Is It Time for Arraycgh to Be the First Line Test for Detection of Chromosome Abnormalities in Hematological Disorders-Example Multiple Myeloma

Abstract 2543

aCGH has become the state-of art tool for assaying copy number changes of the entire genome in recent years. It offers a high resolution, high throughput and an unbiased view of detecting copy number changes in a genome compared to standard cytogenetics. In fact, aCGH has become the standard of care for detection of genomic/cytogenetic abnormalities in a postnatal setting recently (PMID # 20466091). In contrast, the application of aCGH in a clinical setting is lagging behind for acquired disease such as cancer, although aCGH has contributed greatly in our understanding of these disorders. Here we show the utility of aCGH in detecting prognostic significant genomic alterations in multiple myeloma compared to standard chromosome and targeted FISH analysis.

Multiple myeloma (MM) is a proliferation of malignant clonal plasma cells (PC) which accumulate in the bone marrow. It is a heterogeneous disease in which the genetic features of the malignant cells are the major contributing factor. Multiple myeloma is broadly divided into two biological genetic categories, hyperdiploid MM harboring multiple chromosome trisomies and a low frequency of IgH translocations and a non-hyperdiploid MM which have a high frequency of IgH translocations. There are also secondary genetic events that have been characterized in MM. Both the above genetic events in MM have major prognostic influence. The current clinical standard for identifying these genetic events in MM is conventional cytogenetics and targeted FISH analysis. However chromosome abnormalities are only detected in 30–40% of malignant PCs due to a low mitotic index in culture and FISH analysis only targets a few loci and therefore limiting in its use.

In this study we compared the standard chromosome analysis of clinically and morphologically diagnosed MM to aCGH using a custom designed cancer genes targeted 44K Agilent array. It specifically interrogates 493 genes involved in carcinogenesis with evenly distributed probes mapped to each gene at an average spacing of 1 probe/10 kb, or at least 10 probes/gene for genes less than 100 kb in size [PMID: 20724749]. In this study a total of 53 patients with indication of MM, 9% cases (5/53) showed chromosome abnormalities by standard karyotype analysis as compared to 40% (21/53) of the cases that demonstrated a genomic change by aCGH. Furthermore only 3 of the cytogenetic abnormal cases were consistent with a MM profile of hyperdiplody, the other 2 cases had single chromosome events. While analysis of the genomic profile obtained from aCGH analysis clearly showed biological and prognostic stratification. A total of 69% (11/16) showed a hyperdiploid MM profile. In addition, 44% (7/16) cases had a gain of chromosome 1q which has been associated with a poor prognosis. All cases with the 1q gain had normal chromosome analysis. Recently a new mechanism of genomic instability termed chromothripsis has been described in 2–3 % of cancer genomes (PMID: 21215367). This is an acquired single catastrophic event during cancer development. This event has been described in multiple myeloma and has been associated to a poor outcome (PMID:21628407). We observed chromothripsis in 2 chromosomes in 2 cases. Based on this preliminary study it is quite compelling that aCGH provides a more accurate biological or prognostic profile in 69% of cases (11/16) vs 19% (3/21) by conventional cytogenetics. Therefore we conclude that the first line standard testing in Multiple myeloma should be aCGH and FISH for the IgH rearrangements and not conventional cytogenetics and FISH.