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Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Autores: Lin, S. H. ; Sampson, J. N. ; Grunewald, T. G. P. ; Surdez, D. ; Reynaud, S. ; Mirabeau, O. ; Karlins, E. ; Rubio, R. A. ; Zaidi, S. ; Grossetete-Lalami, S. ; Ballet, S. ; Lapouble, E. ; Laurence, V. ; Michon, J. ; Pierron, G. ; Kovar, H. ; Kontny, U. ; Gonzalez-Neira, A. ; Alonso, J. ; Patiño García, Ana; Corradini, N. ; Berard, P. M. ; Miller, J. ; Freedman, N. D. ; Rothman, N. ; Carter, B. D. ; Dagnall, C. L. ; Burdett, L. ; Jones, K. ; Manning, M. ; Wyatt, K. ; Zhou, W. Y. ; Yeager, M. ; Cox, D. G. ; Hoover, R. N. ; Khan, J. ; Armstrong, G. T. ; Leisenring, W. M. ; Bhatia, S. ; Robison, L. L. ; Kulozik, A. E. ; Kriebel, J. ; Meitinger, T. ; Metzler, M. ; Krumbholz, M. ; Hartmann, W. ; Strauch, K. ; Kirchner, T. ; Dirksen, U. ; Mirabello, L.
Título de la revista: PLOS ONE
ISSN: 1932-6203
Volumen: 15
Número: 9
Páginas: e0237792
Fecha de publicación: 2020
Background Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.