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14 results on '"Freedman, M.L."'

1. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author

DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., Jones, M.R., DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., and Jones, M.R.

Abstract

Item does not contain fulltext, BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Published
2022

2. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

Author

Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Altıntaş, Umut Berkay, Kneppers, J.; Severson, T.M.; Siefert, J.C.; Schol, P.; Joosten, S.E.P.; Yu, I.P.L.; Huang, C.F.; Morova, T.; Giambartolomei, C.; Seo, J.H.; Baca, S.C.; Carneiro, I.; Emberly, E.; Pasaniuc, B.; Jerónimo, C.; Henrique, R.; Freedman, M.L.; Wessels, L.F.A.; Bergman, A.M.; Zwart, W., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; Graduate School of Sciences and Engineering, Department of Computational Sciences and Engineering, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Altıntaş, Umut Berkay, Kneppers, J.; Severson, T.M.; Siefert, J.C.; Schol, P.; Joosten, S.E.P.; Yu, I.P.L.; Huang, C.F.; Morova, T.; Giambartolomei, C.; Seo, J.H.; Baca, S.C.; Carneiro, I.; Emberly, E.; Pasaniuc, B.; Jerónimo, C.; Henrique, R.; Freedman, M.L.; Wessels, L.F.A.; Bergman, A.M.; Zwart, W., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; Graduate School of Sciences and Engineering, and Department of Computational Sciences and Engineering

Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact., We would like to acknowledge the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support and the NKI Research High-Performance Computing (RHPC) facility for computational infrastructure. We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. This work was supported by the Prostate Cancer Foundation (21CHAL04), Department of Defense (W81XWH-21-1-0234, W81XWH-19-1-0565), Oncode Institute and Alpe d’HuZes/KWF Dutch Cancer Society (10084).

Published
2022

3. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

Author

Engel C., 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., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana 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., Diez 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., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-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., Engel C., 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., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana 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., Diez 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., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-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., and Scarpitta R.

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 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 1/4 1.78; 95% confidence interval (CI), 1.25-2.52; P 1/4 0.001], as well as elevated risk of Gleason 8 prostate cancer (HR 1/4 3.11; 95% CI, 1.63-5.95; P 1/4 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR 1/4 2.83; 95% CI, 1.71-4.68; P 1/4 0.00004) and elevated risk of Gleason 8 prostate cancer (HR 1/4 4.95; 95% CI, 2.12-11.54; P 1/4 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.Copyright © 2020 American Association for Cancer Research.

Published
2020

5. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

Buckley, Melissa A., Woods, N., Tyrer, J.P., Mendoza-Fandino, Gustavo, Lawrenson, Kate, Hazelett, D.J., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Kelemen, Linda E., Freedman, M.L., Buckley, Melissa A., Woods, N., Tyrer, J.P., Mendoza-Fandino, Gustavo, Lawrenson, Kate, Hazelett, D.J., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Kelemen, Linda E., and Freedman, M.L.

Abstract

Contains fulltext : 201137.pdf (publisher's version ) (Closed access)

Published
2019

6. The physical development of a privilaged group of African children

Author

Kahn, E. and Freedman, M.L.

Abstract

The height (body length) and the weight of children depend on a number of factors of which the most important are age, heredity and environment. In under-developed areas· the exact age of the children is often unknown and this may be one of the reasons why few attempts have been made to establish height and weight standards for African children.

Published
2018

7. Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Author

Giri, V.N. (Veda), Knudsen, K.E. (Karen E.), Kelly, W.K. (William K.), Abida, W. (Wassim), Andriole, G.L. (Gerald), Bangma, C.H. (Chris), Bekelman, J.E. (Justin E.), Benson, M.C. (Mitchell C.), Blanco, A. (Amie), Burnett, A. (Arthur), Catalona, W.J. (William J.), Cooney, K.A. (Kathleen A.), Cooperberg, M.R. (Matthew), Crawford, D. (David), Den, R.B. (Robert B.), Dicker, A.P. (Adam P.), Eggener, S. (Scott), Fleshner, N.E. (Neil), Freedman, M.L. (Matthew L.), Hamdy, F. (Freddie), Hoffman-Censits, J. (Jean), Hurwitz, M.D. (Mark D.), Hyatt, C. (Colette), Isaacs, W.B. (William B.), Kane, C.J. (Christopher J.), Kantoff, P. (Philip), Karnes, R.J. (Jeffrey), Karsh, L.I. (Lawrence I.), Klein, E.A. (Eric A.), Lin, D.W. (Daniel W.), Loughlin, K.R. (Kevin R.), Lu-Yao, G. (Grace), Malkowicz, S.B. (S. Bruce), Mann, M.J. (Mark J.), Mark, J.R. (James R.), McCue, P.A. (Peter A.), Miner, M.M. (Martin M.), Morgan, T. (Todd), Moul, J.W. (Judd W.), Myers, R.E. (Ronald E.), Nielsen, S.M. (Sarah M.), Obeid, E. (Elias), Pavlovich, C.P. (Christian P.), Peiper, S.C. (Stephen C.), Penson, D.F. (David F.), Petrylak, D.P. (Daniel P), Pettaway, C.A. (Curtis A.), Pilarski, R. (Robert), Pinto, P. (Peter), Poage, W. (Wendy), Raj, G.V. (Ganesh V.), Rebbeck, R. (Timothy), Robson, M. (Mark), Rosenberg, M.T. (Matt T.), Sandler, H. (Howard), Sartor, A.O. (Oliver), Schaeffer, E. (Edward), Schwartz, G.F. (Gordon F.), Shahin, M.S. (Mark S.), Shore, N.D. (Neal), Shuch, B. (Brian), Soule, H.R. (Howard R.), Tomlins, S.A. (Scott A), Trabulsi, E.J. (Edouard J.), Uzzo, R. (Robert), Griend, D.J.V. (Donald J. Vander), Walsh, P.C. (Patrick), Weil, C.J. (Carol J.), Wender, R. (Richard), Gomella, L.G. (Leonard G.), Giri, V.N. (Veda), Knudsen, K.E. (Karen E.), Kelly, W.K. (William K.), Abida, W. (Wassim), Andriole, G.L. (Gerald), Bangma, C.H. (Chris), Bekelman, J.E. (Justin E.), Benson, M.C. (Mitchell C.), Blanco, A. (Amie), Burnett, A. (Arthur), Catalona, W.J. (William J.), Cooney, K.A. (Kathleen A.), Cooperberg, M.R. (Matthew), Crawford, D. (David), Den, R.B. (Robert B.), Dicker, A.P. (Adam P.), Eggener, S. (Scott), Fleshner, N.E. (Neil), Freedman, M.L. (Matthew L.), Hamdy, F. (Freddie), Hoffman-Censits, J. (Jean), Hurwitz, M.D. (Mark D.), Hyatt, C. (Colette), Isaacs, W.B. (William B.), Kane, C.J. (Christopher J.), Kantoff, P. (Philip), Karnes, R.J. (Jeffrey), Karsh, L.I. (Lawrence I.), Klein, E.A. (Eric A.), Lin, D.W. (Daniel W.), Loughlin, K.R. (Kevin R.), Lu-Yao, G. (Grace), Malkowicz, S.B. (S. Bruce), Mann, M.J. (Mark J.), Mark, J.R. (James R.), McCue, P.A. (Peter A.), Miner, M.M. (Martin M.), Morgan, T. (Todd), Moul, J.W. (Judd W.), Myers, R.E. (Ronald E.), Nielsen, S.M. (Sarah M.), Obeid, E. (Elias), Pavlovich, C.P. (Christian P.), Peiper, S.C. (Stephen C.), Penson, D.F. (David F.), Petrylak, D.P. (Daniel P), Pettaway, C.A. (Curtis A.), Pilarski, R. (Robert), Pinto, P. (Peter), Poage, W. (Wendy), Raj, G.V. (Ganesh V.), Rebbeck, R. (Timothy), Robson, M. (Mark), Rosenberg, M.T. (Matt T.), Sandler, H. (Howard), Sartor, A.O. (Oliver), Schaeffer, E. (Edward), Schwartz, G.F. (Gordon F.), Shahin, M.S. (Mark S.), Shore, N.D. (Neal), Shuch, B. (Brian), Soule, H.R. (Howard R.), Tomlins, S.A. (Scott A), Trabulsi, E.J. (Edouard J.), Uzzo, R. (Robert), Griend, D.J.V. (Donald J. Vander), Walsh, P.C. (Patrick), Weil, C.J. (Carol J.), Wender, R. (Richard), and Gomella, L.G. (Leonard G.)

Abstract

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driv

Published
2018
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8. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author

Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., Lawrenson, K., Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., and Lawrenson, K.

Abstract

Contains fulltext : 170527.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 x 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Published
2017

9. A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians

Author

Schumacher, F.R. Cheng, I. Freedman, M.L. Mucci, L. Allen, N.E. Pollak, M.N. Hayes, R.B. Stram, D.O. Canzian, F. Henderson, B.E. Hunter, D.J. Virtamo, J. Manjer, J. Gaziano, J.M. Kolone, L.N. Tjønneland, A. Albanes, D. Calle, E.E. Giovannucci, E. David Crawford, E. Haiman, C.A. Kraft, P. Willett, W.C. Thun, M.J. Le Marchand, L. Kaaks, R. Feigelson, H.S. Bueno-de-Mesquita, H.B. Palli, D. Riboli, E. Lund, E. Amiano, P. Andriole, G. Dunning, A.M. Trichopoulos, D. Stampfer, M.J. Key, T.J. Ma, J.

Abstract

The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/ IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj = 8.8 × 10-43) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 × 10-3. IGF-I levels were significantly associated with PCa risk (Ptrend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians. © The Author 2010. Published by Oxford University Press. All rights reserved.

Published
2010

10. Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.

Author

Feigelson, H.S., Cox, D.G., Cann, H.M., Wacholder, S., Kaaks, R., Henderson, B.E., Albanes, D., Altshuler, D., Berglund, G., Berrino, F., Bingham, S, Buring, J.E., Burtt, N.P., Calle, E.E., Chanock, S.J., Clavel-Chapelon, F., Colditz, G., Diver, W.R., Freedman, M.L., Haiman, C.A., Hankinson, S.E., Hayes, R.B., Hirschhorn, J.N., Hunter, D., Kolonel, L.N., Kraft, P., LeMarchand, L., Linseisen, J., Modi, W., Navarro, C., Peeters, P.H.M., Pike, M.C., Riboli, E., Setiawan, V.W., Stram, D.O., Thomas, G., Thun, M.J., Tjonneland, A., Trichopoulos, D., Feigelson, H.S., Cox, D.G., Cann, H.M., Wacholder, S., Kaaks, R., Henderson, B.E., Albanes, D., Altshuler, D., Berglund, G., Berrino, F., Bingham, S, Buring, J.E., Burtt, N.P., Calle, E.E., Chanock, S.J., Clavel-Chapelon, F., Colditz, G., Diver, W.R., Freedman, M.L., Haiman, C.A., Hankinson, S.E., Hayes, R.B., Hirschhorn, J.N., Hunter, D., Kolonel, L.N., Kraft, P., LeMarchand, L., Linseisen, J., Modi, W., Navarro, C., Peeters, P.H.M., Pike, M.C., Riboli, E., Setiawan, V.W., Stram, D.O., Thomas, G., Thun, M.J., Tjonneland, A., and Trichopoulos, D.

Published
2006

11. Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.

Author

JC onderzoeksprogramma Kanker, Epidemiology & Health Economics, Feigelson, H.S., Cox, D.G., Cann, H.M., Wacholder, S., Kaaks, R., Henderson, B.E., Albanes, D., Altshuler, D., Berglund, G., Berrino, F., Bingham, S, Buring, J.E., Burtt, N.P., Calle, E.E., Chanock, S.J., Clavel-Chapelon, F., Colditz, G., Diver, W.R., Freedman, M.L., Haiman, C.A., Hankinson, S.E., Hayes, R.B., Hirschhorn, J.N., Hunter, D., Kolonel, L.N., Kraft, P., LeMarchand, L., Linseisen, J., Modi, W., Navarro, C., Peeters, P.H.M., Pike, M.C., Riboli, E., Setiawan, V.W., Stram, D.O., Thomas, G., Thun, M.J., Tjonneland, A., Trichopoulos, D., JC onderzoeksprogramma Kanker, Epidemiology & Health Economics, Feigelson, H.S., Cox, D.G., Cann, H.M., Wacholder, S., Kaaks, R., Henderson, B.E., Albanes, D., Altshuler, D., Berglund, G., Berrino, F., Bingham, S, Buring, J.E., Burtt, N.P., Calle, E.E., Chanock, S.J., Clavel-Chapelon, F., Colditz, G., Diver, W.R., Freedman, M.L., Haiman, C.A., Hankinson, S.E., Hayes, R.B., Hirschhorn, J.N., Hunter, D., Kolonel, L.N., Kraft, P., LeMarchand, L., Linseisen, J., Modi, W., Navarro, C., Peeters, P.H.M., Pike, M.C., Riboli, E., Setiawan, V.W., Stram, D.O., Thomas, G., Thun, M.J., Tjonneland, A., and Trichopoulos, D.

Published
2006

13. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

Author

Jeroen Kneppers, Tesa M. Severson, Joseph C. Siefert, Pieter Schol, Stacey E. P. Joosten, Ivan Pak Lok Yu, Chia-Chi Flora Huang, Tunç Morova, Umut Berkay Altıntaş, Claudia Giambartolomei, Ji-Heui Seo, Sylvan C. Baca, Isa Carneiro, Eldon Emberly, Bogdan Pasaniuc, Carmen Jerónimo, Rui Henrique, Matthew L. Freedman, Lodewyk F. A. Wessels, Nathan A. Lack, Andries M. Bergman, Wilbert Zwart, Chemical Biology, Immunoengineering, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Altıntaş, Umut Berkay, Kneppers, J., Severson, T.M., Siefert, J.C., Schol, P., Joosten, S.E.P., Yu, I.P.L., Huang, C.F., Morova, T., Giambartolomei, C., Seo, J.H., Baca, S.C., Carneiro, I., Emberly, E., Pasaniuc, B., Jerónimo, C., Henrique, R., Freedman, M.L., Wessels, L.F.A., Bergman, A.M., Zwart, W., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Graduate School of Sciences and Engineering, and Department of Computational Sciences and Engineering

Subjects
Male, Multidisciplinary, Nucleic Acid, Prostatic Neoplasms/genetics, Androgen/genetics, Prostate, General Physics and Astronomy, Prostatic Neoplasms, General Chemistry, Regulatory Sequences, Nucleic Acid, SDG 3 – Goede gezondheid en welzijn, Receptors, Androgen/genetics, General Biochemistry, Genetics and Molecular Biology, Chromatin, Medicine, Biochemistry, SDG 3 - Good Health and Well-being, Receptors, Androgen, Receptors, Humans, Prostatic neoplasms, Receptors, androgen, Regulatory sequences, nucleic acid, Regulatory Sequences
Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact., We would like to acknowledge the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support and the NKI Research High-Performance Computing (RHPC) facility for computational infrastructure. We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. This work was supported by the Prostate Cancer Foundation (21CHAL04), Department of Defense (W81XWH-21-1-0234, W81XWH-19-1-0565), Oncode Institute and Alpe d’HuZes/KWF Dutch Cancer Society (10084).

Published
2022

14. Macrocytic Anemia and Mitochondriopathy Resulting from a Defect in Sideroflexin 4

Author

Diana S. Branco, Vamsi K. Mootha, Tim M. Strom, Salvatore DiMauro, Barry H. Paw, H. Orhan Akman, Jonathan N. Thon, Sarah E. Calvo, Laura S. Kremer, Jeffrey D. Cooney, Skadi Beblo, Joseph E. Italiano, Carla M. Koehler, Gordon J. Hildick-Smith, Holger Prokisch, Andreas Merkenschlager, Yvette Y. Yien, Peter Freisinger, Tobias B. Haack, Nicholas C. Huston, Daniel S. Lieber, Caterina Garone, Dhvanit I. Shah, Matthew L. Freedman, Thomas Meitinger, Non Miyata, M. Alice Donati, Hildick-Smith G.J., Cooney J.D., Garone C., Kremer L.S., Haack T.B., Thon J.N., Miyata N., Lieber D.S., Calvo S.E., Akman H.O., Yien Y.Y., Huston N.C., Branco D.S., Shah D.I., Freedman M.L., Koehler C.M., Italiano Jr. J.E., Merkenschlager A., Beblo S., Strom T.M., Meitinger T., Freisinger P., Donati M.A., Prokisch H., Mootha V.K., DiMauro S., and Paw B.H.

Subjects
Mitochondrial Diseases, Macrocytic, medicine.disease_cause, Medical and Health Sciences, 0302 clinical medicine, Mitochondrial Disease, Erythropoiesi, Genetics(clinical), Erythropoiesis, Exome, Anemia, Macrocytic, Child, Inner mitochondrial membrane, Membrane Protein, Zebrafish, Genetics (clinical), Exome sequencing, Pediatric, Genetics & Heredity, 0303 health sciences, Mutation, Anemia, Hematology, Biological Sciences, 3. Good health, Gene Knockdown Techniques, Female, Human, Adolescent, Mitochondrial disease, Biology, Mitochondrial Proteins, 03 medical and health sciences, Report, Genetics, medicine, Mitochondrial Protein, Animals, Humans, 030304 developmental biology, Animal, Membrane Proteins, medicine.disease, biology.organism_classification, Molecular biology, Gene Knockdown Technique, Immunology, Macrocytic anemia, 030217 neurology & neurosurgery
Abstract

We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respiratory defect observed in both individuals and the macrocytic anemia with megaloblastic features of the more severe case. In vitro and in vivo complementation studies with fibroblasts from the affected individuals and zebrafish demonstrated the requirement of SFXN4 for mitochondrial respiratory homeostasis and erythropoiesis. Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia. © 2013 by The American Society of Human Genetics. All rights reserved.

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