A NEW CLOCK IS RUNNING FOR MULTIPLE MYELOMA:
CIRCADIAN CLOCK PROTEIN-PERIOD 3 (PER-3)
POLYMORPHISM
Serin I.1,*, Pehlivan S.2, Demir I.3, Oyacı Y.2, Pehlivan M.3
*Corresponding Author: Istemi Serin, M.D., University of Health Sciences, Istanbul Training and
Research Hospital, Department of Hematology, Org. Nafiz GURMAN Cad., Fatih, 34098
tel.: +90 532 3172393, e-mail: serinistemi@hotmail.com
page: 37
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DISCUSSION
This study is the first to report on the association
between CR and MM. Literature data on CR and hematological
malignancies are also limited; there are related
studies on solid malignancies. In a current study from 2021 by Dagmura et al. [12],
CR and pancreatic cancer (PC) were studied. The frequency
of the 4R/3R, 3R/3R genotypes, and 3R allele of
PER-2 VNTR in patients with PC were higher than in the
healthy controls (p < 0.001, for all). PER-2 VNTR 4/5
genotype was found to be related to perineural invasion
(p = 0.040). The genotype and allelic distributions of the
PER-3 VNTR variant were similar between the groups
(p> 0.05). In this study, a significant relationship between
PER-2 and perineural invasion, which can be a marker of
poor prognosis, was demonstrated.
Geng et al. [13] examined the association of PER-3
gene variants (rs1012477, 4/5-repeat) with solid malignancies.
In the meta-analysis, data were collected from a
total of 8 separate studies, and no relationship was found
between PER-3 gene variants and cancer susceptibility.
The articles covered in the study were related to prostate,
breast cancer, glioma and colorectal cancer (CRC). In
another study from 2013 [14], the relationship between
CRC and CR was investigated, and the polymorphism of
311T > C on CLOCK-1 gene did not affect the outcome of
patients with CRC, yet it increased the risk of developing
CRC. The evaluation of 4/5 repeat allele polymorphism
in PER-3 was similar in terms of allele and genotype distributions
between the control group and the CRC group.
A previous study showed that the 5- repeat PER-3 VNTR
sequence is related with increase of colorectal adenoma
development [15]. Although there was no difference in cancer susceptibility in our study, the fact that the 4R/4R
genotype was associated with shorter PFS is an important
point for treatment responses.
Clinical data on hematological malignancies and PER-
3 polymorphisms is limited. In a study on diffuse large Bcell
lymphoma patients from 2015 [16], PER-3 rs10462020
variant was significantly different in OS between groups
of mutated and non-mutated genotypes (p = 0.047). In
another study in the same year [17], 9 different CR gene
expressions were examined in cases of newly diagnosed
acute myeloid (AML) and lymphoblastic leukemia (ALL).
In AML patients, the expressions of PER-1, -2, CRY-1,
-2, timeless, muscle and brain aryl hydrocarbon receptor
nuclear translocator (ARNT) -like 1 (BMAL-1) were downregulated,
while CK1ε was up-regulated. In patients with
ALL, the expressions of PER-3 and CRY-1 were downregulated,
while CK1ε and timeless were up-regulated.
Improvement in PER-3 expression was detected in attained
remission patients with AML and ALL, while this was not
detected in relapsed patients after treatment. The CC genes
were changed in acute leukemia patients, and PER-3 upregulation
is related with an improved clinical outcome.
The relationship of CR genes with sleep disturbance
has been extensively studied. Guess et al. [6] found that the
4/4 genotype showed more physical fatigue and sleep disturbances.
Sleep disturbance and increased inflammation
or inflammatory markers have been the subject of many
studies [18–20]. In these studies there is a positive correlation
between sleep disturbance and increased vascular
endothelial growth factor (VEGF) concentration. VEGF
contributes to the pathogenesis of MM. It plays a role in
myeloma development, bone marrow microenvironment
interaction, disease progression and drug resistance. VEGF
and VEGF receptor expression is increased in myeloma
bone marrow [21]. Anti-VEGF treatment strategies are
also discussed in the treatment of myeloma. In addition,
proteosome inhibitors, immunomodulatory drugs (IMIDs)
and bisphosphonates, which are the cornerstones of MM
treatment, have also been shown to reduce VEGF levels
[21]. In our study, the 4R/4R genotype, which is significantly
associated with sleep disorder and physical fatigue,
high VEGF level is thought to be related. Therefore, a
significant short PFS constitutes the most important result
of the study.
This study had also some important limitations. OS
may not have differed significantly due to the narrowing
of the patient population when the genotype was divided
into gene variant subgroups. In addition, not evaluating
synchronous cytokines is another important limitation.
There were also deficiencies in patient data in terms of
comorbidity or genetic mutation subtypes, and it was therefore
not possible to analyze them together.
In conclusion, this study contributes to the literature
in terms of MM and PER-3 gene polymorphism. Although
no significant results were obtained in terms of MM pathogenesis,
it was revealed that the 4R/4R genotype had a
statistically significant short PFS. It is thought that this
information will shed light on new studies in terms of the
therapeutic effect and pathogenesis in MM.
ABBREVIATIONS
MM: Multiple myeloma
ASCT: Autologous stem cell transplantation
ISS: International Staging System
R-ISS: The revised ISS
LDH: Lactate dehydrogenase
FISH: Fluorescent in situ hybridization
SCN: Superior chiasmatic nucleus
PER: Circadian Clock Protein PERIOD 3
CC: Circadian Clock
CRY: Cryptochrome circadian regulator 1
CR: Circadian rhythm
VNTR: Variable number tandem repeat
TNF-α: Tumor necrosis factor-alpha
IFN-Ɣ: Interferon-gamma
IL-1: Interleukin-1
IL-6: Interleukin-6
CRP: C-reactive protein
OS: Overall survival
PFS: Progression free survival
VCD: Bortezomib-cyclophosphamide and
dexamethasone
PR: Partial remission
LD: Lenalidomide-dexamethasone
PCR-RFLP: Polymerase chain reaction-restriction
fragment length polymorphism
OR: Odds ratio
CI: Confidence interval
HWE: Hardy Weinberg Equilibrium
PC: pancreatic cancer
CRC: Colorectal cancer
AML: Acute myeloid leukemia
ALL: Acute lymphoblastic leukemia
BMAL1: Brain and muscle aryl hydrocarbon receptor
nuclear translocator (ARNT) - like 1
TIM: Timeless
VEGF: vascular endothelial growth factor
IMID: Immunomodulatory drugs
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