Mapping of Chromosome 1p Deletions in Myeloma Identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as Being Genes in Regions Associated with Adverse Survival

Abstract

Purpose: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact.Experimental Design: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data.Results: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting.Conclusion: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.

Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

“…Overall, the incidence of 1p loss and 1q gain was 40 and 50%, respectively, which is only slightly higher than that reported in MM by us and several other groups [7,10,12,26]. Notably, SNP-array analysis pointed out the involvement of specific loci such as the CDKN2C loss at 1p and the CKS1B gain at 1q, which have been strongly suggested as putative targets in MM [21,[27][28][29][30][31], although in our dataset a slight correlation (P-value50.04) between DNA CN and the expression levels has been found only for CKS1B (data not shown). Chromosome 16q has been shown to be one of the most involved regions in MM.…”

Robust isolation of malignant plasma cells in multiple myeloma

“…2,9,10 To enable identification of genes specifically expressed in MMPCs, we collected a control data set consisting of 3185 gene expression profiles from a wide range of hematologic disorders and cell types. [11][12][13][14][15] Comparison of these 2 data sets identified a gene expression signature that is representative for a broad range of MMPCs (supplemental Table 1, available on the Blood Web site).…”

Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

“…18 Leone et al focused on CDKN2C deletion, at 1p32.3, which strongly affects cell-cycle regulation and MM pathogenesis. 19 Despite the considerable number of molecular and clinical studies on gain(1q), del(1p) or both [20][21][22][23][24][25] , the real role of chr1 abnormalities in MM remains a matter of debate. As far as gain(1q) is concerned, the poor prognostic impact of this aberration has been demonstrated in several series of patients: (i) in newly diagnosed patients, enrolled in the CMG2002 trial, treated with high-dose chemotherapy and autologous stem cell transplantation 26 ; (ii) in patients with recurrent disease, treated with lenalidomide and dexamethasone 27 ; and (iii) in relapsed or refractory patients treated with bortezomib.…”