Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis

被引:143
作者
Crago, Aimee M. [1 ,2 ,3 ]
Chmielecki, Juliann [4 ,5 ]
Rosenberg, Mara [5 ]
O'Connor, Rachael [1 ,2 ]
Byrne, Caitlin [6 ]
Wilder, Fatima G. [1 ,2 ]
Thorn, Katherine [1 ,2 ]
Agius, Phaedra [6 ]
Kuk, Deborah [7 ]
Socci, Nicholas D. [6 ]
Qin, Li-Xuan [7 ]
Meyerson, Matthew [4 ,5 ,8 ]
Hameed, Meera [9 ]
Singer, Samuel [1 ,2 ,3 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Sarcoma Biol Lab, Dept Surg, New York, NY 10065 USA
[2] Mem Sloan Kettering Canc Ctr, Sarcoma Dis Management Program, Dept Surg, New York, NY 10065 USA
[3] Weill Cornell Med Coll, Dept Surg, New York, NY USA
[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[5] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA
[6] Mem Sloan Kettering Canc Ctr, Bioinformat Core, New York, NY 10065 USA
[7] Mem Sloan Kettering Canc Ctr, Biostat & Epidemiol, New York, NY 10065 USA
[8] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[9] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA
关键词
BETA-CATENIN; MUTATIONS; CANCER; TUMORS; RECURRENCE; MANAGEMENT; PROTEIN; SINGLE;
D O I
10.1002/gcc.22272
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
CTNNB1 mutations or APC abnormalities have been observed in approximate to 85% of desmoids examined by Sanger sequencing and are associated with Wnt/-catenin activation. We sought to identify molecular aberrations in wild-type tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/-catenin activation as the common pathway governing desmoid initiation. (c) 2015 Wiley Periodicals, Inc.
引用
收藏
页码:606 / 615
页数:10
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