Abstract 3092: PTEN mutations correlate with relapse risk in pediatric T-cell lymphoblastic lymphoma patients: Validation of whole exome sequencing results
Authors: Bonn Bettina R. , Huge Andreas , Rohde Marius , Zimmermann Martin , Voss Reinhard , Woessmann Wilhelm , Trümper Lorenz , Rossig Claudia , Juergens Heribert , Seggewiss Jochen , Burkhardt Birgit 
Published: May 2015

Abstract
Prognosis of T-cell lymphoblastic lymphoma (T-LBL) in children and adolescents is poor in case of relapse, but pathogenetic knowledge of the disease which may lead to the establishment of prognostic parameters is still extremely limited. Recently, it was reported that molecular aberrations like NOTCH1 mutations or loss of heterozygosity at chromosome 6q (LOH6q) significantly correlate with relapse risk and survival in patients with T-LBL treated according to NHL-BFM protocols. PI3-kinase (PI3K) consists of two subunits (PIK3R1 and PIK3CA); its activity is repressed by the tumor suppressor PTEN. Mutations in PIK3R1, PIK3CA and PTEN leading to increased cell proliferation have been reported for different cancer types. Next generation sequencing (NGS) technologies facilitate in-depth genome-wide insight into different types of cancer. We performed NGS of pediatric T-LBL patients and validated results regarding the PI3K pathway in a large cohort of patients with respect to mutational frequencies and prognostic relevance.
We analyzed five pediatric T-LBL cases by whole exome sequencing. A total of 107 cases were available for validation of candidate genes. All patients were treated according to NHL-BFM regimen for LBL.
A lymphoma-specific aberration in PIK3R1 was identified via whole exome sequencing and verified by Sanger sequencing. Mutation frequencies in selected exons of PIK3R1, PIK3CA and PTEN were investigated in 107 cases. Five patients (5%) showed mutations in PIK3R1, 7 (7%) in PIK3CA, and 16 (15%) in PTEN. In 22% of the cases (24/107), mutations in at least one of the genes could be detected. These aberrations correlated with inferior probability of event-free survival (pEFS) in the analyzed cohort (pEFS at 5 years 0.80±0.05 vs. 0.61±0.10; p&lt;0.02). This depended on mutations in PTEN, as the effect was more prominent when these aberrations were considered separately (pEFS 0.80±0.04 vs. 0.53±0.13; p&lt;0.005).
Although PTEN is reported to be transcriptionally repressed by NOTCH1, NOTCH1 mutations seem to set off the negative effect of PTEN mutations on outcome instead of acting synergistically in T-LBL. The pEFS of patients with mutations in both genes was 0.88±0.12 (N=10), whereas patients with mutations in PTEN, but wild-type NOTCH1 (N=6), displayed a significantly inferior pEFS compared to all other patients (0.17±0.15 vs. 0.80±0.04; p&lt;0.0001). Moreover, in a Cox regression model with LOH6q, NOTCH1, PTEN and an interaction term (NOTCH1 WT/PTEN mutated) only the interaction was significant (p=0.001).
Thus, we identified mutations in PTEN as another molecular parameter which is significantly associated with prognosis in pediatric T-LBL patients treated according to NHL-BFM protocols. Validation studies on larger series are needed to evaluate the genetic interplay of these alterations and their impact on pediatric T-LBL pathogenesis.
Citation Format: Bettina R. Bonn, Andreas Huge, Marius Rohde, Martin Zimmermann, Reinhard Voss, Wilhelm Woessmann, Lorenz Trümper, Claudia Rossig, Heribert Juergens, Jochen Seggewiss, Birgit Burkhardt. PTEN mutations correlate with relapse risk in pediatric T-cell lymphoblastic lymphoma patients: Validation of whole exome sequencing results. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3092. doi:10.1158/1538-7445.AM2014-3092