Issue 4 - August 2010 - Pacini Editore

162
15 Vlassenbroeck I, Califice S, Diserens AC, et al. Validation of realtime
methylation-specific PCR to determine O6-methylguanine-DNA
methyltransferase gene promoter methylation in glioma. J Mol Diagn
2008;10(4):332-7.
16 Roversi G, Pfundt R, Moroni RF, et al. Identification of novel genomic
markers related to progression to glioblastoma through genomic profiling
of 25 primary glioma cell lines. Oncogene 2006;25(10):1571-
83.
17 Yin D, Ogawa S, Kawamata N, et al. High-resolution genomic copy
number profiling of glioblastoma multiforme by single nucleotide
polymorphism DNA microarray. Mol Cancer Res 2009;7(5):665-77.
18 von Deimling A, Louis DN, von Ammon K, et al. Association of epidermal
growth factor receptor gene amplification with loss of chromosome
10 in human glioblastoma multiforme. J Neurosurg 1992;77:295-
301.
19 Freire P, Vilela M, Deus H, et al. Exploratory analysis of the copy
number alterations in glioblastoma multiforme. PLoS One 2008;3(12):
e4076.
20 Lo KC, Bailey D, Burkhardt T, et al. Comprehensive analysis of loss
of heterozygosity events in glioblastoma using the 100K SNP mapping
arrays and comparison with copy number abnormalities defined by
BAC array comparative genomic hybridization. Genes Chromosomes
Cancer 2008;47(3):221-37.
21 Vlassenbroeck I, Califice S, Diserens AC, et al. Validation of realtime
methylation-specific PCR to determine O6-methylguanine-DNA
methyltransferase gene promoter methylation in glioma. J Mol Diagn
2008;10(4):332-7.
22 Brandes AA, Tosoni A, Franceschi E, et al. Recurrence pattern after
temozolomide concomitant with and adjuvant to radiotherapy in newly
diagnosed patients with glioblastoma: correlation With MGMT promoter
methylation status. J Clin Oncol 2009;27(8):1275-9.
23 Morandi L, Franceschi E, De Biase D, et al. Promoter methylation
analysis of O6-methylguanine-DNA methyltransferase in glioblastoma:
detection by locked nucleic acid based quantitative PCR
using an imprinted gene (SNURF) as a reference. BMC Cancer
2010;10:48
24 Brandes AA, Franceschi E, Tosoni A, et al. O(6)-methylguanine DNAmethyltransferase
methylation status can change between first surgery
for newly diagnosed glioblastoma and second surgery for recurrence:
clinical implications. Neuro Oncol 2010;12(3):283-8.
Pharmacogenetics in hematologic neoplasia
S. Rasi, A. Bruscaggin, S. Franceschetti, R. Bruna, D. Rossi,
G. Gaidano
Division of Hematology, Department of Clinical and Experimental
Medicine, Amedeo avogadro University of Eastern Piedmont, 28100
Novara
The field of pharmacogenetics investigates how genetic inheritance
might influence the patients’ individual response to
drugs. In fact, the majority of drugs exhibit large interindividual
variability in their efficacy and toxicity, and this individual
host response is influenced by genetic polymorphisms,
in particular single nucleotide polymorphisms (SNPs).
The main aim of pharmacogenetics is to optimize therapy
based on the patient’s genotype, in order to maximize the
therapeutic index of a given drug or regimen. Indeed, several
pharmacogenetic studies have documented that host SNPs
affecting genes involved in drug metabolism, detoxification,
transport and targeting are in fact responsible, at least in part,
for the interindividual variability in efficacy and toxicity of
a given pharmacological treatment. Moreover, several drugs
utilized in therapeutic treatment of hematologic neoplasms
rely on DNA damage as part of their mechanisms of tumor
cell killing. On these bases, treatment benefit and/or toxicities
in patients may be modulated by the host DNA repair capacity.
Also in this context, pharmacogenetic studies have shown
that SNPs within genes of DNA repair pathways alter the host
DNA repair capacity, thus affecting the individual response to
drugs and the prognosis of the patients.
5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology
One of the most consolidated pharmacogenetic model in
hematological-oncology is represented by the case of acute
lymphoblastic leukemia (ALL) of childhood. Among hematological
neoplasms, ALL of childhood is the sole disease
whose pharmacogenetics has been characterized in detail,
and has entered clinical practice. The enzyme thiopurine Smethyltransferase
(TPMT), classified as a phase II enzyme,
metabolizes chemotherapeutic agents, and in particular is
responsible for the metabolism of 6-mercaptopurine. The
activity of the TPMT enzyme displays marked variability in
the population, being influenced by SNPs of the TPMT gene
that determine a reduction of the cellular content of TPMT.
In particular, three allelic variants (TPMT*2, TPMT*3A,
and TPMT*3C) are responsible for more than 90% of cases
with an intermediate- or low-enzyme activity. ALL patients
with a wild-type TPMT allele (TPMT*1 or TPMT*1S) and
a non functional variant allele (TPMT*2, TPMT*3A, and
TPMT*3C) have an intermediate activity of TPMT, while
patients with two non functional variant alleles are TPMT
deficient. In the context of ALL of childhood, the TPMT
genotype identifies patients who are at risk of hematopoietic
toxicity after thiopurine therapy. In fact, patients who are
homozygous carriers of these SNPs and are therefore devoid
of TPMT activity, are at higher risk of hematological toxicity
when treated with 6-mercaptopurine. Instead, patients who
are heterozygous carriers of these SNPs have an intermediate
risk of dose-limiting toxicity. A 6-mercaptopurine dose reduction
of 90% is generally required for homozygous-TPMT
deficiency patients, whereas the TPMT heterozygous carriers
require a mean dose reduction only of 35%.
Instead, scant information is available about the impact of
pharmacogenetics in predicting outcome and toxicity in the
context of non-Hodgkin lymphoma (NHL) and available information
is restricted to a limited number of studies. Studies
in follicular lymphoma and diffuse large B cell lymphoma
(DLBCL) aimed at assessing the association between antilymphoma
efficacy of rituximab and SNPs of Fcγ receptors
have reported conflicting results. Fcγ receptors are are involved
in rituximab antibody-dependent cellular toxicity. A
few studies have identified SNPs located in the Fcγ receptors
(FcγRIIIa 158V/F and FcγRIIa 131H/R) as being associated
with tumor response in patients treated with rituximab as
first-line therapy. On the other hand, both in the context of
follicular lymphoma and in DLBCL, other studies failed to
identify an association between prognosis and SNPs of Fcγ
receptors.
In the context of DLBCL, the host pharmacogenetic background
predicts efficacy of R-CHOP21 (R=rituximab,
C=cyclophosphamide, H=doxorubicin, O=vincristine and
P=prednisone) chemotherapy program, that is considered the
standard treatment for this disease. In fact, SNPs modulating
gene expression and/or function of enzymes involved
in R-CHOP pharmacogenetics may contribute to prognostic
stratification and prediction of toxicity in DLBCL patients
treated with R-CHOP21. In particular, host SNPs affecting
alkylating agent detoxification (GSTA1 rs3957357) and
doxorubicin pharmacodynamics (CYBA rs4673) may predict
survival in DLBCL treated with R-CHOP21. GSTA1 encodes
a glutathione S-transferase that catalyses the conjugation of
cyclophosphamide with glutathione to facilitate excretion.
In particular, the GSTA1 rs3957357T minor allele associates
with reduced levels of GSTA1 enzyme in healthy individuals,
and predicts for reduced detoxification of alkylating agents,
thus increasing tumor cell exposure to drug. In fact, DL-
BCL patients carrying GSTA1 rs3957357 CT/TT genotypes