A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

被引：218

作者：

Shah, Sohela ^{[1
,2
]}

Schrader, Kasmintan A. ^{[1
,2
]}

Waanders, Esme ^{[4
,5
]}

Timms, Andrew E. ^{[6
]}

Vijai, Joseph ^{[1
,2
]}

Miething, Cornelius ^{[1
]}

Wechsler, Jeremy ^{[6
]}

Yang, Jun ^{[7
]}

Hayes, James ^{[1
]}

Klein, Robert J. ^{[1
,2
]}

Zhang, Jinghui ^{[8
]}

Wei, Lei ^{[3
,8
]}

Wu, Gang ^{[8
]}

Rusch, Michael ^{[8
]}

Nagahawatte, Panduka ^{[8
]}

Ma, Jing ^{[3
]}

Chen, Shann-Ching ^{[3
]}

Song, Guangchun ^{[3
]}

Cheng, Jinjun ^{[3
,9
]}

Meyers, Paul ^{[10
]}

Bhojwani, Deepa ^{[11
]}

Jhanwar, Suresh ^{[12
]}

Maslak, Peter ^{[13
]}

Fleisher, Martin ^{[14
]}

Littman, Jason ^{[2
]}

Offit, Lily ^{[2
]}

Rau-Murthy, Rohini ^{[2
]}

Fleischut, Megan Harlan ^{[2
]}

Corines, Marina ^{[2
]}

Murali, Rajmohan ^{[12
]}

Gao, Xiaoni ^{[1
]}

Manschreck, Christopher ^{[2
]}

Kitzing, Thomas ^{[1
]}

Murty, Vundavalli V. ^{[15
]}

Raimondi, Susana C. ^{[3
]}

Kuiper, Roland P. ^{[4
,5
]}

Simons, Annet ^{[4
,5
]}

Schiffman, Joshua D. ^{[16
]}

Onel, Kenan ^{[17
]}

Plon, Sharon E. ^{[18
,19
]}

Wheeler, David A. ^{[18
]}

Ritter, Deborah ^{[18
,19
]}

Ziegler, David S. ^{[20
,21
]}

Tucker, Kathy ^{[22
]}

Sutton, Rosemary ^{[21
]}

Chenevix-Trench, Georgia ^{[23
]}

Li, Jun ^{[23
]}

Huntsman, David G. ^{[24
]}

Hansford, Samantha ^{[24
]}

Senz, Janine ^{[24
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA

[3] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[4] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Oncol, NL-6525 ED Nijmegen, Netherlands

[6] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[7] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[8] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA

[9] St Jude Childrens Res Hosp, Pediat Canc Genome Project Lab, Memphis, TN 38105 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA

[11] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Hematol Lab Serv, New York, NY 10021 USA

[14] Mem Sloan Kettering Canc Ctr, Clin Chem Serv, New York, NY 10021 USA

[15] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA

[16] Univ Utah, Primary Childrens Med Ctr, Huntsman Canc Inst, High Risk Pediat Canc Clin, Salt Lake City, UT USA

[17] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA

[18] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA

[19] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[20] Sydney Childrens Hosp, Kids Canc Ctr, Sydney, NSW, Australia

[21] Univ New S Wales, Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia

[22] Prince Wales Hosp, Hereditary Canc Clin, Randwick, NSW 2031, Australia

[23] Queensland Inst Med Res, Canc Genet Lab, Herston, Qld 4006, Australia

[24] Univ British Columbia, Pathol & Lab Med, Seattle, WA USA

[25] Univ Washington, Dept Med, Seattle, WA 98195 USA

[26] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[27] SA Pathol & Ctr Canc Biol, Dept Mol Pathol, Adelaide, SA, Australia

[28] Weill Cornell Coll Med, Dept Pediat, New York, NY USA

[29] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA

[30] Mem Sloan Kettering Canc Ctr, Gen Core Lab, New York, NY 10021 USA

[31] Mem Sloan Kettering Canc Ctr, Bioinformat Core, New York, NY 10021 USA

[32] Univ Penn, Dept Med, Philadelphia, PA 19104 USA

[33] Broad Inst Harvard & MIT, Cambridge, MA USA

[34] Weill Cornell Coll Med, Dept Med, New York, NY USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 10期

基金：

加拿大健康研究院; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院;

关键词：

CIRCULAR BINARY SEGMENTATION; TRANSCRIPTION FACTOR PAX5; DNA-SEQUENCING DATA; GENETIC ALTERATIONS; DIFFERENTIATION; EXPRESSION; CHILDHOOD; BSAP; TRANSACTIVATION; IDENTIFICATION;

D O I：

10.1038/ng.2754

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL)(1-3), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.

引用

页码：1226 / U179

页数：9

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