Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid‐type fibromatosis by whole‐exome sequencing and genomic analysis. Issue 10 (14th July 2015)

• Record Type: Journal Article
• Authors: Crago, Aimee M.; Chmielecki, Juliann; Rosenberg, Mara; O'Connor, Rachael; Byrne, Caitlin; Wilder, Fatima G.; Thorn, Katherine; Agius, Phaedra; Kuk, Deborah; Socci, Nicholas D.; Qin, Li‐Xuan; Meyerson, Matthew; Hameed, Meera; Singer, Samuel
• Is Part Of: Genes, chromosomes & cancer. Volume 54:Issue 10(2015:Oct.)
• Page Start: 606
• Page End: 615
• Publication Date: 2015-07-14
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22272
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>CTNNB1</italic> mutations or <italic>APC</italic> abnormalities have been observed in ∼85% of desmoids examined by Sanger sequencing and are associated with Wnt/β‐catenin activation. We sought to identify molecular aberrations in "wild‐type" tumors (those without <italic>CTNNB1</italic> or <italic>APC</italic> alteration) and to determine their prognostic relevance. <italic>CTNNB1</italic> 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 <italic>CTNNB1</italic> 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 <italic>APC</italic> loss, two had chromosome 6 loss, and one had mutation of <italic>BMI1</italic>. The finding of low‐frequency <italic>CTNNB1</italic> mutation or <italic>APC</italic> loss in wild‐type desmoids was validated in the remaining eight wild‐type desmoids; directed miSeq identified low‐frequency <italic>CTNNB1</italic> mutation in four and comparative genomic hybridization identified <italic>APC</italic> loss in one. These results demonstrate that mutations affecting <italic>CTNNB1</italic> or <italic>APC</italic> 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 <italic>CTNNB1</italic> wild‐type tumors (determined by next‐generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/<italic>BMI1</italic> mutation), supporting Wnt/β‐catenin activation as the common pathway governing desmoid initiation. © 2015 Wiley Periodicals, Inc.</p> </abstract>