15-Dec-2009
Genetic Associations with Bortezomib Mediated Neuropathy in Multiple Myeloma
Sophie L Corthals1, David C Johnson2, Yvonne de Knegt1, Hartmut Goldschmidt3, Henk M Lokhorst4, Stéphane Minvielle5, Florence Magrangeas5, Jean-Luc Harousseau6, Brian G Durie7, Brian van
Ness8, Gareth J Morgan2, Pieter Sonneveld1 , Hervé Avet Loiseau5
1 Erasmus Medical Center, Rotterdam, The Netherlands; 2 Institute of Cancer Research, London, UK; 3 University of Heidelberg, Heidelberg, Germany ; 4 University Medical Center, Utrecht, The
Netherlands; 5
herlands; Universit
Univ
y Hospital of Nantes, Nantes,
Nant
France; 6
France; Centre René Gauducheau, Nantes, France; 7
rance; Cedars Sinai
Sinai Cancer Center,
er Los Angeles, USA; 8
USA; Universit
Univ
y of Mi
M nnesota, Mi
M nneapolis, USA
USA
Introduction
Results
The
proteasome
inhibitor
bortezomib
(VELCADE®;
Millennium
Table 1. Single nucleotide polymorphisms associated with BiNP (P < .001) using a Cochran-Mantel-Haenszel stratified association
Pharmaceuticals, Cambridge, MA) has greatly improved the management of
analysis. The genomic inflation factor is 1.0375.
multiple myeloma (MM).
The dose-limiting adverse effect of bortezomib is peripheral neuropathy, which
frequently requires treatment discontinuation. BiNP is
dose-related and
predominantly sensory resulting from axonal degeneration. It is characterized
bby bi
burning p i
a n, dist l
a paresthesias, numbness and neurop th
a i
th cp i
a n. In the
majority of patients, BiNP is reversible and does not seem to be influenced by
number or type of previous treatments.
Little is known about the mechanisms underlying BiNP .
Figure 3. Haplotype block in the SERPINB2 region viewed in Haploview 4.0.
SNPs associated with BiNP are shown in green.
Association with neuropathy susceptibility genes
Aim
A number of SNPs in the SERPINB2 gene are significantly associated with
BiNP risk. The main effect can be attributed to three SNPs (rs6102, rs6103,
To identify genetic risk factors that associate with development of bortezomib
and rs6104) that lie within a haplotype (Figure 3), and potentially influence
induced peripheral neuropathy in multiple myeloma patients.
SERPINB2 expression levels through their effect on splicing regulation.
We hyp
hy ot
o hesize
z that
tha SNPs
SN
are important in the pat
a ho
h genesis BiNP
BiN and
an may be
Two f
o thetop sii
ign fi
ificantlly associd
iated SNP
SN s, rs2230792 and rs2230793,
relevant to identify patients at high-risk for BiNP.
were located in the Inhibitor of kappa light polypeptide gene enhancer in B-
cells, kinase complex-associated protein (IKBKAP) gene.
Finally, a group of intronic SNPs (rs2137975, rs1399291, rs2056048,
(Pro)inflammatory genes are associated with BiNP
Three SNPs that lie within or in close proximity of the TNF- gene (rs2857605, rs2857598 and rs2228088) are found
rs993568 and rs4128474) in dihydropyrimidine dehydrogenase (DPYD) was
Material and Methods
to be associated with BiNP.
associated with BiNP.
The Poly (ADP-ribose) polymerase (PARP) pathway regulates the expression of genes involved in promoting
A pharmacogenetic association study was performed in 346 multiple myeloma
inflammatory reactions and neuronal dysfunction. A group of five intronic SNPs in PARP-1 (rs2280712, rs1805408,
patients who were treated with bortezomib in two randomized clinical trials. A
rs12198787, rs1002153 and rs1805407) was significantly associated with BiNP.
total of 3404 single nucleotide polymorphisms (SNPs) in 964 genes, spanning
Associations were also seen with a down-regulating promoter polymorphism at position -221 (rs7096206) in mannose-
some 67 molecular pathways (Figure 1), important in the biology of multiple
binding lectin (MBL2), which has been reported to be associated with early onset of systemic lupus erythematosus
myeloma,
y, treatment response and side effects to conventional and novel
(SLE) and two intronic SNPs (rs7071882 and rs2165810) within MBL2.
agents (Van Ness B et al., BMC Med 2008), were analyzed for a possible
association with bortezomib induced peripheral neuropathy (BiNP). A Cochran
MantelHaenszel 2 test was performed, adjusting for the effect on the two
independent cohorts (HOVON-65 and IFM 2005-01) using the program PLINK.
The most significant SNP, rs3136516 (P =
.0001; Figure 2) associated with BiNP is an
intronic SNP and located in prothrombin
Figure 4. Scatter plot of BiNP risk score
(coagulation factor II; F2). Additionally, a
A score for each patient is generated using the program PLINK v1.06 (Purcell S. et al.,
synonymous SNP located in this gene, rs5898,
Am J Hum Genet 2007), and based on an allelic scoring system involving SNPs
sign
si ifi
gn c
ifi an
c tly
an
as
a so
s ci
so at
ci e
at d
e with BiNP
N (P < 05
. )
05 . Scor
Sc e
or values for cont
co r
nt ols
o and BiNP
BiN cases
was also found to highly associated with BiNP
e
are significantly different (
risk.
P = 1.20x10-8)
Conclusions
This international cooperative study suggests that SNPs in (pro)inflammatory
and neuropathy susceptibility genes are associated with BiNP. Our results
Figure 2. SNPs genotyped across the prothrombin gene in the region
of rs3136516.
contribute to a better understanding of the pathogenic mechanisms underlying
Figures were generated using the web-based tool SNAP (Johnson, A.D. et
development of BiNP. The observed associated SNPs differ significantly from
al., Bioinformatics 2008).
those associated with thalidomide induced peripheral neuropathy (Johnson DC
Figure 1: Functional categories on the BOAC SNP panel
s.corthals@erasmusmc.nl
et al., personal communication).
1