High-Resolution Mapping of Common
Gains and Losses in Myeloma
Jonathan J Keats, Wee-Joo Chng, Esteban Braggio, Shanmugam V, Pushparaj
V, Schop R, Mancini C, Price-Troska R, Ahman G, Henderson K, Greipp P,
Dispenzieri A, Bruhn L, Bergsagel PL, Carpten J, Fonseca R
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Outline
· Background on Myeloma Genetics
· Introduction to aCGH Technology
· Results
· Cl
Conclusions
Conventional Cytog
ygenetics Identified
Two Categories of Myeloma
SKY and FISH Improve Detection but
are Limited as Discovery Tools
Sawyer JR et al. Blood 92:4269-78 (1998)
Agilent aCGH Workflow
Ref sample Exp sample
-4
-2
-1
0
+1
+2
+4
Reference Experimental
Cy5
DNA-Cy3
DNA-Cy5
Cy3
Red
Quantitate/
Green
Normalize
Amp
Del
Exp
Ref
CGH Analytics: log2 Ratio
High Resolution aCGH
Evolving Resolution of aCGH
Carrasco R et al. Cancer Cell 9:313-25 (2006)
Largo C et al. Hematologica 92:795-802 (2007)
MMRC Genomics Flagship
Mayo/TGEN/Agilent
Mayo/TGEN/Agilent
Evolving Resolution of aCGH
Carrasco R et al. Cancer Cell 9:313-25 (2006)
Largo C et al. Hematologica 92:795-802 (2007)
MMRC Genomics Flagship
Mayo/TGEN/Agilent
Mayo/TGEN/Agilent
Gene Level View of MDR
The NFKB PATHWAYS
High Resolution aCGH
Frequency of Genomic Aberrations
in Myeloma
Hierarchal Clustering
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
21
Chromosome 14
We Identified MDR, MAR, and CB
Using Known
Known Mutations
Mutations to Identify
Target Genes
99 Minimal Regions of Change
49 MDR and 50 MAR
Contain 352 genes implicated
in cancer
Defining a 6q
gq MDR in Myeloma
Chromosome 6 Zoomed
Incidence of Abnormalities
70
60
ities
50
40
Abnormalicm 30
Geno 20
ofo.N 10
0
Chr 1q Gain 1 3 5 7 9 11 131517 1921232527 29313335 3739 41 4345474951 53555759 61 6365 67 P = 0.38
Ploidy
P = 0.39
Survival Association
· The presence of a complex genome (ie.
More th
than 20
20 b
a
liti
norma
es)
l
corre t
a es
with a worse prognosis
Median survival of 24 versus 88 months
p=0.0016
100
>=20 Aberrations
90
p = 0.0006
80
<20 Aberrations
70
60
50
40
30
20
10
0
0
25
50
75
100
125
OS (mths)
Acknowledgements
Wee-Joo Chng
Rafael Fonseca
Esteban Braggio
John Carpten
Li
Le f
if Bergsagel
Shanmugam V
Pushparaj V
Laurakay Bruhn