Publication Date:
2019-11-13
Description:
Monosomy (-7) and deletions of the long arm of chromosome 7 (del7q) are frequently found in patients with myeloid neoplasms, suggesting a crucial role of this region in disease pathogenicity. -7/del7q conveys a poor prognosis and no targeted therapies exist for patients harboring this defect. We previously characterized the most common deleted regions (CDR) of del7q, including 7q22, 7q34, and 7q35-36, as well as micro deletions on del7q indicative of pathogenic genes. Unlike del5q, -7/del7q is affected both by deletions and somatic UPD, suggesting that loss of heterozygosity (LOH), rather than or in addition to haploinsufficient (HI) gene expression, may play a pathogenic role. Previous studies identified possible driver genes contributing to the pathogenesis of -7/del7q including CUX1, EZH2, LUC7L2, MLL3, and SAMD9/9L. Some of these genes may be affected by somatic mutations in hemizygous (LUC7L2), or homozygous (EZH2) configurations while others are affected by germ line (GL) mutations wherein a disease-prone allele is eliminated upon somatic acquisition of -7/del7q. The pathogenic mechanisms driving evolution of -7/del7q neoplasms, though, have not been clarified and specific therapies similar to lenalidomide in del5q have not been developed yet. The outstanding open questions include: i) the rank of -7/del7q in the clonal hierarchy; ii) genetic predispositions to -7/del7q; iii) new important genes affected by LOH or HI; iv) genetic differences between -7 and del7q; and v) co-associated somatic hits. We performed a complex molecular analysis of -7/del7q patients (N=316) using NGS: 67% with -7 (211/316) and 33% with del7q (105/316). First we performed analyses of clonal architecture using an allelic imbalance pipeline which facilitated reconstruction of clonal hierarchy. In 58% of patients -7/del7q was an ancestral lesion, while in 42% it was preceded by somatic hits such as TP53 (60%), IDH1/2 (30%), and DNMT3A (20%). The frequency of a chr7 abnormality as ancestral vs. secondary was no different in -7 vs. del7q. We then studied somatic hits associated with -7/del7q. The most commonly mutated genes were TP53 (43%), TET2 (17%), DNMT3A (15%), and ASXL1 (11%) and the most frequent additional lesion was del5q (30%). About 40% of -7 and 58% of del7q occurred in the context of complex karyotype (CK). We then compared various clinical and mutational features of patients with -7 vs. del7q: -7 was significantly associated with +8 (p=.002), while del7q was associated with CK (p=.004). Isolated -7/del7q was associated with mutations in TET2 (35% vs. 10%, p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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