Abstract 4946: Investigating candidate genomic alteration which affects the local recurrence in patients with desmoid fibromatosis
Authors: Park Sehhoon , Koh Youngil , Lee Se-Hoon , Ock Chan-Young , Keam Bhumsuk , Kim Tae Min , Kim Dong-Wan , Heo Dae Seog 
Published: August 2015

Abstract
BACKGROUND Desmoid tumor (DT) is known as a locally aggressive tumor caused by altered Wnt/b-catenin signaling pathway. Although high frequency of mutations are observed in APC and CTNNB1, its values as a predictive marker of local recurrence is controversial and only serine to phenyalanie substitution at codone 45 (S45F) in CTNNB1 is reported. We designed a study to investigate candidate mutations which affect the local recurrence in DT.
METHODS Tissues from 25 patients, treated with mass excision, were acquired and targeted gene sequencing (TGS) were performed for the 45 genes in COSMIC data set. Patients were divided into 2 groups, subjects with recurred DT and subjects without disease recurrence. Locus, previous reported in COSMIC data set, with altered frequency &gt; 0.01 was considered as a significant alteration. Statistical significance of each altered locus and candidate genes were tested by Cox-regression analysis and fisher's exact test. Time to recurrence is used in survival analysis and P under 0.05 is considered as a significant result. Primary endpoint of this study is evaluating a hazard ratio (HR) for each alteration.
RESULTS Out of 25 patients, 13 patients (52.0%) have recurred after initial treatment. APC mutation is observed in 13 patients (52.0%) and CTNNB1 mutation in 21 patients (84.0%) with no CTNNB1 S45F mutation observed. Median follow up duration was 72.3 months. More subjects were recurred with HRAS mutation (38.5% vs 0%, P = 0.039) and HR was increased (HR = 3.65, 95% confidential interval [CI] 1.09-12.15, P = 0.035). However, other genes, including CTNNB1 and APC, did not satisfied statistical significance. Among the 575 alterations detected by TGS, 9 missense mutation in 5 genes showed increased HR by Cox-proportional analysis and values are followed: (1) CTNNB1 S45G (HR 27.6, P = 0.007) (2) FGFR3 V266M (HR 14.8, P = 0.008); (3) CDKN2A P81L (HR 5.1, P = 0.020), D105E (HR 11.1, P = 0.049), R107C (HR 23.5, P = 0.026); (4) PTPN11 S502L (HR 23.5, P = 0.026); (5) TP53 A189V (HR 23.5, P = 0.026), C182Y (HR 23.5, P = 0.026), S96G (HR 23.5, P = 0.026). Out of 5 subjects with above alterations, 4 subjects recurred within 15.0 months and median time to relapse was shorter compared to the subjects without alteration (10.5 months vs 18 months, P = 0.057).
CONCLUSIONS In this study, we identified 6 genes and 9 specific locus which are related with recurrence of desmoid tumor. Our result is coincidence with previous result that an alteration in codon 45 of CTNNB1 is related with desmoid tumor recurrence. Values of other significant alteration in our report should be validated with confirmatory studies.
Citation Format: Sehhoon Park, Youngil Koh, Se-Hoon Lee, Chan-Young Ock, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo. Investigating candidate genomic alteration which affects the local recurrence in patients with desmoid fibromatosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4946. doi:10.1158/1538-7445.AM2015-4946