BTG1 deletions do not predict outcome in Down syndrome acute lymphoblastic leukemia

Abstract

Children with Down syndrome (DS) have an increased risk of developing acute myeloid and B-cell precursor acute lymphoblastic leukemia (BCP-ALL). 1 The prognosis of DS ALL is at best similar and often inferior to that of sporadic ALL (non-DS) patients. 2,3 DS ALL is characterized by unique biological features when compared with non-DS ALL. For instance, DS ALL has a lower frequency of the favorable genetic abnormalities t(12;21)(p13;q22) (ETV6-RUNX1) and the unfavorable t(9;22)(q34;q11) (BCR-ABL1), 3,4 but a higher frequency of JAK2 mutations and CRLF2 rearrangements. 5,6 Using genome-wide screening techniques, several (novel) genomic aberrations involved in the pathogenesis of (non-) DS ALL were identified. 7,8 The potential prognostic impact of most of these novel aberrations and whether these patients may benefit from specific therapies targeted to these unique genetic features needs to be investigated further. The B-cell translocation gene 1 (BTG1) was recently described as a recurrent lesion in pediatric BCP-ALL. 7,9,10 It was originally identified as a translocation partner of c-MYC in B-cell chronic lymphocytic leukemia. 11,12 BTG1 is a highly conserved gene and belongs to the family of BTG/TOB genes. 11,13 It has a role in several crucial cellular processes, such as proliferation, and apoptosis. Recently, Lundin et al. 14 reported on a high frequency of BTG1 deletions (B29%) in DS ALL. However, the study included a limited number of DS ALL patients (n ¼ 17) and hence may not be an accurate estimate of the frequency of BTG1 deletions in DS ALL. Therefore, we investigated the frequency of BTG1 deletions in a large series of DS ALL patients and in addition analyzed the prognostic significance of BTG1 abnormalities. We screened a population-based cohort of 116 DS ALL patients enrolled in consecutive DCOG and UK treatment protocols (DCOG ALL 8, 9 and 10 and UK ALL ALL97, ALL97/99 and ALL2003). 8 Clinical and cell-biological data, including cytogenetics, were available for all cases. DCOG and UK centrally reviewed diagnosis, classification and clinical follow-up of the patients. The Institutional Review Board approved the investigations, and informed consent was obtained according to local law and regulations. To identify BTG1 deletions, we performed multiplex ligationdependent probe amplification (MLPA) analysis using the SALSA MLPA kit P335-A3 ALL-IKZF1 (MRC Holland, Amsterdam, the Netherlands), which contains probes for selected B-cell development and differentiation genes. 8 The BTG1 gene is covered by four probes, probes to exon 1, exon 2 and two additional probes localized to the highly conserved promoter region of the gene (area 1 and 2). The full list and location of the MLPA probes can be downloaded from the MRC Holland website (http://www.mrc-holland.com). Peak heights o0.7 (0.75 for MRC UKALL samples) and 41.3 times the control peak height were considered abnormal, with those o0.7 (0.75) representing deletions, and those 41.3 representing duplications. The Kaplan-Meier method was used to estimate the ...

Gene alterations involving the CRLF2‐JAK pathway and recurrent gene deletions in Down syndrome‐associated acute lymphoblastic leukemia in Japan

“…BTG1 deletions were detected in 8 of 32 patients (25%), with a frequency similar to that of Lundin et al () (29%) and higher than that of Buitenkamp et al () (6.9%). However, we could not confirm the previously reported associations of BTG1 deletions with male predominance and older age (Lundin et al, ).…”

“…IKZF1 deletions have been detected in approximately 20–30% of DS‐ALL patients, and are associated with a poor outcome (Buitenkamp et al, ; Patrick et al, ). The initial report of frequent BTG1 deletions in older male DS‐ALL patients (29%) was not confirmed in a subsequent study using a larger cohort (Lundin et al, ; Buitenkamp et al, ), and EBF1 deletions have rarely been found in DS‐ALL cases (Kearney et al, ; Hertzberg et al, ; Ensor et al, ; Loudin et al, ; Buitenkamp et al, ). The frequencies and clinical implications of these gene deletions in Asian DS‐ALL patients also remain to be determined.…”

Integrated multigene expression panel to prognosticate patients with gastric cancer

“…Elevated SYT8 levels were significantly and specifically associated with peritoneal metastasis, and intraperitoneal administration of an SYT8 -specific small interfering RNA inhibited the growth of peritoneal nodules and prolonged survival in mouse xenograft models [ 24 ]. BTG1 reportedly is a mediator of B-cell differentiation and may act as a tumor suppressor because of its inhibitory effects on proliferation and cell cycle progression [ 25 , 26 ]. In our previous study, downregulation of BTG1 was associated with larger tumor size and lymph node metastasis [ 27 ].…”

Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

“…Individuals with DS have a paradoxical association with cancer, with a reduced incidence of most solid tumours, but an increased incidence of all types of leukaemia in childhood, due to mechanisms that are only partially understood 24 . The mechanistic paradigms currently explaining DS-ALL leukaemogenesis paint an incomplete picture: CRLF2 overexpression has been seen as the most frequently recurrent event, which then selects for events activating the JAK2 pathway in approximately a third of the CRLF2-rearranged cases, 10-12,25 . In western populations, the frequency of CRLF2 rearrangements and/or overexpression ranges around 5-12% in non-DS ALL, and up to 62% in DS-ALL 11,13,26 .…”