In the present study, we described a case of isolated del(20q) abnormality with additional 11q CN-LOH identified using SNP-A-based karyotyping. Our patient was found to have CNS involvement in the leukemia and was unable to achieve remission. During the follow-up, no additional abnormalities or clonal evolutions were detected by MC. This result suggests that identifying additional CN-LOH using SNP-A may be associated with a poor prognosis.
An isolated del(20q) is generally associated with a better prognosis in MDS, whereas AML patients have a significantly shorter overall survival [1
]. Cases that have del(20q) with one or more additional chromosomal abnormalities predict a poor prognosis [3
]. Therefore, we hypothesized that AML patients with isolated del(20q) may have, in fact, additional chromosomal abnormalities not identified by MC. One study also showed that additional CN-LOH or copy number changes could be identified by SNP-A analysis in patients with del(20q) as the isolated abnormality by MC [6
As for the prognostic impact of 11q CN-LOH, one study showed that the 11q CN-LOH region was present only in a few fractions of the cells in the MDS phase; however, in the late relapse AML sample, the 11q CN-LOH region was present in more than 90% of leukemic cells. This finding suggests that clones with 11q CN-LOH may have conferred a selective growth advantage during the AML transformation and may be associated with a poor prognosis [7
In particular, somatic CN-LOH on 11q is associated with homozygous mutations of the c-Cbl
gene as a known oncogene encoding E3 ubiquitin ligase, which is involved in the ubiquitylation and degradation of active protein tyrosine kinase receptors [7
]. A previous study showed that oncogenic c-Cbl
mutations were acquired in a subset of myeloproliferative neoplasms (MPN) with poor prognosis or during evolution to AML and that clones with homozygous mutations have a selective growth advantage over those with heterozygous mutations [9
]. In the present study, c-Cbl
mutation sequencing was not conducted.
For a prognostic impact of the additional abnormalities that were not detected by MC, another study confirmed that cases with isolated del(5q), which is known to be a good prognostic factor, showed adverse clinical courses when additional genomic imbalances were identified using array CGH [10
]. Similarly, we treated a 40-yr-old man with relapsed AML (data not shown). MC revealed del(9)(q22q34) as an isolated abnormality. SNP-A identified not only deletions in the regions of 9q13-q22.3, but also additional genomic aberrations of CN-LOH on 6p25.3-p12.1 and 7q31.33-q36.3. Because of general weakness, the patient received conservative treatment without chemotherapy, and he died due to complications from pneumonia and sepsis. In contrast, a separate case involved a 69-yr-old man with chronic myelomonocytic leukemia with isolated del(20q) according to MC (data not shown). SNP-A showed interstitial deletion on chromosome 20q (20q11.23-q13.32), but no additional abnormalities were observed. He received 5 cycles of azacitidine chemotherapy and continued complete hematologic remission until the last follow-up (3 yr), although isolated del(20q) was persistently identified by MC.
Taken together, we recommend that in cases with isolated chromosomal abnormalities such as del(20q), del(5q), and del(9q), molecular techniques such as SNP-A or array CGH should be performed to identify additional CN-LOH, which may be associated with the poor prognosis.
Apart from the ability to detect CN-LOH, another advantage of SNP-A is its high-resolution power (less than 1 Mbp), which allows for further detection of cryptic lesions that cannot be detected by MC as well as the precise delineation of aberrations. The small size of chromosome 20 and the limited number of G-bands on its long arm has hampered cytogenetic characterization of 20q breakpoints; subtle deletions or rearrangements may be beyond the resolution of traditional MC. Using SNP-A, our case showed an interstitial deletion pattern of 20q. The deletion was located between bands 20q11.22 and 20q13.31 (23 Mbp), and the distal region was duplicated (20q13.31-q13.33, 4 Mbp). For the commonly deleted region (CDR) of chromosome 20q, a study using SNP-A defined 2 CDRs [6
]; CDR1 was located between bands 20q11.23 and 20q12 and CDR2 was within bands 20q13.12. The deleted regions in our case encompassed these 2 CDRs. Similarly to our case, another study demonstrated that the 20q deletion showed an interstitial pattern according to SNP-A in most cases [6
]. The rarity of true monosomy 20 suggests that retained or duplicated genes on chromosome 20 are essential for the survival of mutant clones [6
]. Taken together, these findings indicate that tumor suppressor genes are located in the deletion region and oncogenes, in the duplicated region of chromosome 20.
In summary, we report a case of an isolated del(20q) abnormality with additional genomic aberrations identified using SNP-A-based karyotyping. This study suggests that a presumably isolated chromosomal abnormality according to MC may have additional genomic aberrations, including CN-LOH. SNP-A-based karyotyping may be helpful for identifying true isolated cases from cases in combination with additional genomic aberrations not detected by MC. Further study is needed to determine whether additional aberrations identified by SNP-A have a negative effect on prognosis in larger cohorts of AML patients.