Mirabello, L. (Lisa)

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    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.
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    Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients
    (John Wiley & Sons, Ltd, 2018) Ballinger, M.L. (Mandy L.); Patiño-García, A. (Ana); Panagiotou, O.A. (Orestis A.); Tirabosco, R. (Roberto); Gastier-Foster, J.M. (Julie M.); Spector, L. (Logan); Gokgoz, N. (Nalan); Hoover, R.N. (Robert N.); Flanagan, A.M. (Adrienne M.); Wunder, J.S. (Jay S.); Serra, M. (Massimo); Thomas, D.M. (David M.); Wacholder, S. (Sholom); Mirabello, L. (Lisa); Barkauskas, D.A. (Donald A.); Caminada-de-Toledo, S.R. (Silvia Regina); Gorlick, R.G. (Richard G.); Hicks, B. (Belynda); Hattinger, C. (Claudia); Savage, S.A. (Sharon A.); Chanock, S.J. (Stephen J.); Picci, P. (Piero); Karlins, E. (Eric); Wheeler, W. (William); Scotlandi, K. (Katia); Lecanda, F. (Fernando); Yeager, M. (Meredith); Tucker, M. (Margaret); Petrilli, A.S. (Antonio S.); Koster, R. (Roelof); Andrulis, I.L. (Irene L.)
    Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease.
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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.
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    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.
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    Height at diagnosis and birth-weight as risk factors for osteosarcoma
    (Springer, 2011) Patiño-García, A. (Ana); Craft, A.W. (Alan W.); Hoover, R.N. (Robert N.); Schüz, J. (Joachim); Douglass, C. (Chester); Mirabello, L. (Lisa); Savage, S.A. (Sharon A.); Daw, N.C. (Najat C.); Pfeiffer, R. (Ruth); Murphy, G. (Gwen); Troisi, R.J. (Rebecca J.)
    OBJECTIVES: Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma. METHODS: Patient data from seven studies of height and three of birth-weight were obtained, resulting in 1,067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1,000 age- and gender-matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis. RESULTS: Compared to average birth-weight subjects (2,665-4,045 g), individuals with high birth-weight (≥ 4,046 g) had an increased osteosarcoma risk (OR 1.35, 95% CI 1.01-1.79). Taller than average (51st - 89th percentile) and very tall individuals (≥ 90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95% CI 1.18-1.54 and OR 2.60, 95% CI 2.19-3.07, respectively; P (trend) < 0.0001). CONCLUSIONS: This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology.
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    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.
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    Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma
    (American Medical Association, 2020) Mirabello, L. (Lisa); Zhu, B. (Bin); Koster, R. (Roelof); Karlins, E. (Eric); Dean, M.C. (Michael C.); Yeager, M. (Meredith); Gianferante, M. (Matthew); Spector, L. (Logan); Morton, L.M. (Lindsay M.); Karyadi, D. (Danielle); Robison, L.L. (Leslie L.); Armstrong, G.T. (Gregory T.); Bhatia, S. (Smita); Song, L. (Lei); Pankratz, N. (Nathan); Pinheiro, M. (Maisa); Gastier-Foster, J.M. (Julie M.); Gorlick, R.G. (Richard G.); Caminada-de-Toledo, S.R. (Silvia Regina); Petrilli, A.S. (Antonio S.); Patiño-García, A. (Ana); Lecanda, F. (Fernando); Gutierrez-Jimeno, M. (Miriam)
    Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, setting, and participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main outcomes and measures: The frequency of rare pathogenic or likely pathogenic genetic variants. Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.