Results of the bone marrow karyotype and FISH studies demonstrated highly complex intrachromosomal rearrangements of chromosome 5. The chromosomal stemline had a der(5)del(q15q32)inv(p13q32) as the sole abnormality. FISH studies using telomere-specific probes confirmed the presence of the pericentric inversion (Fig. 3B).
Both MDS/MPN metaphase and interphase FISH panel studies showed loss of most of the coding regions leaving only a remnant of the 5′ end of the PDGFRβ gene. This explains the lack of clinical and morphologic changes typically seen in PDGFRβ-related myeloproliferative disease. Based on WHO classification guidelines, we did not designate this case as an MPN associated with PDGFRβ rearrangement due to the lack of a fusion gene and we did not anticipate a favorable response to imatinib-related therapy.
Deletions of 5q are the only genetic abnormalities that truly define a specific MDS subtype [16, 17]. Most patients with isolated del(5q) MDS can remain in a chronic stable condition for many years [2, 3], with a majority of patients dying from complications of MDS without transforming to AML [4, 5]. Therefore, some patients require tailored MDS-specific treatment(s).
In a previous report of a Ph-negative CML-like patient, one year following diagnosis and treatment, the disease progressed to a myeloid blast crisis. Multicolor banding studies revealed a complex interchromosomal translocation between two chromosome 5 homologues as the sole abnormality resulting in del(5)(q21;q23) [18]. This report, much like the case we are presenting, shows the importance of using a multimodality approach for detailed characterizations of complex cytogenetic aberrations.
An unusual case of MDS with a paracentric inv(5)(q15q33) as the only observed abnormality was recently reported in a patient undergoing routine quarterly monitoring; this patient did not require treatment [19]. Another patient was previously described having complex intrachromosomal rearrangements of chromosome 5, including a paracentric inversion [20]. In this case, the chromosome 5 rearrangements progressively evolved into three sequential clones. This patient had an initial good response to lenalidomide, but treatment was stopped after a year due to adverse effects with subsequent disease progression and the disease advanced to RAEB-2 within 6 months [20].
There are two main routes of cytogenetic clonal evolution reported in MDS with 5q deletion [10]. The majority of MDS patients undergo stepwise accumulation of cytogenetic events over a long period of time. However, a few patients, like the one we present in this case report, may have undergone an one-time catastrophic event reminiscent of chromothripsis [21]. Chromothripsis is a sudden catastrophic event in which one or more chromosomes are shattered or pulverized, and subsequently stitched back together in random order to form one or more derivative chromosome(s) with complex rearrangements and loss of heterozygosity [21, 22]. The numerous chromosomal variants characteristic of both complex karyotypes and chromothripsis portend a very poor prognosis as seen in our patient. Since chromothripsis produces highly complex genomic aberrations, its reliable detection requires a comprehensive approach that combines molecular analysis, FISH, and classical cytogenetic methods.
Whole genome SNP microarray analysis revealed at least three separate deletions interspersed in the 5q14q32 region without any duplications. These deletions encompassed approximately 315 OMIM® genes including the critical EGR1 and RPS14 genes. All of the 5q deletions were found in the same copy number state, suggesting they originated as part of a single event (Table 1). The only other aberration seen on microarray analysis was a 20p13p12.3 (6.4 MB) duplication. The 5q FISH and microarray results indicated a mosaic state in the bone marrow sample comprised of approximately 40% neoplasm. Mosaic deletions of 5q (45–50%) including EGR1 and RPS14 are generally sensitive to lenalidomide according to NxClinical software analysis.
In addition to the 5q deletions, SNP microarray analysis showed 17p mosaic copy neutral LOH. This, along with the finding of a pathogenic missense variant in the TP53 gene (hg19: chr17:7577574T > C); NM000546.5(TP53): c.707A > G, p.(Tyr236Cys), suggested a unique mechanism led to the formation of a biallelic LOF for the TP53 gene. Loss of heterozygosity of the 17p region harboring TP53 is a common genetic event in cancer and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes [23]. The wider involvement of LOH is a feature in both heritable and sporadic cancers and is often considered as evidence for the existence of tumor suppressor gene(s) in the region of LOH.
This study reaffirms a multimodality approach is required to understand some of the genetic changes encountered in MDS, like those seen in this case. It is presumed that residual wild-type TP53 activity in patients with mono-allelic deletion/LOF is sufficient to maintain chromosome stability; however, bi-allelic hits to TP53 have been shown to be strongly associated with high-risk features such as complex karyotypes as seen in this patient [10].