACKGROUND: Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. OBJECTIVE AND DESIGN: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. RESULTS: 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. CONCLUSION: Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Published
2018

59. Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses

Author

Painter, JN, O'Mara, TA, Morris, AP, Cheng, THT, Gorman, M, Martin, L, Hodson, S, Jones, A, Martin, NG, Gordon, S, Henders, AK, Attia, J, McEvoy, M, Holliday, EG, Scott, RJ, Webb, PM, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Ruebner, M, Hall, P, Czene, K, Doerk, T, Duerst, M, Hillemanns, P, Runnebaum, I, Lambrechts, D, Amant, F, Annibali, D, Depreeuw, J, Vanderstichele, A, Goode, EL, Cunningham, JM, Dowdy, SC, Winham, SJ, Trovik, J, Hoivik, E, Werner, HMJ, Krakstad, C, Ashton, K, Otton, G, Proietto, T, Tham, E, Mints, M, Ahmed, S, Healey, CS, Shah, M, Pharoah, PDP, Dunning, AM, Dennis, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Zondervan, KT, Nyholt, DR, MacGregor, S, Montgomery, GW, Tomlinson, I, Easton, DF, Thompson, DJ, Spurdle, AB, Painter, JN, O'Mara, TA, Morris, AP, Cheng, THT, Gorman, M, Martin, L, Hodson, S, Jones, A, Martin, NG, Gordon, S, Henders, AK, Attia, J, McEvoy, M, Holliday, EG, Scott, RJ, Webb, PM, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Ruebner, M, Hall, P, Czene, K, Doerk, T, Duerst, M, Hillemanns, P, Runnebaum, I, Lambrechts, D, Amant, F, Annibali, D, Depreeuw, J, Vanderstichele, A, Goode, EL, Cunningham, JM, Dowdy, SC, Winham, SJ, Trovik, J, Hoivik, E, Werner, HMJ, Krakstad, C, Ashton, K, Otton, G, Proietto, T, Tham, E, Mints, M, Ahmed, S, Healey, CS, Shah, M, Pharoah, PDP, Dunning, AM, Dennis, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Zondervan, KT, Nyholt, DR, MacGregor, S, Montgomery, GW, Tomlinson, I, Easton, DF, Thompson, DJ, and Spurdle, AB

Abstract

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Published
2018

60. Identification of nine new susceptibility loci for endometrial cancer

Author

O'Mara, TA, Glubb, DM, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Bolla, MK, Brauch, H, Brenner, H, Brinton, L, Buchanan, DD, Burwinkel, B, Chang-Claude, J, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Clarke, CL, Clendenning, M, Cook, LS, Couch, FJ, Cox, A, Crous-Bous, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, SC, Duerst, M, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Healey, CS, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hopper, JL, Hunter, DJ, Jones, A, Krakstad, C, Kristensen, VN, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, RL, Mints, M, Montgomery, GW, Nassir, R, Olsson, H, Orlow, I, Otton, G, Palles, C, Perry, JRB, Peto, J, Pooler, L, Prescott, J, Proietto, T, Rebbeck, TR, Risch, HA, Rogers, PAW, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Swerdlow, AJ, Tham, E, Trovik, J, Turman, C, Tyrer, JP, Vachon, C, Vanden Berg, D, Vanderstichele, A, Wang, Z, Webb, PM, Wentzensen, N, Werner, HMJ, Winham, SJ, Wolk, A, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Pharoah, PDP, Dunning, AM, Kraft, P, De Vivo, I, Tomlinson, I, Easton, DF, Spurdle, AB, Thompson, DJ, O'Mara, TA, Glubb, DM, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Bolla, MK, Brauch, H, Brenner, H, Brinton, L, Buchanan, DD, Burwinkel, B, Chang-Claude, J, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Clarke, CL, Clendenning, M, Cook, LS, Couch, FJ, Cox, A, Crous-Bous, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, SC, Duerst, M, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Healey, CS, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hopper, JL, Hunter, DJ, Jones, A, Krakstad, C, Kristensen, VN, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, RL, Mints, M, Montgomery, GW, Nassir, R, Olsson, H, Orlow, I, Otton, G, Palles, C, Perry, JRB, Peto, J, Pooler, L, Prescott, J, Proietto, T, Rebbeck, TR, Risch, HA, Rogers, PAW, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Swerdlow, AJ, Tham, E, Trovik, J, Turman, C, Tyrer, JP, Vachon, C, Vanden Berg, D, Vanderstichele, A, Wang, Z, Webb, PM, Wentzensen, N, Werner, HMJ, Winham, SJ, Wolk, A, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Pharoah, PDP, Dunning, AM, Kraft, P, De Vivo, I, Tomlinson, I, Easton, DF, Spurdle, AB, and Thompson, DJ

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018

61. PKN1 modulates TGFß and EGF signaling in HEC-1-A endometrial cancer cell line

Author

Attarha S, Saini RK, Andersson S, Mints M, and Souchelnytskyi S

Subjects
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract

Sanaz Attarha,1,2 Ravi Kanth Rao Saini,3 Sonia Andersson,2 Miriam Mints,2 Serhiy Souchelnytskyi1,4,5 1Department of Oncology–Pathology, 2Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 3Department of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; 4OCD-AB, Uppsala, Sweden; 5Neurocentrum, Karolinska University Hospital, Solna, Sweden Background: The response of cells to TGFβ and EGF is mediated by a network of various intracellular regulators. The signaling crosstalk between different regulators is of key importance for tumorigenesis. The crosstalk may explain the modulation of cellular responses to the same regulator by another signaling molecule. As PKN1 – a serine/threonine kinase implicated in tumorigenesis – was identified as potential crosstalk node for TGFβ and EGF signaling, the cellular functions that may be affected by PKN1 in a crosstalk of TGFβ and EGF were explored. Methods: To investigate the contribution of PKN1 to TGFβ and EGF signaling, transiently PKN1-transfected HEC-1-A endometrial cancer cells were generated and subjected to treatment with TGFβ1, EGF, and their combination. Proliferation, apoptosis, invasion, wound healing, and migration assays were performed. The impact of PKN1 on the expression and phosphorylation of intracellular proteins was monitored by immunoblotting. Results: It was demonstrated that PKN1 modulated the responses of HEC-A-1 endometrial cancer cells to TGFβ1 and EGF. PKN1 had an inhibitory effect on the stimulation of cell migration, and PKN1 kinase activity was required for the inhibitory effect of TGFβ and EGF on cell proliferation and invasiveness. It was observed that phosphorylation of Smad2, FAK, and Erk1/2 correlated with responses of the cells to TGFβ1 and EGF. Conclusion: PKN1 modulates TGFβ- and EGF-dependent regulation of cell proliferation, migration, and invasiveness, and therefore is a component of the network signaling downstream of TGFβ and EGF. Keywords: PKN1 kinase, TGFβ, EGF, cell migration, proliferation, invasiveness

Published
2014

63. Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

Author

Cuppens, T., Annibali, D., Coosemans, A., Trovik, J., Haar, N. Ter, Colas, E., Garcia-Jimenez, A., Vijver, K. van der, Kruitwagen, R.P., Brinkhuis, M., Zikan, M., Dundr, P., Huvila, J., Carpen, O., Haybaeck, J., Moinfar, F., Salvesen, H.B., Stukan, M., Mestdagh, C., Zweemer, R.P., Massuger, L.F.A.G., Mallmann, M.R., Wardelmann, E., Mints, M., Verbist, G., Thomas, D, Gomme, E., Hermans, E, Moerman, P., Bosse, T., Amant, F., Cuppens, T., Annibali, D., Coosemans, A., Trovik, J., Haar, N. Ter, Colas, E., Garcia-Jimenez, A., Vijver, K. van der, Kruitwagen, R.P., Brinkhuis, M., Zikan, M., Dundr, P., Huvila, J., Carpen, O., Haybaeck, J., Moinfar, F., Salvesen, H.B., Stukan, M., Mestdagh, C., Zweemer, R.P., Massuger, L.F.A.G., Mallmann, M.R., Wardelmann, E., Mints, M., Verbist, G., Thomas, D, Gomme, E., Hermans, E, Moerman, P., Bosse, T., and Amant, F.

Abstract

Contains fulltext : 170511.pdf (publisher's version ) (Closed access), Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-alpha, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. (c)2017 AACR.

Published
2017

64. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Author

Moller, P, Seppala, T, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Jenkins, M, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Genuardi, M, Mecklin, J-P, Moslein, G, Sampson, JR, Capella, G, Moller, P, Seppala, T, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Jenkins, M, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Genuardi, M, Mecklin, J-P, Moslein, G, Sampson, JR, and Capella, G

Abstract

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

Published
2017

65. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

Author

Moller, P, Seppala, T, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Sampson, JR, Capella, G, Mecklin, J-P, Moslein, G, Moller, P, Seppala, T, Bernstein, I, Holinski-Feder, E, Sala, P, Evans, DG, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Frayling, IM, Plazzer, J-P, Pylvanainen, K, Sampson, JR, Capella, G, Mecklin, J-P, and Moslein, G

Abstract

OBJECTIVE: Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Published
2017

66. Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report

Author

Seppala, T, Pylvanainen, K, Evans, DG, Jarvinen, H, Renkonen-Sinisalo, L, Bernstein, I, Holinski-Feder, E, Sala, P, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Jenkins, M, Genuardi, M, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Frayling, IM, Plazzer, J-P, Sampson, JR, Capella, G, Moslein, G, Mecklin, J-P, Moller, P, Seppala, T, Pylvanainen, K, Evans, DG, Jarvinen, H, Renkonen-Sinisalo, L, Bernstein, I, Holinski-Feder, E, Sala, P, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R, Jeffries, J, Vasen, H, Burn, J, Nakken, S, Hovig, E, Rodland, EA, Tharmaratnam, K, Cappel, WHDVTN, Hill, J, Wijnen, J, Jenkins, M, Genuardi, M, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Frayling, IM, Plazzer, J-P, Sampson, JR, Capella, G, Moslein, G, Mecklin, J-P, and Moller, P

Abstract

BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. RESULTS: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). CONCLUSIONS: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with

Published
2017

67. Five endometrial cancer risk loci identified through genome-wide association analysis

Author

Cheng, THT, Thompson, DJ, O'Mara, TA, Painter, JN, Glubb, DM, Flach, S, Lewis, A, French, JD, Freeman-Mills, L, Church, D, Gorman, M, Martin, L, National Study of Endometrial Cancer Genetics Group (NSECG), Hodgson, S, Webb, PM, Australian National Endometrial Cancer Study Group (ANECS), Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Henders, AK, Martin, NG, Montgomery, GW, Nyholt, DR, Ahmed, S, Healey, CS, Shah, M, Dennis, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, I, Amant, F, Schrauwen, S, Zhao, H, Lambrechts, D, Depreeuw, J, Dowdy, SC, Goode, EL, Fridley, BL, Winham, SJ, Njølstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, K, Otton, G, Proietto, T, Liu, T, Mints, M, Tham, E, RENDOCAS, CHIBCHA Consortium, Li, MJ, Yip, SH, Wang, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Dunlop, M, Houlston, R, Palles, C, Hopper, JL, AOCS Group, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Cunningham, JM, Pharoah, PDP, Dunning, AM, Edwards, SL, Easton, DF, Tomlinson, I, Spurdle, AB, Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Humans, Female, Genetic Predisposition to Disease, Promoter Regions, Genetic, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 8, Endometrial Neoplasms, Genome-Wide Association Study
Abstract

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Published
2016

70. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author

Painter, J.N., O'Mara, T.A., Batra, J., Cheng, T., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Kaufmann, S., Hillman, K.M., Walpole, C., Moya, L., Pollock, P., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Magdalena Echeverry De Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Santos, E., Teixeira, M.R., Carvajal-Carmona, L., Shu, X-O., Long, J., Zheng, W., Xiang, Y-B., Montgomery, G.W., Webb, P.M., Scott, R.J., McEvoy, M., Attia, J., Holliday, E., Martin, N.G., Nyholt, D.R., Henders, A.K., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Ashton, K., Proietto, T., Otton, G., Tzortzatos, G., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., French, J.D., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Edwards, S.L., Thompson, D.J., Spurdle, A.B., Canc, N.S.E., Consortium, CHIBCHA, Canc, ANE, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository

Subjects
Genotype, Chromosome Mapping, Computational Biology, Genetic Variation, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Endometrial Neoplasms, Epigenesis, Genetic, Haplotypes, Genetic Loci, Risk Factors, Case-Control Studies, Cell Line, Tumor, Databases, Genetic, Humans, Female, RNA, Messenger, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. ispartof: Human Molecular Genetics vol:24 issue:5 pages:1478-92 ispartof: location:England status: published

Published
2015

71. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N.., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Pooley, K., Beesley, J., Cheng, T., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Wentzensen, N., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Scott, R.J., Ashton, K., Proietto, T., Otton, G., Wersaell, O., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A.-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Spurdle, A.B., Thompson, D.J., NSECG, ANECS, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
National Study of Endometrial Cancer Genetics Group, Australian Ovarian Cancer Study, Polymorphism, Single Nucleotide, Chromosomes, Promoter Regions, Paediatrics and Reproductive Medicine, Databases, Uterine Cancer, Genetic, Complementary and Alternative Medicine, Risk Factors, Models, Australian National Endometrial Cancer Study Group, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Testing, Aetiology, Polymorphism, Promoter Regions, Genetic, Telomerase, Cancer, Genetics & Heredity, Neoplastic, Models, Genetic, Nucleic Acid, RENDOCAS, Prevention, Human Genome, Membrane Proteins, Single Nucleotide, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Haplotypes, Genetic Loci, Chromosomes, Human, Pair 5, Female, GENICA Network, Pair 5, Databases, Nucleic Acid, Human
Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. ispartof: Human Genetics vol:134 issue:2 pages:231-45 ispartof: location:Germany status: published

Published
2015

72. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author

Cheng, T.H.T., Thompson, D., Painter, J., O'Mara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D.D., Win, A.K., Hopper, J., Jenkins, M., Lindor, N.M., Newcomb, P.A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Giles, G.G., Pharoah, P., Peto, J., Cox, A., Swerdlow, A., Couch, F., Cunningham, J.M., Goode, E.L., Winham, S.J., Lambrechts, D., Fasching, P., Burwinkel, B., Brenner, H., Brauch, H., Chang-Claude, J., Salvesen, H.B., Kristensen, V., Darabi, H., Li, J., Liu, T., Lindblom, A., Hall, P., Echeverry de Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Jr, A.S., Teixeira, M.R., Dunning, A.M., Dennis, J., Otton, G., Proietto, T., Holliday, E., Attia, J., Ashton, K., Scott, R.J., McEvoy, M., Dowdy, S.C., Fridley, B.L., Werner, H.M.J., Trovik, J., Njolstad, T.S., Tham, E., Mints, M., Runnebaum, I., Hillemanns, P., Doerk, T., Amant, F., Schrauwen, S., Hein, A., Beckmann, M.W., Ekici, A., Czene, K., Meindl, A., Bolla, M.K., Michailidou, K., Tyrer, J.P., Wang, Q., Ahmed, S., Healey, C.S., Shah, M., Annibali, D., Depreeuw, J., Al-Tassan, N.A., Harris, R., Meyer, B.F., Whiffin, N., Hosking, F.J., Kinnersley, B., Farrington, S.M., Timofeeva, M., Tenesa, A., Campbell, H., Haile, R.W., Hodgson, S., Carvajal-Carmona, L., Cheadle, J.P., Easton, D., Dunlop, M., Houlston, R., Spurdle, A., Tomlinson, I., and Other departments

Subjects
Male, CARCINOMA, MICROSATELLITE INSTABILITY, DNA-POLYMERASE, LOCI, MTHFR C677T, VARIANTS, LYNCH-SYNDROME, Article, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Alleles, Adaptor Proteins, Signal Transducing, RISK, Homeodomain Proteins, Science & Technology, Polymorphism, Genetic, MUTATIONS, Intracellular Signaling Peptides and Proteins, Proteins, Endometrial Neoplasms, Neoplasm Proteins, Multidisciplinary Sciences, Repressor Proteins, Science & Technology - Other Topics, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. ispartof: Scientific Reports vol:5 pages:17369- ispartof: location:England status: published

Published
2015
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73. Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines

Author

Mints, M. and Serhiy Souchelnytskyi

Subjects
Epidermal Growth Factor, Estradiol, Original contributions, Antineoplastic Agents, Breast Neoplasms, Drug Combinations, Transforming Growth Factor beta, Cell Line, Tumor, Humans, Female, skin and connective tissue diseases, hormones, hormone substitutes, and hormone antagonists, Cell Proliferation, Signal Transduction
Abstract

Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFβ and 17β-oestradiol, three important regulators of breast tumourigenesis, and their respective inhibitors in different combinations. Materials and Methods: We screened the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFβ and 17β-oestradiol, Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation data. Results: In MDA-MB-231 cells, TGFβ1 was found inhibitory when cells were simultaneously treated with EGF and 17β-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the inhibitory effect of TGFβ in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points, showing enhanced TGFβ and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade respectively, and combined TGFβ-EGF expression to decrease the risk of metastasis. Conclusion: Our study shows significant differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form metastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these differences are unexpected and confirmed by clinical observations. Key Words: breast cancer, combinatorial treatment, EGF, oestrogen, TGFβ.

Published
2014

74. Three-dimensional density model of the earth’s crust of the territory of the Republic of Niger

Author

Glaznev V.N., Mints M.V., and Yakuba I.A.

Subjects
earth’s crust, gravity field, three-dimensional inverse problem of gravimetry, Geology, QE1-996.5
Abstract

The paper considers the results of calculation of the three-dimensional density model of the Earth’s crust for the territory of the Republic of Niger in conditions of incomplete initial geological and geophysical information. A brief description of the geological structure of the research region is given and the task of the study is formulated. The initial data set of density modeling is described, including: the anomalous gravity field, the initial model of the medium, the constraints on the desired solution, and the weight functions of redistribution of field incompatibilities. Inversion of the anomalous gravity field was performed in a three-dimensional formulation for a regular grid with a 25×25 km spacing in the plan and 14 layers of irregular vertical grid. The density model of the crystalline crust obtained by solving the inverse problem was combined with a priori data on the density of the upper mantle layer and the previously constructed layered model of the sedimentary cover of the region. The main features of the density model of the Earth’s crust are considered and its density heterogeneities are compared with the regional geological and tectonic data. The leading role of young structures of the West African rift System and their relationship with density inhomogeneities in the lower and middle crust of the territory of the Republic of Niger was noted.

Published
2021
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77. The Gynecological Surveillance Of Women With Lynch Syndrome In Sweden

Author

Mints, M., Tzortzatos, G., Andersson, E., Soller, M., Askmalm, M. Stenmark, Zagoras, T., Georgii-Hemming, Patrik, Lindblom, A., Tham, E., Mints, M., Tzortzatos, G., Andersson, E., Soller, M., Askmalm, M. Stenmark, Zagoras, T., Georgii-Hemming, Patrik, Lindblom, A., and Tham, E.

Published
2015

78. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author

Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, Spurdle, AB, Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, and Spurdle, AB

Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Published
2015

79. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, LG, O'Mara, TA, Painter, JN, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Pooley, K, Beesley, J, Cheng, T, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Wentzensen, N, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Wersaell, O, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Spurdle, AB, Thompson, DJ, Carvajal-Carmona, LG, O'Mara, TA, Painter, JN, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Pooley, K, Beesley, J, Cheng, T, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Wentzensen, N, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Wersaell, O, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Spurdle, AB, and Thompson, DJ

Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Published
2015

80. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author

Cheng, THT, Thompson, D, Painter, J, O'Mara, T, Gorman, M, Martin, L, Palles, C, Jones, A, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Giles, GG, Pharoah, P, Peto, J, Cox, A, Swerdlow, A, Couch, F, Cunningham, JM, Goode, EL, Winham, SJ, Lambrechts, D, Fasching, P, Burwinkel, B, Brenner, H, Brauch, H, Chang-Claude, J, Salvesen, HB, Kristensen, V, Darabi, H, Li, J, Liu, T, Lindblom, A, Hall, P, Echeverry de Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Aguiar, S, Teixeira, MR, Dunning, AM, Dennis, J, Otton, G, Proietto, T, Holliday, E, Attia, J, Ashton, K, Scott, RJ, McEvoy, M, Dowdy, SC, Fridley, BL, Werner, HMJ, Trovik, J, Njolstad, TS, Tham, E, Mints, M, Runnebaum, I, Hillemanns, P, Doerk, T, Amant, F, Schrauwen, S, Hein, A, Beckmann, MW, Ekici, A, Czene, K, Meindl, A, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, Ahmed, S, Healey, CS, Shah, M, Annibali, D, Depreeuw, J, Al-Tassan, NA, Harris, R, Meyer, BF, Whiffin, N, Hosking, FJ, Kinnersley, B, Farrington, SM, Timofeeva, M, Tenesa, A, Campbell, H, Haile, RW, Hodgson, S, Carvajal-Carmona, L, Cheadle, JP, Easton, D, Dunlop, M, Houlston, R, Spurdle, A, Tomlinson, I, Cheng, THT, Thompson, D, Painter, J, O'Mara, T, Gorman, M, Martin, L, Palles, C, Jones, A, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Giles, GG, Pharoah, P, Peto, J, Cox, A, Swerdlow, A, Couch, F, Cunningham, JM, Goode, EL, Winham, SJ, Lambrechts, D, Fasching, P, Burwinkel, B, Brenner, H, Brauch, H, Chang-Claude, J, Salvesen, HB, Kristensen, V, Darabi, H, Li, J, Liu, T, Lindblom, A, Hall, P, Echeverry de Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Aguiar, S, Teixeira, MR, Dunning, AM, Dennis, J, Otton, G, Proietto, T, Holliday, E, Attia, J, Ashton, K, Scott, RJ, McEvoy, M, Dowdy, SC, Fridley, BL, Werner, HMJ, Trovik, J, Njolstad, TS, Tham, E, Mints, M, Runnebaum, I, Hillemanns, P, Doerk, T, Amant, F, Schrauwen, S, Hein, A, Beckmann, MW, Ekici, A, Czene, K, Meindl, A, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, Ahmed, S, Healey, CS, Shah, M, Annibali, D, Depreeuw, J, Al-Tassan, NA, Harris, R, Meyer, BF, Whiffin, N, Hosking, FJ, Kinnersley, B, Farrington, SM, Timofeeva, M, Tenesa, A, Campbell, H, Haile, RW, Hodgson, S, Carvajal-Carmona, L, Cheadle, JP, Easton, D, Dunlop, M, Houlston, R, Spurdle, A, and Tomlinson, I

Abstract

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

Published
2015

100. Melting of eclogite facies sedimentary rocks in the Belomorian Eclogite Province, Russia.

Author

Dokukina, K. A., Mints, M. V., and Konilov, A. N.

Subjects
*ECLOGITE, *SEDIMENTARY rocks, *SUBDUCTION, *MESOARCHAEAN, *SEDIMENTS
Abstract

The eclogites exposed along northeastern boundary of the Belomorian orogen in the eastern Fennoscandian Shield were formed as a result of Mesoarchean–Neoarchean subduction and collision. As has been shown previously, the common protolith of the Salma-type subduction-related eclogite was oceanic layered gabbro. In this paper, we characterize eclogites formed from volcanic–sedimentary rocks of the upper oceanic crust, which comprised pillow lavas and associated aluminous sediments that filled the interpillow space intercalated with lava flows. As a result of eclogite facies metamorphism, the aluminous sediments have been transformed into coarse-grained garnet–phengite–quartz rocks under pressure no lower than 21 kbar at a temperature of ~650 °C. Alternatively, we cannot rule out the possibility that the garnet–phengite–quartz veins represent solidified felsic melts that were produced by melting of boron-bearing hydrothermally altered oceanic crust in the subduction zone. During transfer to the upper crust under high-P granulite facies conditions, phengite underwent incongruent melting with formation of complex polymineralic pseudomorphs consisting of feldspar, biotite, muscovite and kyanite with corundum and dumortierite. The peak of high-T metamorphism during exhumation of the eclogites is estimated at 850–900 °C, i.e. at least 50–100 °C higher than previous estimates. [ABSTRACT FROM AUTHOR]

Published
2017
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