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Identification of novel pathogenic copy number aberrations in multiple myeloma: the Malaysian context.

ABSTRACT: BACKGROUND:Multiple myeloma is an incurable disease. Little is known about the genetic and molecular mechanisms governing the pathogenesis of multiple myeloma. The risk of multiple myeloma predispositions varies among different ethnicities. More than 50% of myeloma cases showed normal karyotypes with conventional cytogenetic analysis due to the low mitotic activity and content of plasma cells in the bone marrow. In the present study, high resolution array comparative genomic hybridization technique was used to identify copy number aberrations in 63 multiple myeloma patients of Malaysia. RESULTS:Copy number aberrations were identified in 100% of patients analyzed (n?=?63). Common chromosomal gains were detected at regions 1q, 2q, 3p, 3q, 4q, 5q, 6q, 8q, 9q, 10q, 11q, 13q, 14q, 15q, 21q and Xq while common chromosomal losses were identified at regions 3q and 14q. There were a total of 25 and 5 genes localized within the regions of copy number gains and losses, respectively (>30% penetrance). The LYST, CLK1, ACSL1 and NFKBIA are genes localized within the copy number aberration regions and they represent novel information that has never been previously described in multiple myeloma patients. CONCLUSIONS:In general, due to the differences in genetic background, dietary and lifestyle practices of Malaysian compared to the Caucasian population, these chromosomal alterations might be unique for Asian MM patients. Genes identified in this study could be potential molecular therapeutic targets for the treatment and management of patients with multiple myeloma.

SUBMITTER: Ivyna Bong PN

PROVIDER: S-EPMC4021726 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Identification of novel pathogenic copy number aberrations in multiple myeloma: the Malaysian context.

Ivyna Bong Pau Ni PN Ng Ching Ching CC Lam Kah Yuen KY Megat Baharuddin Puteri Jamilatul Noor PJ Chang Kian Meng KM Zakaria Zubaidah Z

Molecular cytogenetics 20140401 1

<h4>Background</h4>Multiple myeloma is an incurable disease. Little is known about the genetic and molecular mechanisms governing the pathogenesis of multiple myeloma. The risk of multiple myeloma predispositions varies among different ethnicities. More than 50% of myeloma cases showed normal karyotypes with conventional cytogenetic analysis due to the low mitotic activity and content of plasma cells in the bone marrow. In the present study, high resolution array comparative genomic hybridizatio ...[more]

PMID: 24690091

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Project description:DNA copy number aberrations (CNAs) are of biological and medical interest because they help identify regulatory mechanisms underlying tumor initiation and evolution. Identification of tumor-driving CNAs (driver CNAs) however remains a challenging task, because they are frequently hidden by CNAs that are the product of random events that take place during tumor evolution. Experimental detection of CNAs is commonly accomplished through array comparative genomic hybridization (aCGH) assays followed by supervised and/or unsupervised statistical methods that combine the segmented profiles of all patients to identify driver CNAs. Here, we extend a previously-presented supervised algorithm for the identification of CNAs that is based on a topological representation of the data. Our method associates a two-dimensional (2D) point cloud with each aCGH profile and generates a sequence of simplicial complexes, mathematical objects that generalize the concept of a graph. This representation of the data permits segmenting the data at different resolutions and identifying CNAs by interrogating the topological properties of these simplicial complexes. We tested our approach on a published dataset with the goal of identifying specific breast cancer CNAs associated with specific molecular subtypes. Identification of CNAs associated with each subtype was performed by analyzing each subtype separately from the others and by taking the rest of the subtypes as the control. Our results found a new amplification in 11q at the location of the progesterone receptor in the Luminal A subtype. Aberrations in the Luminal B subtype were found only upon removal of the basal-like subtype from the control set. Under those conditions, all regions found in the original publication, except for 17q, were confirmed; all aberrations, except those in chromosome arms 8q and 12q were confirmed in the basal-like subtype. These two chromosome arms, however, were detected only upon removal of three patients with exceedingly large copy number values. More importantly, we detected 10 and 21 additional regions in the Luminal B and basal-like subtypes, respectively. Most of the additional regions were either validated on an independent dataset and/or using GISTIC. Furthermore, we found three new CNAs in the basal-like subtype: a combination of gains and losses in 1p, a gain in 2p and a loss in 14q. Based on these results, we suggest that topological approaches that incorporate multiresolution analyses and that interrogate topological properties of the data can help in the identification of copy number changes in cancer.

Dataset Information

Identification of novel pathogenic copy number aberrations in multiple myeloma: the Malaysian context.

Publications

Identification of novel pathogenic copy number aberrations in multiple myeloma: the Malaysian context.

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