Superior to CINGECS (Table 3; individual survival curves in Figure S6). However on multivariate analysis, only EMC92 (HR = 2.14, CI = 1.73?.65, p = 3.29610212) remained statistically significant beside CINGECS (HR = 1.26, CI = 1.04?.53, p = 0.0198). Therefore, CINGECS was associated with poor outcome independent of otherChromosome Instability and Prognosis in MMGEP signatures in both newly diagnosed and relapsed myeloma treated by either transplant-based therapy or novel agents.DiscussionCancer genomes contain genomic Title Loaded From File alterations of variable complexity and CIN has been coined to characterize these compromised genomes. The existence of CIN in cancer genome clearly demonstrates malfunction or incompleteness of mechanisms responsible for maintaining genome integrity and detailed elucidation of molecular phenotypes associated with it can be very useful in understanding the etiology of cancer as well as clinical decision making since CIN has been shown to be associated with disease progression and Title Loaded From File chemotherapeutic responses.[35?8]. MM is characterized by highly complex genomic alterations. While specific genetic abnormalities have been associated with disease outcome [39,40], the prognostic and biological relevance of underlying genome instability/complexity has not been well characterized in MM yet. Although we and others [26,27] have reported high-risk signatures associated with expression of genes involved in mitotic checkpoints and postulated that dysregulation of genes involved in maintaining chromosomal integrity may indicate underlying CIN as an important mediator of poor prognosis, these were at best indirect inference as none of these studies have shown an association between expression of these signatures with a measure of CIN. A measure of CIN, CINGEC, estimated by a novel algorithm described in this study that assesses the number of aberration events necessary to account for both aneuploidy and structural alterations captured in high-throughput copy number data is shown to have direct association with disease progression and survival in MM. In addition, its associated GEP signature CINGECS was also significantly associated with poor prognosis in three independent MM datasets. Furthermore, it was independent of other prognostic signatures. Our results therefore strongly implicate CIN as a biologically and prognostically important factor in MM. Comparison of CINGECS with two existing CIN signatures is quite illuminating. Carter et al. introduced a signature (CIN70) called total functional aneuploidy which is the sum of all absolute t statistic between expression levels of genes in a cytoband against average expression over the whole genome. [30] Recently, Chibon et al. derived a signature from sarcoma data (CINSARC) by combining aCGH imbalance comparison, histologic grade comparison, and CIN70 signature contents. [31] Since both CIN70 and CINSARC signatures are in principle based on aneuploidy and cell cycle, genes related to mitosis and proliferation are enriched in the signatures. However, CINGECS contains many DNA damage response related genes such as response to DNA damage stimulus, DNA repair, nucleotide-excision repair, DNA gap filling in addition to those enriched in aneuploidy centered signatures. This is a distinctive advantage of CINGEC estimation algorithm that considers all structural alterations equally regardless of genomic regions they span. It is also consistent with recent findings that defects in the response to D.Superior to CINGECS (Table 3; individual survival curves in Figure S6). However on multivariate analysis, only EMC92 (HR = 2.14, CI = 1.73?.65, p = 3.29610212) remained statistically significant beside CINGECS (HR = 1.26, CI = 1.04?.53, p = 0.0198). Therefore, CINGECS was associated with poor outcome independent of otherChromosome Instability and Prognosis in MMGEP signatures in both newly diagnosed and relapsed myeloma treated by either transplant-based therapy or novel agents.DiscussionCancer genomes contain genomic alterations of variable complexity and CIN has been coined to characterize these compromised genomes. The existence of CIN in cancer genome clearly demonstrates malfunction or incompleteness of mechanisms responsible for maintaining genome integrity and detailed elucidation of molecular phenotypes associated with it can be very useful in understanding the etiology of cancer as well as clinical decision making since CIN has been shown to be associated with disease progression and chemotherapeutic responses.[35?8]. MM is characterized by highly complex genomic alterations. While specific genetic abnormalities have been associated with disease outcome [39,40], the prognostic and biological relevance of underlying genome instability/complexity has not been well characterized in MM yet. Although we and others [26,27] have reported high-risk signatures associated with expression of genes involved in mitotic checkpoints and postulated that dysregulation of genes involved in maintaining chromosomal integrity may indicate underlying CIN as an important mediator of poor prognosis, these were at best indirect inference as none of these studies have shown an association between expression of these signatures with a measure of CIN. A measure of CIN, CINGEC, estimated by a novel algorithm described in this study that assesses the number of aberration events necessary to account for both aneuploidy and structural alterations captured in high-throughput copy number data is shown to have direct association with disease progression and survival in MM. In addition, its associated GEP signature CINGECS was also significantly associated with poor prognosis in three independent MM datasets. Furthermore, it was independent of other prognostic signatures. Our results therefore strongly implicate CIN as a biologically and prognostically important factor in MM. Comparison of CINGECS with two existing CIN signatures is quite illuminating. Carter et al. introduced a signature (CIN70) called total functional aneuploidy which is the sum of all absolute t statistic between expression levels of genes in a cytoband against average expression over the whole genome. [30] Recently, Chibon et al. derived a signature from sarcoma data (CINSARC) by combining aCGH imbalance comparison, histologic grade comparison, and CIN70 signature contents. [31] Since both CIN70 and CINSARC signatures are in principle based on aneuploidy and cell cycle, genes related to mitosis and proliferation are enriched in the signatures. However, CINGECS contains many DNA damage response related genes such as response to DNA damage stimulus, DNA repair, nucleotide-excision repair, DNA gap filling in addition to those enriched in aneuploidy centered signatures. This is a distinctive advantage of CINGEC estimation algorithm that considers all structural alterations equally regardless of genomic regions they span. It is also consistent with recent findings that defects in the response to D.
