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

Abstract

CTNNB1 mutations or APC 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 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. Wholeexome 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 HHS Public Access

Adult desmoid tumors: biology, management and ongoing trials

“…Ultimately, the so-called ‘wild-type’ desmoid tumor (without CTNNB1 or APC mutations) does not exist, or is misdiagnosed (other spindle cell proliferation mimicking desmoid tumor) [2 ▪▪ ,8] or desmoid tumor with CTNNB1 or APC mutations unrecognized by nonsensitive standard diagnostic methods [6 ▪▪ ], and exceptional desmoid tumor with other molecular alterations of the Wnt/APC/β-catenin pathway [6 ▪▪ ].…”

High cyclin A expression, but not Ki67, is associated with early recurrence in desmoid tumors

“…Other management options include surgery, radiotherapy, and/or medical therapy . Approximately 95% of sporadic desmoids carry a mutation in the β‐catenin CTNNB1 or the APC gene . Patients with familial adenomatous polyposis (FAP) harbor a germline APC mutation that predisposes to the development of desmoid tumors .…”

Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis

“…This pathway is activated by genetic mutations including CTNNB1 exon 3 and adenomatous polyposis coli (APC) protein, that stabilize the β-catenin protein which accumulates in the cytoplasm and then translocates to the nucleus [4]. It then binds to the T cell factor/lymphoid enhancer factor to activate genes, such as cyclin D1, and contributes to the oncogenesis of various human tumors including desmoidtype fibromatosis (DTF) of soft tissue [5].…”