Cargando…
Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study
BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684709/ https://www.ncbi.nlm.nih.gov/pubmed/26522332 http://dx.doi.org/10.1016/S1470-2045(15)00369-1 |
_version_ | 1782406211622141952 |
---|---|
author | Moriyama, Takaya Metzger, Monika L. Wu, Gang Nishii, Rina Qian, Maoxiang Devidas, Meenakshi Yang, Wenjian Cheng, Cheng Cao, Emily, Quinn Raimondi, Susana Gastier-Foster, Julie M. Raetz, Elizabeth Larsen, Eric Martin, Paul L. Bowman, W. Paul Winick, Naomi Komada, Yoshihiro Wang, Shuoguo Edmonson, Michael Xu, Heng Mardis, Elaine Fulton, Robert Pui, Mullighan, Charles Evans, William E. Zhang, Jinghui Hunger, Stephen P. Relling, Mary V. Nichols, Kim E. Loh, Mignon L. Yang, Jun J. |
author_facet | Moriyama, Takaya Metzger, Monika L. Wu, Gang Nishii, Rina Qian, Maoxiang Devidas, Meenakshi Yang, Wenjian Cheng, Cheng Cao, Emily, Quinn Raimondi, Susana Gastier-Foster, Julie M. Raetz, Elizabeth Larsen, Eric Martin, Paul L. Bowman, W. Paul Winick, Naomi Komada, Yoshihiro Wang, Shuoguo Edmonson, Michael Xu, Heng Mardis, Elaine Fulton, Robert Pui, Mullighan, Charles Evans, William E. Zhang, Jinghui Hunger, Stephen P. Relling, Mary V. Nichols, Kim E. Loh, Mignon L. Yang, Jun J. |
author_sort | Moriyama, Takaya |
collection | PubMed |
description | BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL. METHODS: Whole-exome sequencing of an index family with multiple cases of ALL was performed to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in 4,405 children from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital frontline ALL trials. Patients were included in this study on the basis of their enrollment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterized bioinformatically and correlated with clinical and demographic features in 2,021 children with ALL. FINDINGS: We identified a novel nonsense ETV6 variant (p.R359X) with a high penetrance of familial ALL. Subsequent targeted sequencing of ETV6 in 4,405 childhood ALL cases discovered 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frame shift variants) that are potentially related to ALL risk in 35 cases (0.79%). Fifteen (48%) of the 31 ALL-related ETV6 variants clustered in the ETS domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukemia diagnosis than others (10.2 years [IQR 5.3-13.8] vs 4.7 years [IQR 3.0-8.7], P=0.017). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (9 of 14 cases [64.3%] vs 538 of 2,007 cases [26.8%]; P=0.0050). INTERPRETATION: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. FUNDING: This study was supported by the National Institutes of Health and by the American Lebanese Syrian Associated Charities. |
format | Online Article Text |
id | pubmed-4684709 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-46847092016-12-01 Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study Moriyama, Takaya Metzger, Monika L. Wu, Gang Nishii, Rina Qian, Maoxiang Devidas, Meenakshi Yang, Wenjian Cheng, Cheng Cao, Emily, Quinn Raimondi, Susana Gastier-Foster, Julie M. Raetz, Elizabeth Larsen, Eric Martin, Paul L. Bowman, W. Paul Winick, Naomi Komada, Yoshihiro Wang, Shuoguo Edmonson, Michael Xu, Heng Mardis, Elaine Fulton, Robert Pui, Mullighan, Charles Evans, William E. Zhang, Jinghui Hunger, Stephen P. Relling, Mary V. Nichols, Kim E. Loh, Mignon L. Yang, Jun J. Lancet Oncol Article BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL. METHODS: Whole-exome sequencing of an index family with multiple cases of ALL was performed to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in 4,405 children from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital frontline ALL trials. Patients were included in this study on the basis of their enrollment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterized bioinformatically and correlated with clinical and demographic features in 2,021 children with ALL. FINDINGS: We identified a novel nonsense ETV6 variant (p.R359X) with a high penetrance of familial ALL. Subsequent targeted sequencing of ETV6 in 4,405 childhood ALL cases discovered 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frame shift variants) that are potentially related to ALL risk in 35 cases (0.79%). Fifteen (48%) of the 31 ALL-related ETV6 variants clustered in the ETS domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukemia diagnosis than others (10.2 years [IQR 5.3-13.8] vs 4.7 years [IQR 3.0-8.7], P=0.017). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (9 of 14 cases [64.3%] vs 538 of 2,007 cases [26.8%]; P=0.0050). INTERPRETATION: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. FUNDING: This study was supported by the National Institutes of Health and by the American Lebanese Syrian Associated Charities. 2015-10-28 2015-12 /pmc/articles/PMC4684709/ /pubmed/26522332 http://dx.doi.org/10.1016/S1470-2045(15)00369-1 Text en http://creativecommons.org/licenses/by/4.0/ This manuscript version is made available under the CC BY-NC-ND 4.0 license. |
spellingShingle | Article Moriyama, Takaya Metzger, Monika L. Wu, Gang Nishii, Rina Qian, Maoxiang Devidas, Meenakshi Yang, Wenjian Cheng, Cheng Cao, Emily, Quinn Raimondi, Susana Gastier-Foster, Julie M. Raetz, Elizabeth Larsen, Eric Martin, Paul L. Bowman, W. Paul Winick, Naomi Komada, Yoshihiro Wang, Shuoguo Edmonson, Michael Xu, Heng Mardis, Elaine Fulton, Robert Pui, Mullighan, Charles Evans, William E. Zhang, Jinghui Hunger, Stephen P. Relling, Mary V. Nichols, Kim E. Loh, Mignon L. Yang, Jun J. Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title | Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title_full | Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title_fullStr | Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title_full_unstemmed | Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title_short | Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study |
title_sort | germline genetic variation in etv6 and risk of childhood acute lymphoblastic leukemia: a systematic genetic study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684709/ https://www.ncbi.nlm.nih.gov/pubmed/26522332 http://dx.doi.org/10.1016/S1470-2045(15)00369-1 |
work_keys_str_mv | AT moriyamatakaya germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT metzgermonikal germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT wugang germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT nishiirina germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT qianmaoxiang germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT devidasmeenakshi germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT yangwenjian germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT chengcheng germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT cao germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT emilyquinn germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT raimondisusana germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT gastierfosterjuliem germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT raetzelizabeth germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT larseneric germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT martinpaull germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT bowmanwpaul germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT winicknaomi germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT komadayoshihiro germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT wangshuoguo germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT edmonsonmichael germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT xuheng germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT mardiselaine germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT fultonrobert germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT pui germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT mullighancharles germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT evanswilliame germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT zhangjinghui germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT hungerstephenp germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT rellingmaryv germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT nicholskime germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT lohmignonl germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy AT yangjunj germlinegeneticvariationinetv6andriskofchildhoodacutelymphoblasticleukemiaasystematicgeneticstudy |