Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants

被引：10

作者：

Stundon, Jennifer L. ^{[1
,2
]}

Ijaz, Heba ^{[1
,3
]}

Gaonkar, Krutika S. ^{[4
,5
]}

Kaufman, Rebecca S. ^{[1
,5
,6
]}

Jin, Run ^{[4
,6
]}

Karras, Anastasios ^{[1
]}

Vaksman, Zalman ^{[1
,5
]}

Kim, Jung ^{[7
]}

Corbett, Ryan J. ^{[4
,6
]}

Lueder, Matthew R. ^{[4
,6
,8
]}

Miller, Daniel P. ^{[4
,6
]}

Guo, Yiran ^{[4
,6
]}

Santi, Mariarita ^{[8
]}

Li, Marilyn ^{[8
]}

Lopez, Gonzalo ^{[1
]}

Storm, Phillip B. ^{[4
,6
]}

Resnick, Adam C. ^{[4
,6
]}

Waanders, Angela J. ^{[9
,10
]}

MacFarland, Suzanne P. ^{[1
,2
]}

Stewart, Douglas R. ^{[7
]}

Diskin, Sharon J. ^{[1
,2
,5
,11
]}

Rokita, Jo Lynne ^{[4
,5
,6
]}

Cole, Kristina A. ^{[1
,2
,11
]}

机构：

[1] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA

[2] Univ Penn, Dept Pediat, Philadelphia, PA USA

[3] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA USA

[4] Childrens Hosp Philadelphia, Ctr Data Driven Discovery Biomed, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Dept Bioinformat & Hlth Informat, Philadelphia, PA USA

[6] Childrens Hosp Philadelphia, Div Neurosurg, Philadelphia, PA USA

[7] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA

[8] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA USA

[9] Ann & Robert H Lurie Childrens Hosp Chicago, Div Hematol Oncol NeuroOncol & Stem Cell Transplan, Chicago, IL USA

[10] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL USA

[11] Univ Penn, Abramson Family Canc Res Inst, Perelman Sch Med, Philadelphia, PA USA

来源：

NEURO-ONCOLOGY | 2023年 / 25卷 / 07期

关键词：

alternative lengthening of telomeres; ATRX; mismatch repair; pediatric brain tumors; pHGG; Telomere; CANCER; HYPERMUTATION; MAINTENANCE; MECHANISM;

D O I：

10.1093/neuonc/noac278

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. Results ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

引用

页码：1331 / 1342

页数：12