Rothman, N. (Nathaniel)
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- Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome(Nature Publishing Group: Nature Communications, 2016) Machiela, M.J. (Mitchell J.); Goldstein, A.M. (Alisa M.); Hu, N. (Nan); Koh, W.P. (Woon-Puay); Stevens, V.L. (Victoria L.); Wiencke, J.K. (John K.); Hunter, D.J. (David J.); Patiño-García, A. (Ana); Chen, C. (Chu); Seow, A. (Adeline); Khaw, K.T. (Kay-Tee); Kim, Y.T. (Young Tae); Schwartz, A.G. (Ann G.); Wong, M.P. (Maria Pik); Hsiung, C.A. (Chao A.); Xia, L. (Lucy); Hankinson, S.E. (Susan E.); Liao, L. (Linda); Fuchs, C.S. (Charles S.); Zhou, W. (Weiyin); Silverman, D.T. (Debra T.); Sampson, J. (Joshua); Chen, C. (Constance); McNeill, L.H. (Lorna H.); Li, D. (Donghui); McWilliams, R.R. (Robert R.); Park, J.Y. (Jae Yong); Zheng, W. (Wei); Olson, S.H. (Sara H.); Wu, Y.L. (Yi-Long); Magliocco, A.M. (Anthony M.); Tang, Z.Z. (Ze-Zhong); Arslan, A.A. (Alan A.); Jenab, M. (Mazda); Hu, W. (Wei); Mitchell, J.M. (J. Machiela); Wolpin, B.M. (Brian M.); Canzian, F. (Federico); Chaffee, K.G. (Kari G.); Amundadottir, L. (Laufey); Qiao, Y.L. (You-Lin); Butler, M.A. (Mary A.); Schwartz, K.L. (Kendra L.); Lu, L. (Lingeng); Purdue, M. (Mark); Hoover, R.N. (Robert N.); Davis, F.G. (Faith G.); Johansen, C. (Christoffer); Lissowska, J. (Jolanta); Hutchinson, A. (Amy); Kooperberg, C. (Charles); Freedman, N.D. (Neal D.); Chang, I.S. ( I-Shou); Stram, D. (Daniel); Wunder, J.S. (Jay S.); Harris, C.C. (Curtis C.); Petersen, G. (Gloria); Doherty, J. (Jennifer); Stolzenberg-Solomon, R.Z. (Rachael Z.); Wentzensen, N. (Nicolas); Setiawan, V.W. (Veronica Wendy); Garcia-Closas, M. (Montserrat); Liang, X. (Xiaolin); Wacholder, S. (Sholom); Kim, Y.H. (Yeul Hong); Brinton, L.A. (Louise A.); Zeleniuch-Jacquotte, A. (Anne); Friedenreich, C.M. (Christine M.); Duell, E.J. (Eric J.); Beane-Freeman, L.E. (Laura E.); Gallinger, S. (Steven); Zanetti, K.A. (Krista A.); Blot, W.J. (William J.); Teras, L.R. (Lauren R.); Wang, Z. (Zhaoming); Fraumeni, J.F. (Joseph F.); Hautman, C. (Christopher); Klein, R. (Robert); White, E. (Emily); Kraft, P. (Peter); Buring, J.E. (Julie E.); Giovannucci, E.L. (Edward L.); Figueroa, J.D. (Jonine D.); Yang, P.C. (Pan-Chyr); Chung, C.C. (Charles C.); Pooler, L. (Loreall); Tobias, G.S. (Geoffrey S.); Severi, G. (Gianluca); Hong, Y.C. (Yun-Chul); Mirabello, L. (Lisa); Prokunina-Olsson, L. (Ludmila); Burdett, L. (Laurie); Wu, C. (Chen); Haiman, C.A. (Christopher A.); Black, A. (Amanda); Holly, E.A. (Elizabeth A.); Liu, J. (Jianjun); Ruder, A.M. (Avima M.); Hicks, B. (Belynda); Peplonska, B. (Beata); LaCroix, A. (Andrea); Gaziano, J.M. (J. Michael); Caporaso, N.E. (Neil E.); Shin, M.H. (Min-Ho); Shu, X.O. (Xiao-Ou); Zhou, B. (Baosen); Lan, Q. (Qing); Dagnall, C. (Casey); Bock, C.H. (Cathryn H.); Real, F.X. (Francisco X.); Yang, Q. (Qi); Yu, K. (Kai); Gaudet, M.M. (Mia M.); Prescott, J. (Jennifer); Wu, T. (Tangchun); Kolonel, L.N. (Laurence N.); Malats, N. (Nuria); Visvanathan, K. (Kala); Savage, S.A. (Sharon A.); Aldrich, M.C. (Melinda C.); Chanock, S.J. (Stephen J.); Bracci, P.M. (Paige M.); Rodriguez-Santiago, B. (Benjamin); Riboli, E. (Elio); Klein, A.P. (Alison P.); Spitz, M.R. (Margaret R.); Risch, H.A. (Harvey A.); Perez-Jurado, L.A. (Luis A.); Lin, D. (Dongxin); Chen, K. (Kexin); Gillanders, E.M. (Elizabeth M.); Taylor, P.R. (Philip R.); Yang, H.P. (Hannah P.); Jacobs, K. (Kevin); Ding, T. (Ti); Abnet, C.C. (Christian C.); Wu, Y.Q. (Yan Q.); Peters, U. (Ulrike); Sheng, X. (Xin); Landi, M.T. (María Teresa); Le-Marchand, L. (Loic); Goldin, L. (Lynn); Gao, Y.T. (Yu-Tang); Fan, J.H. (Jin-Hu); Orlow, I. (Irene); Berndt, S.I. (Sonja I.); Epstein, C.G. (Caroline G.); Karlins, E. (Eric); Chatterjee, N. (Nilanjan); Cullen, M. (Michael); Moore, L.E. (Lee E.); Kim, H.N. (Hee Nam); Wheeler, W. (William); Melin, B.S. (Beatrice S.); De Vivo, I. (Immaculata); Giles, G.G. (Graham G.); Krogh, V. (Vittorio); Amos, C. (Christopher); Shen, H. (Hongbing); Crous Bou, M. (Marta); Yeager, M. (Meredith); Wang, J.C. (Jiu-Cun); Tucker, M. (Margaret); Schumacher, F. (Fredrick); Carreon, T. (Tania); Ziegler, R.G. (Regina G.); Kurtz, R.C. (Robert C.); Van Den Berg, D. (David); Henriksson, R. (Roger); Gapstur, S.M. (Susan M.); Hallmans, G. (Goran); Bueno-de-Mesquita, H.B. (H. Bas); Rothman, N. (Nathaniel); Dean, M.C. (Michael C.); Cook, L.S. (Linda S.); Matsuo, K. (Keitaro); Rajaraman, P. (Preetha)To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
- Detectable clonal mosaicism and its relationship to aging and cancer(Nature Publishing Group, 2012-12) Johnson, A. (Alison); Goldstein, A.M. (Alisa M.); Hu, N. (Nan); Koh, W.P. (Woon-Puay); Landgren, A. (Annelie); Stevens, V.L. (Victoria L.); Wiencke, J.K. (John K.); Hunter, D.J. (David J.); Patiño-García, A. (Ana); Khaw, K.T. (Kay-Tee); Virtamo, J. (Jarmo); Schwartz, A.G. (Ann G.); Yuan, J.M. (Jian-Min); Rybicki, B.A. (Benjamin A.); Boutron-Ruault, M.C. (Marie-Christine); Wolk, A. (Alicja); Mandelson, M.T. (Margaret T.); McGlynn, K.A. (Katherine A.); Hankinson, S.E. (Susan E.); Liao, L. (Linda); Fuchs, C.S. (Charles S.); Zhou, W. (Weiyin); Erickson, R.L. (Ralph L.); Silverman, D.T. (Debra T.); Sampson, J. (Joshua); Hassan, M. (Manal); McNeill, L.H. (Lorna H.); Li, D. (Donghui); McWilliams, R.R. (Robert R.); Zheng, W. (Wei); Olson, S.H. (Sara H.); Thomas, G. (Gilles); Tang, Z.Z. (Ze-Zhong); Arslan, A.A. (Alan A.); Jenab, M. (Mazda); Elena, J.W. (Joanne W.); Rabe, K.G. (Kari G.); Villa, O. (Olaya); Wolpin, B.M. (Brian M.); Canzian, F. (Federico); Amundadottir, L. (Laufey); Qiao, Y.L. (You-Lin); Butler, M.A. (Mary A.); Cotterchio, M. (Michelle); Schwartz, K.L. (Kendra L.); Liu, C. (Chenwei); Kogevinas, M. (Manolis); Purdue, M. (Mark); Hoover, R.N. (Robert N.); Davis, F.G. (Faith G.); Johansen, C. (Christoffer); Lissowska, J. (Jolanta); Mendelsohn, J.B. (Julie B.); Hutchinson, A. (Amy); Kooperberg, C. (Charles); Marenne, G. (Gaelle); Freedman, N.D. (Neal D.); Sesso, H.D. (Howard D.); Stram, D. (Daniel); Wunder, J.S. (Jay S.); Harris, C.C. (Curtis C.); Jiao, L. (Li); Henderson, B.E. (Brian E.); Petersen, G. (Gloria); Stolzenberg-Solomon, R.Z. (Rachael Z.); Ahlbom, A. (Anders); Wentzensen, N. (Nicolas); Garcia-Closas, M. (Montserrat); Wacholder, S. (Sholom); McKean-Cowdin, R. (Roberta); Brinton, L.A. (Louise A.); Zeleniuch-Jacquotte, A. (Anne); Duell, E.J. (Eric J.); Andersson, U. (Ulrika); Beane-Freeman, L.E. (Laura E.); Kovaks, J. (Joseph); Berg, C.D. (Christine D.); Gallinger, S. (Steven); Zanetti, K.A. (Krista A.); Sierrasesumaga, L. (Luis); Blot, W.J. (William J.); Teras, L.R. (Lauren R.); Wang, Z. (Zhaoming); Fraumeni, J.F. (Joseph F.); Schwenn, M. (Molly); White, E. (Emily); Kraft, P. (Peter); Buring, J.E. (Julie E.); Giovannucci, E.L. (Edward L.); Figueroa, J.D. (Jonine D.); Albanes, D. (Demetrius); Chung, C.C. (Charles C.); Hoffman-Bolton, J.A. (Judith A.); Tobias, G.S. (Geoffrey S.); Severi, G. (Gianluca); Mirabello, L. (Lisa); Prokunina-Olsson, L. (Ludmila); Burdett, L. (Laurie); Barkauskas, D.A. (Donald A.); Feychting, M. (Maria); Haiman, C.A. (Christopher A.); Black, A. (Amanda); Michaud, D.S. (Dominique S.); Holly, E.A. (Elizabeth A.); Cook, M.B. (Michael B.); Ruder, A.M. (Avima M.); Gorlick, R.G. (Richard G.); Wrensch, M. (Margaret); Peplonska, B. (Beata); LaCroix, A. (Andrea); Weinstein, S.J. (Stephanie J.); Chow, W.H. (Wong-Ho); Gaziano, J.M. (J. Michael); Caporaso, N.E. (Neil E.); Chang, K. (Kenneth); Shu, X.O. (Xiao-Ou); Hsing, A.W. (Ann W.); Gonzalez, J.R. (Juan R.); Bock, C.H. (Cathryn H.); Real, F.X. (Francisco X.); Kratz, C.P. (Christian P.); Yu, K. (Kai); Rotunno, M. (Melissa); Gaudet, M.M. (Mia M.); Consonni, D. (Dario); Kolonel, L.N. (Laurence N.); Malats, N. (Nuria); Visvanathan, K. (Kala); Savage, S.A. (Sharon A.); Aldrich, M.C. (Melinda C.); Chanock, S.J. (Stephen J.); Bracci, P.M. (Paige M.); Rodriguez-Santiago, B. (Benjamin); Riboli, E. (Elio); Baris, D. (Dalsu); Klein, A.P. (Alison P.); Spitz, M.R. (Margaret R.); Deng, X. (Xiang); Risch, H.A. (Harvey A.); Perez-Jurado, L.A. (Luis A.); Gross, M.D. (Myron D.); Gillanders, E.M. (Elizabeth M.); Taylor, P.R. (Philip R.); Jacobs, K. (Kevin); Ding, T. (Ti); Hartge, P. (Patricia); Greene, M.H. (Mark H.); Abnet, C.C. (Christian C.); Wu, Y.Q. (Yan Q.); Peters, U. (Ulrike); Trichopoulos, D. (Dimitrios); Landi, M.T. (María Teresa); Horner, M.J. (Marie-Josephe); Le-Marchand, L. (Loic); Goldin, L. (Lynn); Gao, Y.T. (Yu-Tang); Fan, J.H. (Jin-Hu); Berndt, S.I. (Sonja I.); Epstein, C.G. (Caroline G.); Signorello, L.B. (Lisa B.); Chatterjee, N. (Nilanjan); Cullen, M. (Michael); Moore, L.E. (Lee E.); Wheeler, W. (William); Melin, B.S. (Beatrice S.); Giles, G.G. (Graham G.); Tjonneland, A. (Anne); Inskip, P.D. (Peter D.); Krogh, V. (Vittorio); Amos, C. (Christopher); Graubard, B.I. (Barry I.); Bertazzi, P.A. (Pier Alberto); Yeager, M. (Meredith); Goggins, M. (Michael); Yu, H. (Herbert); Tucker, M. (Margaret); Schumacher, F. (Fredrick); Carreon, T. (Tania); Ziegler, R.G. (Regina G.); Kurtz, R.C. (Robert C.); Henriksson, R. (Roger); Gapstur, S.M. (Susan M.); Hallmans, G. (Goran); Xiang, Y.B. (Yong-Bing); Bueno-de-Mesquita, H.B. (H. Bas); Rothman, N. (Nathaniel); Andrulis, I.L. (Irene L.); Dean, M.C. (Michael C.); Rajaraman, P. (Preetha)In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
- Genome-wide association study identifies two susceptibility loci for osteosarcoma(Nature Publishing Group, 2013-07) Hunter, D.J. (David J.); Patiño-García, A. (Ana); Silverman, D.T. (Debra T.); Tirabosco, R. (Roberto); Gastier-Foster, J.M. (Julie M.); Spector, L. (Logan); Meltzer, P.S. (Paul S.); Gokgoz, N. (Nalan); Kogevinas, M. (Manolis); Purdue, M. (Mark); Hoover, R.N. (Robert N.); Amary, M.F. (María Fernanda); Flanagan, A.M. (Adrienne M.); Wunder, J.S. (Jay S.); Serra, M. (Massimo); Thomas, D.M. (David M.); Marina, N. (Neyssa); Wacholder, S. (Sholom); Halai, D. (Dina); Douglass, C. (Chester); Sierrasesumaga, L. (Luis); Wang, Z. (Zhaoming); Fraumeni, J.F. (Joseph F.); Kraft, P. (Peter); Chung, C.C. (Charles C.); Mirabello, L. (Lisa); Barkauskas, D.A. (Donald A.); Caminada-de-Toledo, S.R. (Silvia Regina); Gorlick, R.G. (Richard G.); Caporaso, N.E. (Neil E.); Khanna, C. (Chand); Hattinger, C. (Claudia); Malats, N. (Nuria); Helman, L. (Lee); Savage, S.A. (Sharon A.); Chanock, S.J. (Stephen J.); Jacobs, K. (Kevin); Landi, M.T. (María Teresa); Berndt, S.I. (Sonja I.); Picci, P. (Piero); Lecanda, F. (Fernando); Ilhan, I.E. (Inci Ergurhan); Kurucu, N. (Nilgün); Yeager, M. (Meredith); Tucker, M. (Margaret); Troisi, R.J. (Rebecca J.); Petrilli, A.S. (Antonio S.); Sari, N. (Neriman); Rothman, N. (Nathaniel); Andrulis, I.L. (Irene L.)Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
- Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.(Nature Research, 2018) Machiela, M.J. (Mitchell J.); Wyatt, K. (Kathleen); Bhatia, S. (Smita); Patiño-García, A. (Ana); Armstrong, G.T. (Gregory T.); Zaidi, S. (Sakina); Cox, D.G. (David G.); Zhou, W. (Weiyin); Grünewald, T.G.P. (Thomas G. P.); Tirode, F. (Franck); Hartmann, W. (Wolfgang); Dirksen, U. (Uta); Kirchner, T. (Thomas); Kulozik, A. (Andreas E.); Khan, J. (Javed); Hoover, R.N. (Robert N.); Laurence, V. (Valérie); Freedman, N.D. (Neal D.); Kontny, U. (Udo); Alonso, J. (Javier); Delattre, O. (Olivier); Surdez, D. (Didier); Mirabeau, O. (Olivier); Pierron, G. (Gaelle); Manning, M. (Michelle); Grossetete-Lalami, S. (Sandrine); Mirabello, L. (Lisa); Burdett, L. (Laurie); Leisenring, W.M. (Wendy M.); Ballet, S. (Stelly); Strauch, K. (Konstantin); Kovar, H. (Heinrich); Gaspar, N. (Nathalie); Dagnall, C. (Casey); Kriebel, J. (Jennifer); Chanock, S.J. (Stephen J.); Michon, J. (Jean); Metzler, M. (Markus); Jones, K. (Krisitine); Reynaud, S. (Stephanie); Corradini, N. (Nadege); Picci, P. (Piero); Morton, L.M. (Lindsay M.); Karlins, E. (Eric); Rubio, R.A. (Rebeca Alba); Meitinger, T. (Thomas); Lapouble, E. (Eve); Yeager, M. (Meredith); Bérard, P.M. (Perrine Marec); Robison, L.L. (Leslie L.); Tucker, M. (Margaret); Gonzalez-Neira, A. (Anna); Rothman, N. (Nathaniel)Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.