The genetic landscape of high-risk neuroblastoma

被引：865

作者：

Pugh, Trevor J. ^{[1
,2
,3
]}

Morozova, Olena ^{[4
,5
]}

Attiyeh, Edward F. ^{[6
,7
,8
]}

Asgharzadeh, Shahab ^{[9
,10
,11
]}

Wei, Jun S. ^{[12
]}

Auclair, Daniel ^{[1
]}

Carter, Scott L. ^{[1
]}

Cibulskis, Kristian ^{[1
]}

Hanna, Megan ^{[1
,3
]}

Kiezun, Adam ^{[1
]}

Kim, Jaegil ^{[1
]}

Lawrence, Michael S. ^{[1
]}

Lichenstein, Lee ^{[1
]}

McKenna, Aaron ^{[1
]}

Pedamallu, Chandra Sekhar ^{[1
,3
]}

Ramos, Alex H. ^{[1
,2
]}

Shefler, Erica ^{[1
]}

Sivachenko, Andrey ^{[1
]}

Sougnez, Carrie ^{[1
]}

Stewart, Chip ^{[1
]}

Ally, Adrian ^{[4
]}

Birol, Inanc ^{[4
]}

Chiu, Readman ^{[4
]}

Corbett, Richard D. ^{[4
]}

Hirst, Martin ^{[4
]}

Jackman, Shaun D. ^{[4
]}

Kamoh, Baljit ^{[4
]}

Khodabakshi, Alireza Hadj ^{[4
]}

Krzywinski, Martin ^{[4
]}

Lo, Allan ^{[4
]}

Moore, Richard A. ^{[4
]}

Mungall, Karen L. ^{[4
]}

Qian, Jenny ^{[4
]}

Tam, Angela ^{[4
]}

Thiessen, Nina ^{[4
]}

Zhao, Yongjun ^{[4
]}

Cole, Kristina A. ^{[6
,7
,8
]}

Diamond, Maura ^{[6
,7
,8
]}

Diskin, Sharon J. ^{[6
,7
,8
]}

Mosse, Yael P. ^{[6
,7
,8
]}

Wood, Andrew C. ^{[6
,7
,8
]}

Ji, Lingyun ^{[9
,10
,11
]}

Sposto, Richard ^{[9
,10
,11
]}

Badgett, Thomas ^{[12
]}

London, Wendy B. ^{[2
,13
,14
]}

Moyer, Yvonne ^{[15
,16
]}

Gastier-Foster, Julie M. ^{[15
,16
]}

Smith, Malcolm A. ^{[17
]}

Auvil, Jaime M. Guidry ^{[18
]}

Gerhard, Daniela S. ^{[18
]}

机构：

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

[2] Harvard Univ, Sch Med, Boston, MA USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Univ British Columbia, British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1M9, Canada

[5] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[6] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[7] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[8] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[9] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA

[10] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA

[11] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA

[12] NIH, Pediat Oncol Branch, Oncogen Sect, Ctr Canc Res, Gaithersburg, MD USA

[13] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA USA

[14] Childrens Oncol Grp, Boston, MA USA

[15] Nationwide Childrens Hosp, Biopathol Ctr, Columbus, OH USA

[16] Ohio State Univ, Coll Med, Columbus, OH 43210 USA

[17] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA

[18] NCI, Off Canc Genom, Bethesda, MD 20892 USA

[19] Abramson Family Canc Res Inst, Philadelphia, PA USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 03期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

ACTIVATING MUTATIONS; SOMATIC MUTATIONS; NOONAN-SYNDROME; SOLID TUMORS; ALK KINASE; CANCER; PTPN11; SUSCEPTIBILITY; AMPLIFICATION; PROTEINS;

D O I：

10.1038/ng.2529

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.

引用

页码：279 / 284

页数：6

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