Session: 636. Myelodysplastic Syndromes—Basic and Translational Studies: Poster II
Hematology Disease Topics & Pathways:
Diseases, MDS, Myeloid Malignancies
The most common co-associated molecular lesions with -7/del(7q) were: TP53 (31%), DNMT3A (13%), TET2 (13%), RUNX1 (12%), ASXL1 (11%), del(5q) (25%) and CK (54%). Del(7q) vs. -7 differed in the frequency of TP53 (39 vs. 29%; P=.03), DNMT3A (19 vs. 11%; P=.03), and IDH1/2 (13 vs. 52%; P<.01). Isolated -7/del(7q) was associated with mutations of TET2 (24% vs. 9%, P<.001), SRSF2 (12% vs. 3%, P<.001), EZH2 (10% vs. 3%, P<.001), and SETBP1 (8% vs. 2%; P<.001). Complex -7/del(7q) correlated with TP53 (39% vs. 4%; P<.01) and PTPN11 (9% vs. 6%; P=.02). When we focused on mutations on genes located in the 7q common deleted regions (CDR1, 7q22 and CDR2, 7q35-q36), EZH2 was the most represented 7q mutant gene (6 mutants in del(7q) and 24 mutants in -7) totaling 5% of all -7/del(7q) cases. Other mutated genes on 7q were: CUX1 in 1% del(7q) and 1% -7, CUL1 in 1% of del(7q), and LUC7L2 which was only found mutated in -7.
Comparing the -7/del(7q) clone (calculated using allelic imbalance bio-analytic pipeline) to co-associated mutations allow us to identify the rank of -7/del(7q) in the clonal hierarchy: -7/del(7q) was an ancestral event in 58% and a secondary hit in 42% of the patients. When -7/del(7q) was the dominant hit, patients had fewer associated mutations, while in cases with secondary -7/del7q somatic mutations of TP53 (60%), IDH1/2 (30%), and DNMT3A (20%) were the ancestral hits suggesting a different clonal architecture according to -7/del(7q) clone size.
Expression data was available for 49 of -7/del(7q) and 643 diploid cases for chr.7. Of the 694 informative genes on chr.7: 147 were deleted in all patients according to CNV analysis. We restricted the analysis to 15 uniformly HI genes selected because the expression inversely correlated with the level of 7q ploidy (ACTR3B, FASTK, GSTK1, IMPDH1, LRRC4, MEST, MGAM, NUP205, PRRT4, SLC37A3, SSBP1, TMEM209, TNPO3, ZC3HC1, ZNF277). Expression for these genes was then analyzed following normalization by -7/del7q clonal size. Unsupervised clustering grouped 72% of -7/del(7q) in one expression cluster. Classical -7/del(7q) signature genes fulfilled these criteria and with uniform HI in all cases. However, when we also included CUL1, CUX1, EZH2, KMT2C, and LUC7L2 to this analysis, the precision of -7/del(7q) clustering was 75% and defined a subcluster (#6). We were also able to identify cases previously misclassified (n=9) which were dispersed into 3 other clusters (14%, 8%, 3%) while 4% (n=23) of diploid cases were also misclassified and re-assigned into cluster 6. When we restricted the analysis to -7 cases only, a signature of 6 unique genes (C7orf43, CDK14, POLM, STAG3L5P, TRIM4) were found. Interestingly only POLM was on 7p, while the rest were on 7q22.1.
In sum, we describe an integrated genomic and transcriptomic analysis of -7/del(7q) and we present data showing a complex heterogeneity of genes with HI expression which suggest that the clinical picture of patients carrying -7/del(7q) might be the result of a combination of clonality and HI.
Disclosures: Patel: Alexion: Other: educational speaker, Speakers Bureau. Sekeres: Pfizer: Consultancy; Takeda/Millenium: Consultancy; BMS: Consultancy. Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.
See more of: Oral and Poster Abstracts