t(14;16) TRANSLOCATION

 

The t(14;16) translocation involves c-MAF, a leucine zipper-containing transcription factor.
MAF = musculoaponeurotic fibrosarcoma oncogene homolog.

 

Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor?
Blood. 2011 Feb 10;117(6):2009-11.
Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, Decaux O, Lamy T, Legros L, Fuzibet JG, Michallet M, Corront B, Lenain P, Hulin C, Mathiot C, Attal M, Facon T, Harousseau JL, Minvielle S, Moreau P; Intergroupe Francophone du Myélome.
This study is a retrospective analysis of 32 patients with t(14;16), found among 1003 patients with newly diagnosed myeloma (3%). Patients with t(14;16) had an overall survival similar to that of patients without the translocation.

t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs.
Blood Cancer J. 2015 Feb 27;5:e285.
Narita T, Inagaki A, Kobayashi T, Kuroda Y, Fukushima T, Nezu M, Fuchida S, Sakai H, Sekiguchi N, Sugiura I, Maeda Y, Takamatsu H, Tsukamoto N, Maruyama D, Kubota Y, Kojima M, Sunami K, Ono T, Ri M, Tobinai K, Iida S.
This is a retrospective study of 35 myeloma patients with the rare 14;16 translocation.

APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.
Nat Commun. 2015 Apr 23;6:6997.
Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, Proszek PZ, Melchor L, Pawlyn C, Kaiser MF, Johnson DC, Qiang YW, Jones JR, Cairns DA, Gregory WM, Owen RG, Cook G, Drayson MT, Jackson GH, Davies FE, Morgan GJ.
The authors did whole exomic sequence of 463 cases of newly diagnosed multiple myeloma. They found an APOBEC mutational signature in 4% of cases. They were associated to the translocations t(14;16) and t(14;20), which result in deregulation of the MAF and MAFB genes, respectively. APOBEC is a family of enzymes editing the DNA, and they deaminate cytosine to uracil in single-stranded DNA.
  - In MAF and MAFB, the mutations were only seen in the basic-leucine zipper domain
  - In FGFR3, the mutations were scattered throughout the gene

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice.
Blood. 2016 Mar 31;127(13):1676-86.
Zhang Z, Tong J, Tang X, Juan J, Cao B, Hurren R, Chen G, Taylor P, Xu X, Shi CX, Du J, Hou J, Wang G, Wu D, Stewart AK, Schimmer AD, Moran MF, Mao X.

 


t(14;20) TRANSLOCATION

 

MAFB is a transcription factor belonging to the AP1 superfamily of basic leucine zipper proteins.

 

Identification of primary MAFB target genes in multiple myeloma.
Exp Hematol. 2009 Jan;37(1):78-86.
van Stralen E, van de Wetering M, Agnelli L, Neri A, Clevers HC, Bast BJ.

This study attempts to identify MAFB target genes in MM. Authors identified 14 upregulated genes, and evaluated their downstream consequences in the combined MAFB/C-MAF pathway.

The t(14;20)(q32;q12): a rare cytogenetic change in multiple myeloma associated with poor outcome.
Br J Haematol. 2010 Jun;149(6):901-4.
Vekemans MC, Lemmens H, Delforge M, Doyen C, Pierre P, Demuynck H, Bries G, Lemmens J, Meeus P, Straetmans N, Bauwens D, Vidrequin S, Rack K, Vandenberghe P, Wlodarska I, Michaux L.
In this study, median overall survival of 15 patients with the t(14;20) translocation was only 19 months.

APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.
Nat Commun. 2015 Apr 23;6:6997.
Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, Proszek PZ, Melchor L, Pawlyn C, Kaiser MF, Johnson DC, Qiang YW, Jones JR, Cairns DA, Gregory WM, Owen RG, Cook G, Drayson MT, Jackson GH, Davies FE, Morgan GJ.
The authors did whole exomic sequence of 463 cases of newly diagnosed multiple myeloma. They found an APOBEC mutational signature in 4% of cases. They were associated to the translocations t(14;16) and t(14;20), which result in deregulation of the MAF and MAFB genes, respectively. APOBEC is a family of enzymes editing the DNA, and they deaminate cytosine to uracil in single-stranded DNA.
  - In MAF and MAFB, the mutations were only seen in the basic-leucine zipper domain
  - In FGFR3, the mutations were scattered throughout the gene

 


t(7;14) TRANSLOCATION

 

Identification of a novel t(7;14) translocation in multiple myeloma resulting in overexpression of EGFR.
Genes Chromosomes Cancer. 2013 Sep;52(9):817-22.
Walker BA, Wardell CP, Ross FM, Morgan GJ.

 


DELETION 17p13

 

17p13 is he locus for the tumor suppressor gene p53. Deletion 17p13 confers a negative effect on survival. It is associated with more aggressive course and extramedullary disease.

 

 


DELETION 13

 

Chromosome 13 deletion is an important negative prognostic factor, when detected at metaphase cytogenetics. It is closely associated with high-risk abnormalities, particularly the t(4;14) translocation.

 

Deletion of the retinoblastoma gene in multiple myeloma.
Leukemia. 1994 Aug;8(8):1280-4.
Dao DD, Sawyer JR, Epstein J, Hoover RG, Barlogie B, Tricot G.
These authors found deletion of the retinoblastoma gene (Rb-1) in 12 of 23 patients with multiple myeloma by FISH. Conventional cytogenetics showed abnormal chromosome 13 in only 4 of 23 of these patients. Of note, Rb-1 gene suppresses IL-6 production and secretion.

High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH.
Shaughnessy J, Tian E, Sawyer J, Bumm K, Landes R, Badros A, Morris C, Tricot G, Epstein J, Barlogie B.
Blood. 2000 Aug 15;96(4):1505-11.
These authors wanted to localize a minimal deleted region of chromosome 13. They studied plasma cells from 50 MM patients tested with FISH using a panel of 11 probes spanning the entire long arm of chromosome 13. 86% of patients had aberrant signal, with heterogeneity both in deletion frequency and extent.

Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy.
Leukemia. 2001 Jun;15(6):981-6.
Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ, Kay NE, Van Ness B, Greipp PR, Dewald GW.
These authors attempted to characterize the chromosome 13q deletions at the molecular level. They studied 351 newly diagnosed MM patients, using DNA probes for several locus specific probes (LSI). They found 13q deletions in 176 (54%) of cases, and that chromosome 13 deletions in MM predominantly involved loss of large segments of the 13q arm or monosomy 13, and only occasionally represented an interstitial deletion.

Interstitial deletions at the long arm of chromosome 13 may be as common as monosomies in multiple myeloma. A genotypic study.
Haematologica. 2002 Aug;87(8):828-35.
Nomdedéu JF, Lasa A, Ubeda J, Saglio G, Bellido M, Casas S, Carnicer MJ, Aventín A, Sureda A, Sierra J, Baiget M.
These authors performed a genotyping analysis on MM plasma cells was performed to identify the minimally deleted region at chromosome 13. 4 patients showed monosomy and 7 had interstitial deletions in the telomeric region. The minimal region with deletion was found at the centromeric 13q32.2 locus and at the telomeric 13q32.3 locus.

Multiple myeloma with monosomy 13 developed in trisomy 13 acute myelocytic leukemia: numerical chromosome abnormality during chromosomal segregation process.
Sashida G, Ito Y, Nakajima A, Kawakubo K, Kuriyama Y, Yagasaki F, Bessho M, Ohyashiki K.
Cancer Genet Cytogenet. 2003 Mar;141(2):154-6.
This is a case report of a patient with acute myelocytic leukemia (AML-M2) who had trisomy 13 as the sole cytogenetic anomaly. At relapse of AML, this patient had a normal karyotype and developed multiple myeloma. FISH showed that the MM plasma cells had monosomy 13, whereas the relapsed blast cells of AML carried disomy of chromosome 13. Therefore, this case showed a clonal evolution of trisomy 13 AML and monosomy 13 MM, which probably derived from the leukemic clone at relapse.

Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma.
Haematologica. 2007 Jan;92(1):56-65.
Agnelli L, Bicciato S, Fabris S, Baldini L, Morabito F, Intini D, Verdelli D, Callegaro A, Bertoni F, Lambertenghi-Deliliers G, Lombardi L, Neri A.
These authors analyzed the transcriptional features of monosomy 13 in MM. Plasma cells from 80 newly diagnosed MM patients were characterized by cytogenetics, FISH, and gene expression profiling. 67 differentially expressed genes in patients with and without -13 were identified. Functional analyses of selected genes indicated their involvement in protein biosynthesis, ubiquitination and transcriptional regulation.

 

 


1q21 GAIN/AMPLIFICATION (CKS1B)

 

CKS1B is the cyclin kinase subunit 1B. The gene is located in the chromosome 1q21 region.
Overexpression of CKS1B has been associated with disease progression and worse clinical outcomes.

 

Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma.
Hematology. 2005;10 Suppl 1:117-26.
Shaughnessy J.

Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation.
Br J Haematol. 2006 Sep;134(6):613-5.
Chang H, Yeung J, Xu W, Ning Y, Patterson B.
Authors investigated the CKS1B amplification status at 1q21 in clonal plasma cells from 123 patients: 23 MGUS, 75 MM and 26 plasma cell leukemia (PCL). While CKS1B amplification was absent in MGUS patients, such amplification (3-8 copies) was detected in 36% of newly diagnosed MM, 52% relapsed MM and 62% PCL (P < 0.001). The results suggest that CKS1B amplification is associated with progression from MGUS to MM, and from MM to PCL.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2016 Dec;22(12):2159-2164.
Bock F, Lu G, Srour SA, Gaballa S, Lin HY, Baladandayuthapani V, Honhar M, Stich M, Shah ND, Bashir Q, Patel K, Popat U, Hosing C, Korbling M, Delgado R, Rondon G, Shah JJ, Thomas SK, Manasanch EE, Isermann B, Orlowski RZ, Champlin RE, Qazilbash MH.
This is a retrospective study comparing post-transplant outcomes of patients with multiple myeloma with 1q21+ (gain/amplification of the CKS1B gene on the chromosome 1q21 region) (58 patients) vs those without it (58 patients). Median follow-up after the autolous stem cell transplant was 25.4 months. The results showed the adverse prognostic impact of 1q21+:
  - Median progression-free survival: 15 months with 1q21+, and 33 months without it (p=0.002)
  - Overall survival at 2 years: 62% with 1q21+, and 91% without it (p=0.02)

Gain of chromosome 1q portends worse prognosis in multiple myeloma despite novel agent-based induction regimens and autologous transplantation.
Leuk Lymphoma. 2017 Aug;58(8):1823-1831.
Shah GL, Landau H, Londono D, Devlin SM, Kosuri S, Lesokhin AM, Lendvai N, Hassoun H, Chung DJ, Koehne G, Jhanwar SC, Landgren O, Levine R, Giralt SA.
In this retrospective study of 95 patients with multiple myeloma treated with an autologous stem cell transplant, 21% of them had gains of chromosome 1 (+1q). These patients had a worse median progression-free survival (2.1 vs 4.3 years), even with the transplant, confirming the high-risk nature of this chromosomal abnormality.

 

 


GENE EXPRESSION PROFILING

 

Microarray gene expression profile (GEP) can provide a molecular classification of multiple myeloma based on specific gene expression patterns. It has a significant prognostic implication, but it is currently not accepted as standard of care. The main problem with the use of GEP in mutliple myeloma is that there is no overlap of genes and no consensus among the various groups who defined this technique in myeloma.

 

Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.
Blood. 2002 Mar 1;99(5):1745-57.
Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van Rhee F, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J Jr.
These authors performed a gene expression profiling using high-density oligonucleotide microarrays interrogating about 6800 genes in plasma cells from 74 patients with newly diagnosed MM, 5 with MGUS, 31 healthy subjects, and 7 MM cell lines. 4 distinct subgroups of MM (MM1, MM2, MM3, and MM4) were identified. The expression pattern of MM1 was similar to normal PCs and MGUS, whereas MM4 was similar to MM cell lines. The M4 subgroup was associated with poor prognosis, abnormal karyotype, and high serum beta2-microglobulin levels. 120 candidate genes were identified that discriminated normal and malignant plasma cells. Many of those genes are involved in cell adhesion, apoptosis, cell cycle, signaling, and transcription. Gene expression profiling can be used for a gene-based classification system for MM.

Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays.
Oncogene. 2002 Oct 3;21(44):6848-57.
De Vos J, Thykjaer T, Tarte K, Ensslen M, Raynaud P, Requirand G, Pellet F, Pantesco V, Rème T, Jourdan M, Rossi JF, Ørntoft T, Klein B.
These authors used the DNA microarray technology with Affymetrix microarrays to compared the gene expression profiles of MM cells from 9 patients with MM, 8 MM cell lines, and 8 samples of normal plasma cells. 250 genes were significantly up-regulated and 159 down-regulated in MM plasma cells compared to normal plasma cells.

Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.
Blood. 2003 Feb 1;101(3):1128-40.
Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr.

Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease.
Blood. 2003 Jun 15;101(12):4998-5006.
Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S, Bertucci F, Birnbaum D, Nguyen C, Harousseau JL, Bataille R, Houlgatte R, Minvielle S.

Interpreting the molecular biology and clinical behavior of multiple myeloma in the context of global gene expression profiling.
Immunol Rev. 2003 Aug;194:140-63.
Shaughnessy JD Jr, Barlogie B.
[Review]

Insights into extramedullary tumour cell growth revealed by expression profiling of human plasmacytomas and multiple myeloma.
Br J Haematol. 2003 Sep;122(5):728-44.
Hedvat CV, Comenzo RL, Teruya-Feldstein J, Olshen AB, Ely SA, Osman K, Zhang Y, Kalakonda N, Nimer SD.
These authors analyzed the gene expression profiles of MM), plasma cell leukemia (PCL), and extramedullary plasmacytoma (EPC), to identify tumor-specific alterations required for grow outside the normal bone marrow environment. They found 156 genes significantly upregulated and 85 genes significantly downregulated in the EPCs. Several of the upregulated genes were involved in angiogenesis (such as CD31 and endoglin) and adhesion.

Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis.
Blood. 2003 Dec 15;102(13):4504-11.
Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WH, Munshi NC, Morgan GJ, Anderson KC.
These authors used microarray analysis in PCs from 5 healthy donors, 7 patients with MGUS, and 24 patients with MM. They found 263 genes differentially expressed between normal and MGUS plasma cells, and 380 genes differentially expressed between normal and MM plasma cells, 197 of which also differentially expressed between normal and and MGUS plasma cells. Since only 74 genes were differentially expressed between MGUS and MM plasma cells, it appeared that the differences between MGUS and MM are smaller than those between normal and MGUS plasma cells. Differentially expressed genes included:
 - Oncogenes/tumor-suppressor genes (LAF4, RB1, and disabled homolog 2)
 - Cell-signaling genes (RAS family members, B-cell signaling and NF-kappaB genes)
 - DNA-binding and transcription-factor genes (XBP1, zinc finger proteins, forkhead box, and ring finger proteins)
 - Developmental genes (WNT and SHH pathways)

Identification of genes modulated in multiple myeloma using genetically identical twin samples.
Blood. 2004 Mar 1;103(5):1799-806.
Munshi NC, Hideshima T, Carrasco D, Shammas M, Auclair D, Davies F, Mitsiades N, Mitsiades C, Kim RS, Li C, Rajkumar SV, Fonseca R, Bergsagel L, Chauhan D, Anderson KC.
These authors compared the gene expression profile of plasma cells cells from a MM patient with plasma cells from a genetically identical twin, to eliminate the confounding factor represented by the genetic heterogeneity between individuals. They found 296 up-regulated genes and 103 down-regulated genes.

Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myélome.
J Clin Oncol. 2008 Oct 10;26(29):4798-805.
Decaux O, Lodé L, Magrangeas F, Charbonnel C, Gouraud W, Jézéquel P, Attal M, Harousseau JL, Moreau P, Bataille R, Campion L, Avet-Loiseau H, Minvielle S; Intergroupe Francophone du Myélome.
These authors used gene expression profiles of plasma cells from 182 MM patients obtained at diagnosis to identify prognostic markers. The validity of our model was assessed in in three independent cohorts of 853 MM patients. High-risk patients had overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients had hyperdiploid signatures.

Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients.
Blood. 2010 Oct 7;116(14):2543-53.
Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, Bertsch U, Buijs A, Stevens-Kroef M, Beverloo HB, Vellenga E, Zweegman S, Kersten MJ, van der Holt B, el Jarari L, Mulligan G, Goldschmidt H, van Duin M, Sonneveld P.

 

 


Giampaolo Talamo, M.D.