SNP Array-Based Analysis of Chromosome 17 Reveals Biallelic TP53 Mutations Due to Uniparental Disomy 17p in Advanced MDS and AML with Cooperating Deletions of Chromosomes 5 and 7
Authors: Jasek Monika , Gondek Lukasz P. , Bejanyan Nelli , Tiu Ramon V. , Huh Jungwon , Theil Karl S. , Keefe Christine O’ , McDevitt Michael A. , Maciejewski Jaroslaw P. 
Published: April 2020

Abstract
Areas of loss of heterozygosity (LOH) can be precisely delineated using single nucleotide polymorphism arrays (SNP-A) allowing for detection of submicroscopic chromosomal defects and segmental somatic uniparental disomy (UPD) not revealed by metaphase cytogenetic analysis (MC). This study focused on aberration of chromosome 17. We analyzed marrow specimens in 1162 MDS/AML by MC and found 39 patients whose karyotype involved monosomy 17. All had a complex karyotype, aggressive histomorphologic features (1/39 low risk, 26/39 advanced MDS/sAML, 2/39 MDS/MPD, and 10/39 pAML) with a median survival of 3 months. In addition to loss of chromosome 17, 35/39 patients also showed either −5/del(5q) (N=10), −7/del(7q) (N=2), or both (N=23). To better delineate the boundaries of LOH on 17th chromosome, we analyzed a subset of 532 patients by SNP-A and identified 43/532 samples with an abnormal chromosome 17; 28 had interstitial deletions and 15 had somatic UPD. In 17/19 samples with monosomy 17 by MC, SNP-A revealed a deletion in 17p or 17q, indicating incomplete loss of chromosome 17 material. SNP-A yielded a total of 11 additional lesions on 17q not detected by MC. We were able to define two commonly deleted regions (CDR1 and CDR2). CDR1 (bp 6,828,482 to 8,075,871; 1.25 Mb) encompassed around 90 genes, including TP53, and was present in 11/14 samples with del17p. CDR2 (bp 25,320,435 to 27,355,332; 2Mb) was detected in 7/14 patients and encompassed approximately 33 genes, including NF1. Overall, the frequency of UPD17 was high: 17p UPD was detected in 7 and 17q in 8 samples analyzed. In all cases with 17p UPD, the region of UPD overlapped with CDR1. CDR2 overlapped with the region of 17q UPD in 4/8 samples. In analogy to monosomy 17, 18/21patients with LOH 17p (7 UPD, 14 losses) had a complex karyotype, 21/21 had aggressive histomorphologic features (1/21 RCMD, 3/21 RCMD-RS, 6/21 RAEB-1/2, 3/21 pAML, 8/21sAML) and a poor prognosis with a median survival of 2.6 months. Moreover, in 13/14 patients with del(17p) by SNP-A, −5/del(5q) (N=1) or both −5/del(5q) and −7/del(7q) (N=12) were present. One patient did not show deletions of chromosomes 5 or 7, but had del (4)(q26) and del(6)(q23.2). No patient had del(17p) as the sole abnormality. Strong association between 17p UPD and abnormalities of chromosomes 5 and/or 7 was also noted: of 7 patients with 17p UPD, 3 had 5/del(5q), 1 showed −7/del(7q), and 3 had −5/del(5q) and −7/del(7q). We hypothesized that LOH within the 17p CDR1 that includes TP53 might be associated with a distinct clinical phenotype and point toward pathogenic TP53 mutations. Overall, 18 instances of 17p LOH included the TP53 locus. When TP53 exons 5–9 were screened for mutations in patients with 17p LOH, we found biallelic TP53 mutations in 5/6 patients with somatic 17p UPD and in 6/8 patients with 17p deletions. We detected 10 missense mutations and 1 insertion. All missense mutations were located in the DNA-binding domain of TP53 (4/10 in exon 5: C141Y, V172F, C176Y, H179Q; 2/10 exon 6: H193N, H193R; 1/10 exon 7: R249G and 3/10 exon 8: V272L, V272M, R273H). Our study demonstrates that LOH of 17p in myeloid malignancies should prompt consideration of TP53 mutation. TP53 mutation is linked with an aggressive clinical phenotype and is highly associated with partial or complete loss of chromosomes 5 and/or 7. To our knowledge this is the first report of biallelic TP53 mutations due to UPD17p in myeloid malignancies, and indicates that both heterozygous and homozygous mutations can be encountered and comprise part of the pathologic continuum of the selection process of malignant myeloid clones.