br Discussion While the DNA

Discussion While the DNA copy number data were in agreement with the FISH findings, the genome-wide DNA copy number analysis also uncovered many other abnormalities indicative of chaotic genomic disruption. Chromothripsis is thought to occur during a single cellular catastrophe and may occur in at least 2%–3% of all cancers, across many subtypes. Interestingly, the very first reported evidence of chromothripsis was found via a genome-wide sequencing screen of 10 CLL patients, one (a previously untreated 62-yr-old woman) showing massive rearrangement of chromosome arm 4q and focal alterations of semagacestat 1, 12, and 15. The copy number changes in 4q alternated between 1 and 2, with regions of copy number 1 showing loss of heterozygosity (LOH), whereas regions of copy number 2 retained heterozygosity. The whole genome sequencing revealed that the many discontinuous regions of copy number 1 in 4q were not caused by simple deletions but instead were the result of a series of complex rearrangements spanning 4q. In that same report, subsequent study uncovered a second CLL patient with losses of single copies of CDKN2A and miR-15a/16-a due to a cluster of interchromosomal rearrangements involving chromosomes 4, 9, and 13. In our patient, the discontinuous regions of LOH in chromosomes 2, 5, 6 and 7 are also separated by regions retaining heterozygosity (Fig. 1). Notably, the clinical course in the initial CLL patient reported by Stephens et al. showed rapid deterioration and quickly relapsed. Sequence analysis of a relapse specimen collected 31 months after diagnosis revealed no new genomic rearrangements, suggesting that the process generating this complex genomic remodeling had occurred before the patient was diagnosed and was not indicative of further genomic instability. As noted above, while FISH evidence for a deletion of chromosome 17p13.1 (TP53) is generally associated with a poor prognosis, CLL patients with del(17p13.1) exhibit clinical heterogeneity. Some TP53-deficient CLL patients have a relatively indolent course. One reason for such heterogeneity may be that not all cases with loss of one copy of TP53 have a mutation in the remaining allele. Thus, there is insufficient evidence for rigid therapeutic recommendations to be made based on deletion of 17p alone, although survival may be predicted using other risk factors for progressive disease including the presence of unmutated immunoglobulin heavy-chain variable region genes (IGHV). As in other hematological malignancies, the genetic profile of CLL may evolve during the disease course. For example, while del(17p13.1) is uncommon at the time of diagnosis (5%–10%), it is observed in about 45% of patients with relapsed or refractory CLL. In del(17p13.1) CLL cases, clonal evolution with acquisition of other genomic imbalances is associated with unmutated IGVH, resistance to therapy, and short survival. As array-based DNA copy number analysis becomes more widely used in the clinical setting, it will be important to determine if chromothripsis represents yet another risk factor of progressive disease, as we predict. Unfortunately, we do not know whether or not the disease course was rapid in our CLL patient, because the DNA was from a de-identified sample that was used for a validation study of a DNA copy number assay. The deletion of 14q seen in our patient included the IGH locus at 14q32.33. This is noteworthy, because loss of 14q has been reported as a recurrent aberration acquired during the natural history of CLL. The acquisition of a del(14) may thus be indicative of CLL in transformation. In a study of a large German cohort, del(14q) was found in ∼2% of newly diagnosed CLLs, and these patients typically required more immediate therapy. The investigators used a panel of 14q probes to determine that the del(14) was usually interstitial and heterogeneous in size, with a breakpoint cluster at the centromeric site in 14q24.1; in most cases the breakpoint at the telomeric site was within the IGH locus while ∼25% showed a deletion of the entire IGH locus, as was the case in our patient.
Conflict of interest
Acknowledgments We thank Yu Cao, MS, for technical assistance with the DNA copy number assay. This study was supported by the National Cancer Institute Award CA-06927 and an appropriation from the Commonwealth of Pennsylvania. The Genomics Facility of Fox Chase Cancer Center shared facility was used in the course of this work. The study sponsors had no involvement in the study design, collection, analysis and interpretation of data.
Multiple myeloma and mantle cell lymphoma are well defined B-cell malignancies with significant disease burden worldwide. Understanding of the pathogenesis of both entities has improved over the years, leading to new therapies and improved survival rates. The hallmark of MCL is t(11;14)(q13;q32); this genetic alteration leads to overexpression of cyclin D1, an important regulator of the cell cycle. While the same translocation and overexpression of cyclin D1 has been recognized in a subset of patients with MM, its role in the pathogenesis of myeloma is still undetermined. The occurrence of MCL and MM in the same patient is very rare. To our knowledge, there are only limited case reports of MCL and MM affecting the same patient. Here we report a case of MM which arose in a patient previously diagnosed and successfully treated for MCL. We also review literature to explore the relationship, if any, between these two entities to understand how genetic factors might contribute to their development in a single individual.