Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors

Abstract

Desmoid tumors are fibroblastic/myofibroblastic proliferations. Previous studies reported that CTNNB1 mutations were detected in 84% and that mutations of the APC gene were found in several cases of sporadic desmoid tumors lacking CTNNB1 mutations. Forty tumors were analyzed by comparative genomic hybridization (CGH). Karyotype and fluorescence in situ hybridization revealed a nonrandom occurrence of trisomy 8 associated with an increased risk of recurrence. We report the first molecular characterization including a large series of patients. We performed array CGH on frozen samples of 194 tumors, and we screened for APC mutations in patients without CNNTB1 mutation. A high frequency of genomically normal tumors was observed. Four relevant and recurrent alterations (loss of 6q, loss of 5q, gain of 20q, and gain of Chromosome 8) were found in 40 out of 46 tumors with chromosomal changes. Gain of Chromosomes 8 and 20 was not associated with an increased risk of recurrence. Cases with loss of 5q had a minimal common region in 5q22.5 including the APC locus. Alterations of APC, including loss of the entire locus, and CTNNB1 mutation could explain the tumorigenesis in 89% of sporadic desmoids tumors and desmoids tumors occurring in the context of Gardner's syndrome. A better understanding of the pathogenetic pathways in the initiation and progression of desmoid tumors requires studies of 8q and 20q gains, as well as of 6q and 5q losses, and study of the Wnt/beta-catenin pathway.

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

Gene Expression Profiling of Desmoid Tumors by cDNA Microarrays and Correlation with Progression-Free Survival

“…Biologically, alterations of the APC (mutation or loss of the entire locus) and CTNNB1 mutation might constitute an initial mutually exclusive alteration (3,4). Moreover, Salas and colleagues described three recurrent and relevant alterations of chromosomes 8, 20, and 6 by array comparative genomic hybridization (CGH) array.…”

Molecular Analysis of Desmoid Tumors with a High-Density Single-Nucleotide Polymorphism Array Identifies New Molecular Candidate Lesions

“…Inapreviousstudy,CGHlossofChr6or6q,Chr5q,gain ofChr20,andalterationofChr8qwereobservedwithafre-quency of 3-11% [8] and confirmed previous observations [15,16]. However, in the literature, the frequency of these aberrationsisvariableforthelossinChrs6(10-20%)and5q (5-11%)andthegaininChrs8(3-30%)and20(7-30%).In addition, a prognostic impact of trisomy 8 was suggested in 1oftheseanalyses.Inourstudy,notrisomy8wasdetected.…”

“…In previous studies, which performed CGH analysis and classical karyotyping, most of the desmoids were described with a normal karyotype in 50-77% of the analyzed samples [8,14]. Using high-density SNP array analysis, our observation showed copy number changes in every single tumor.…”