AKT1 and BRAF mutations in pediatric aggressive fibromatosis

Abstract

Aside from the CTNNB1 and adenomatous polyposis coli (APC) mutations, the genetic profile of pediatric aggressive fibromatosis (AF) has remained poorly characterized. The aim of this study was to shed more light on the mutational spectrum of pediatric AF, comparing it with its adult counterpart, with a view to identifying biomarkers for use as prognostic factors or new potential therapeutic targets. CTNNB1,APC,AKT1,BRAF TP53, and RET Sanger sequencing and next‐generation sequencing (NGS) with the 50‐gene Ion AmpliSeq Cancer Hotspot Panel v2 were performed on formalin‐fixed samples from 28 pediatric and 33 adult AFs. The prognostic value of CTNNB1,AKT1, and BRAF mutations in pediatric AF patients was investigated. Recurrence‐free survival (RFS) curves were estimated with the Kaplan–Meier method and statistical comparisons were drawn using the log‐rank test. In addition to the CTNNB1 mutation (64%), pediatric AF showed AKT1 (31%), BRAF (19%), and TP53 (9%) mutations, whereas only the CTNNB1 mutation was found in adult AF. The polymorphism Q472H VEGFR was identified in both pediatric (56%) and adult (40%) AF. Our results indicate that the mutational spectrum of pediatric AF is more complex than that of adult AF, with multiple gene mutations involving not only CTNNB1 but also AKT1 and BRAF. This intriguing finding may have clinical implications and warrants further investigations.

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases

“…Based on our previous results analyzing mesenteric DTF 20 , we first examined the mutational CTNNB1 status in correlation with clinicopathological features. Previous studies reported genomic CTNNB1 alterations in 67-92% of sporadic DTF cases demonstrated by conventional Sanger sequencing and limited to CTNNB1 exon 3 [7][8][9][19][20][21] (summarized in Table 3). In our present study, we conducted NGS with an increased sensitivity (≥10% allelic frequency) and detected deleterious CTNNB1 mutations in an enlarged fraction of n = 181/204 (89%) DTF cases.…”

“…The majority of genetic studies published so far applied conventional Sanger sequencing of CTNNB1 (limited to exon 3), focusing predominantly on the mutational subtype of sporadic DTF. Recently, Meazza et al analyzed a small cohort of DTF employing NGS for mutational analysis and reported potential clinical implications for pediatric (patients age ≤18 years) DTF harboring gain-of-function mutations in AKT1 and BRAF 19 . These findings suggest a more complex mutational spectrum of DTF than expected so far, which may potentially be associated with therapeutic implications.…”

Identification of potentially druggable molecular alterations in skin adnexal malignancies

“…Genomic DNA was extracted from FFPE tumor sections with the GeneRead DNA FFPE kit (Qiagen, Hilden, Germany) and its quantity/quality was assessed by bioanalyzer. Mutational data were obtained by targeted next‐generation sequencing (T‐NGS) using the Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA, USA) with the Ion‐Torrent Personal Genome Machine platform (Life Technologies) . Library preparation, emulsion polymerase chain reaction (PCR) and chip loading were performed as previously described .…”

“…Library preparation, emulsion polymerase chain reaction (PCR) and chip loading were performed as previously described . Data were processed by using Torrent Suite and variants were analyzed as previously described . We looked at molecular alterations, which could potentially pave the way for targeted therapeutic approaches, and we leveraged on the alterations already reported in salivary gland cancer and basal cell carcinoma whose histological profiles could resemble the ones of SAC.…”

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

“…The libraries were prepared by IonAmpliSeq Library kit 2.0 (Thermo Fisher). 16 Emulsion polymerase chain reaction and chip loading were performed on the IonChef System (Thermo Fisher), according to the manufacturer's instructions. Sequencing was performed on the ION S5 XL System (Thermo Fisher) using Ion 540 Chips and Ion 540 Kit-Chef according to the manufacturer's instructions (MAN0010846).…”