|Year : 2022 | Volume
| Issue : 3 | Page : 697-703
Acute myeloid leukemia patients with variant or unusual translocations involving chromosomes 8 and 21 – A comprehensive cytogenetic profiling of three cases with review of literature
TV Akhila Raj1, Preethi Gopinath1, JA Geetha Raj1, Geetha Narayanan2, Sreejith G Nair2, Deepa Susan Joy Philip2, Suresh Raveendran3, Priya Geetha1, Hariharan Sreedharan1
1 Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Division of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
3 Department of Research, Jubilee Mission Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
|Date of Submission||01-Feb-2021|
|Date of Acceptance||12-Jul-2021|
|Date of Web Publication||25-Apr-2022|
Additional Professor, Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Regional Cancer Centre, Medical College Post, Thiruvananthapuram - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
Background: t(8;21)(q22;q22) is the most frequent recurrent translocation in acute myeloid leukemia (AML) resulting in an in-frame fusion of RUNX1/RUNX1T1 that regulates various genes involved in the signaling pathways. This leukemogenic alteration is usually associated with a favorable clinical outcome. Variants of t(8;21) can be formed involving a third or fourth chromosome in ~3-4% of t(8;21)-AML. Due to the rarity of variant t(8;21), its clinicopathological features and prognostic significance are still unclear. Here we present three AML cases with cryptic rearrangements of chromosomes 8 and 21 without standard RUNX1/RUNX1T1.
Materials and Methods: Conventional karyotyping and fluorescence in situ hybridization and/or spectral karyotyping of the pretreatment bone marrow aspirate of de novo AML patients were performed to delineate chromosomal abnormalities.
Results: We identified three cases with novel variants of t(8;21); der(13)t(8;21;13), isodicentric derivative 8 with chromosome 21[,+idicder(8)(q11.1)t(8;21)(q22;q11.1)] and der(21)t(8;12;21)(q22;q?;q22).
Conclusion: AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 forms a distinct WHO subcategory and hence the identification of variants or unusual translocations associated with t(8;21) deserves more attention. Contribution to the variant/ unusual t(8;21) database will further refine the risk stratification and may help to significantly advance the current treatment regimen.
Keywords: Acute myeloid leukemia, cytogenetics, RUNX1/RUNX1T1, spectral karyotyping, variant/unusual translocations
|How to cite this article:|
Akhila Raj T V, Gopinath P, Geetha Raj J A, Narayanan G, Nair SG, Joy Philip DS, Raveendran S, Geetha P, Sreedharan H. Acute myeloid leukemia patients with variant or unusual translocations involving chromosomes 8 and 21 – A comprehensive cytogenetic profiling of three cases with review of literature. J Can Res Ther 2022;18:697-703
|How to cite this URL:|
Akhila Raj T V, Gopinath P, Geetha Raj J A, Narayanan G, Nair SG, Joy Philip DS, Raveendran S, Geetha P, Sreedharan H. Acute myeloid leukemia patients with variant or unusual translocations involving chromosomes 8 and 21 – A comprehensive cytogenetic profiling of three cases with review of literature. J Can Res Ther [serial online] 2022 [cited 2022 Sep 25];18:697-703. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/697/343915
| > Introduction|| |
The genomic landscape of acute myeloid leukemia (AML) is broad and heterogeneous due to the wide spectrum of chromosomal abnormalities and gene mutations, which appear to be crucial in the early stages of leukemogenesis. Approximately 50%–60% of de novo AML patients harbor abnormal karyotype and certain abnormalities were associated with specific, sometimes distinguishing, immunophenotypic, morphologic, and clinical characteristics., Hence, diagnostic karyotype of leukemic blast cells is an inevitable parameter in predicting prognosis as well as for triaging patients for optimal treatment. Advancements in novel prognostic markers and the growing knowledge of disease progression help to improve the conventional treatment strategies and better survival of many of the cancers. However, a heterogeneous background of AML remains to be a hindrance to curative therapy and the mainstay of AML treatment for the past five decades is chemotherapy using cytarabine (Ara-C).
World Health Organization (WHO) category of AML with recurrent abnormalities comprises nine distinct abnormalities, of which t(8;21), inv(16), and t(15;17) associated with favorable prognosis and are considered as diagnostic of AML regardless of blast count. t(8;21) with RUNX1/RUNX1T1 is the most common recurrent translocation in both adult and pediatric AML. This leukemogenic alteration leads to the formation of a chimeric gene, RUNX1/RUNX1T1 on the derivative chromosome 8. Both RUNX1 and RUNX1T1 are part of a transcriptional complex that controls important target genes involved in hematopoiesis., Fusion protein can disrupt the core binding factor transcription complex, leading to abnormalities in cell differentiation, proliferation, and apoptosis. It is also thought that the fusion product is a driver of myeloid leukemogenesis in this AML subtype.
t(8;21) tends to be found in ~10% of AML with maturation (M2) and often detected with secondary cytogenetic events such as loss of sex chromosomes (−X/−Y), del9(q), +8, etc.,, Moreover, RUNX1/RUNX1T1 fusion gene can be formed through complex variant translocations involving a third or fourth chromosome in about 3%–4% of t(8;21) AML patients.,
As the fusion gene has prognostic significance, identification of variants and its impact on clinical outcome is necessary to elucidate. There are reports suggesting that loss of X chromosome does not seem to have any clinical significance, while loss of Y chromosome may form a critical mutational event and thus be associated with a weak prognosis., However, exact clinical impact of these additional and variant chromosomal rearrangements remains disputable due to the rarity of the cases. Here, we report conventional and molecular cytogenetic profiling of three AML cases with a variant translocation involving 8 and 21, which has previously not been reported in the literature.
| > Materials and Methods|| |
Bone marrow aspirate obtained from the patients prior to treatment was used for cytogenetic analysis. BM cells were cultured using RPMI 1640 media (Himedia) followed by harvesting and GTG banding by standard protocol. A total of 20–25 metaphase spreads were analyzed for each patient using Genasis Software (Applied Spectral Imaging, Migdal Ha'Emek, Israel). Karyotypes were described according to the International System for Human Cytogenetic Nomenclature.
Fluorescence in situ hybridization (FISH) using SPEC RUNX1/RUNX1T1 and SPEC PML/RARA dual-color dual-fusion probe and CEN X/Yq12 dual-color probe (ZytoVision, Germany) was performed in interphase and/or metaphase cells according to the manufacturer's instructions. A total of 100 interphase nuclei were analyzed using a fluorescence microscope (Olympus BX53, Tokyo, Japan) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes and the counterstain 4',6-diamidino-2-phenylindole. Hybridization signals were acquired with a Spectra Cube SD200 spectral imaging system (applied spectral imaging). A minimum of 5 metaphase spreads were also analyzed, for those patients identified with atypical signal patterns. For the confirmation of variant abnormalities, spectral karyotyping was performed in metaphase spreads using SKY paint Probes (HiSKY, ASI, Israel) according to the manufacturer's instructions. A total of five metaphases were analyzed using an ASI imaging system.
Direct sequencing of amplified polymerase chain reaction (PCR) products was carried out in all the three patients for the detection of c-KIT mutations.
| > Results|| |
We identified three cases of complex variant/unusual translocations involving chromosomes 8 and 21 without classical RUNX1/RUNX1T1 fusion gene. All the patients have attended the Medical Oncology Clinic, Regional Cancer Centre (RCC), Thiruvananthapuram, Kerala, during the period of March 2016 to October 2018. This study was approved by institutional human ethics committee and informed consent was obtained from all the patients.
A 22-year-old female patient was referred to our hospital with anemic symptoms, fatigue and thrombocytopenia. General examination of the patient showed a pallor and systemic clinical examination showed normal organ functions. The WHO performance status of the patient was 2. On admission, she had a hemoglobin level of 5.1 g/dL, total white blood cell (WBC) count of 14,300/mm3, platelet count of 6000/mm3, and serum lactate dehydrogenase level of 907 u/L. Bone marrow biopsy revealed 30% of blasts with moderate cytoplasm and nuclei with immature chromatin. The antigenic profile of the abnormal cell population was CD34+, CD117+, CD13+, CD33+, CD45+, HLA Dr+, and MPO dim+ve.
Conventional and molecular cytogenetic findings
Due to the inferior resolution of GTG banded metaphases obtained, karyotype analysis failed to identify any abnormality in the leukemic blast cells. FISH on interphase nuclei and metaphases revealed an atypical signal pattern for RUNX1/RUNX1T1 dual-color dual-fusion (DCDF) probe. We observed two red (RUNX1T1) and two green (RUNX1) signals. In addition to this colocalization of RUNX1 and RUNX1T1 (Fusion) signals was identified on another chromosome. This atypical pattern (2R2G1F) reinforces the possibility of involvement of a third chromosome [Figure 1]a and [Figure 1]b. Later, SKY analysis made possible the identification and confirmation of a variant complex chromosomal rearrangement of t(8;21) involving chromosome 13 [Figure 1]c. Combining the FISH and SKY results, all cells possess an unbalanced translocation involving chromosomes 8, 13, and 21 with a single fusion gene on chromosome 13 and a region of chromosome 13 translocated to chromosome 21. There is no gain of chromosomal material on chromosome 8. The final karyotype of this patient was 46, XX, der(8) del(8q), der(13) t(8;21;13), der(21)t(13;21).ishder(8) del(8q)(RUNX1T1+), der(13)t(8;21;13)(RUNX1T1+, RUNX1+), der(21)(RUNX1+).
|Figure 1: (Patient 1) fluorescence in situ hybridization using SPEC RUNX1/RUNX1TI dual-color dual-fusion probe on (a) interphase nuclei and (b) metaphase spread showing one normal orange (RUNX1T1) and one normal green (RUNX1) signals on normal chromosomes 8 and 21, respectively. One orange and green signals on derived chromosomes 8 and 21, respectively. One orange–green fusion signal on an unknown chromosome (c) spectral karyotype of the patient showing a variant translocation involving chromosomes 8, 21 and 13 with the fusion segment on the chromosome 13|
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The patient underwent standard 7 + 3 regimen induction chemotherapy followed by a reinduction. The patient tolerated chemotherapy well without any serious postchemotherapy complications. She has proceeded to consolidation with high-dose cytarabine (HiDAC). Four cycles of HiDAC were completed without any delays and complications. The patient endured well the treatment and continuing the follow-up. The patient remains in CR for 59 months.
A 68-year-old female with a history of night sweat, loss of appetite, and hypertension presented to the outpatient clinic of our hospital with fever, abdominal pain, and loose stool. She had also undergone hysterectomy at the age of 43. The ultrasonography of her abdomen showed fatty liver and mild right pleural effusion. During initial diagnosis, she had pallor, lymphadenopathy, and pancytopenia. General health was poor in clinical examination and WHO performance status was 2. On admission, her complete blood count showed total WBC count of 1800/mm3, platelet count of 50,000 mm3, hemoglobin level of 8.3 g/dL, and an elevated LDH level of 259 u/L. BMA report showed the presence of 70% blast cells and Auer rods in many of the blast cells. The immunophenotypic portrayal by flow cytometry was positive for CD33, anti-MPO, and CD34.
Conventional and molecular cytogenetic findings
Conventional karyotyping identified a cryptic chromosomal rearrangement involving chromosomes 8 and 21 along with monosomy 17 in all the twenty metaphases analyzed. Instead of a standard t(8;21), the patient harbors a novel variant translocation in which the entire chromosome 21 was translocated to a highly rearranged chromosome 8 [Figure 2]a. Hybridization with RUNX1/RUNX1T1 DCDF probe in interphase nuclei revealed an atypical signal pattern, four red and two green signals with no fusion signals. FISH on metaphase showed the derivative chromosome 8 carrying two copies of RUNX1T1, each on p and q arms, along with one copy of RUNX1, hence confirmed it as an isodicentric derivative chromosome 8 with translocated chromosome 21. Apart from this, two RUNX1T1 and one RUNX1 signals were present on two normal 8th and one normal 21st chromosomes, respectively [Figure 2]b. Loss of one copy of chromosome 17 was confirmed by PML/RARA DCDF probe and the final karyotype of the patient was described as 45, XX, +idicder(8)(q11.1) t(8;21)(q22;q11.1),-17, 21.ishidicder (8)(q11.1) t(8;21)(RUNX1T1X2, RUNX1+).
|Figure 2: (Patient 2) (a) G-banded karyotype of the bone marrow cells showing variant t(8;21). Arrows indicate the aberrant chromosomes. Fluorescence in situ hybridization using SPEC RUNX1/RUNX1T1 DCDF probe on metaphase spread showed (b) one normal orange (RUNX1T1) and one normal green (RUNX1) signals on normal chromosomes 8 and 21. Two orange and one green signals on the derivative chromosome 8|
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Multidisciplinary tumor board planned palliative chemotherapy with low-dose cytarabine and supportive care for the patient. Palliative chemotherapy was given to the patient for 7 days and after discussing about the nature of the disease, treatment options, and complications; bystanders decided to discontinue the treatment. The patient was then referred to the nearby local hospital for best supportive care and expired 2 months after the discharge from our hospital.
A 25-year-old female patient with a history of abdominal pain, fever, and pain on the right thigh was referred from a local hospital. Packed red blood transfusion was given to the patient from the referring hospital. General and systemic examination of the patient showed pallor and functional neurological disorder and her WHO performance status was 3. Surgical pathology report showed fragmented spicules of bone with intervening marrow showing areas of hemorrhage. Evaluation at RCC identified cellulitis on the right thigh. She was found to have 8.1 g/dL hemoglobin, 27,800 mm3 WBC, and 68,000 mm3 platelets on admission at RCC. BMA report showed 18% myeloid blast cells, presence of Auer rods in some of the cells, and myeloperoxidase positive in all the blast cells. Leukemic blast cells were positive for CD13, CD33, CD64 dim+, CD117, anti-MPO, CD11C, CD19, CD34, and HLA-DR. Multidisciplinary tumor board of RCC planned antibiotics + supportive care and standard 7 + 3 induction regimen. However, her relatives refused further treatment. The patient was then discharged and referred to a local hospital.
Conventional and molecular cytogenetic findings
Cytogenetic studies on 20 metaphase spreads revealed two distinct abnormal clones of variant and standard t(8;21) in addition to the normal clones of 46, XX. In all the abnormal cells, loss of sex chromosome (−X) was detected. From GTG banded karyotype, an abnormality was interpreted as t(8;21) with del(12q) in seven metaphase spreads [Figure 3]a and remaining with standard t(8;21). Later, FISH analysis using RUNX1/RUNX1T1 DCDF probe on interphase nuclei and metaphase spreads identified 1R1G2F signal pattern in 20% and an atypical single fusion pattern of 2R2G1F in 35% of the interphase nuclei analyzed. In those cells with 2R2G1F pattern, fusion signal was identified in der(8) and der(21), RUNX1 and RUNX1T1 signals were seen a little bit separated. It is suspected that an unknown genetic material inserted in between RUNX1 and RUNX1T1 gene, thus blocked the formation of fusion gene on chromosome 21 [Figure 3]b. Results indicate the possibility of an abnormal variant of t(8;21), and so spectral karyotyping was performed on metaphase spreads. Finally, abnormality was identified as novel variant translocation involving chromsomes 8, 12, and 21 [Figure 3]c. Here, a small portion of 12q along with 8q22 binds to the q21 region of chromosome 21. Since the involvement of any other chromosome could not be identified, the remaining portion of 12q is suspected to be deleted. Final karyotype was interpreted as follows: 45, X,-X, der(8) t(8;21)(q22;q22), der(12) del(12q), der(21) t(8;12;21) (q22;q?;q22)/45,X,-X,t(8;21)(q22;q22)/46,XX.ish der(8)t(8;21)(q22;q22),(RUNX1T1+,RUNX1+),der(21) t(8;12;21)(q22;q?;q22)(RUNX1+)[40/100].
|Figure 3: (Patient 3) (a) G-banded karyotype of the bone marrow cells showing variant t(8;21). Arrows indicate the aberrant chromosomes. Fluorescence in situ hybridization using SPEC RUNX1/RUNX1T1 DCDF probe on metaphase spread showed (b) one normal orange (RUNX1T1) and one normal green (RUNX1) signals on normal chromosomes 8 and 21. One orange and green signals on der (21) without fusion and a fusion signal on der(8). (c) Spectral karyotyping showing 45, X,-X, t(8;12;21)|
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Molecular diagnostic findings
Direct sequencing was performed in the amplified PCR products for the identification of c-KIT mutation status of the patients. On analysis, a mutation in exon 17 of c-KIT gene in patient 3 was identified, c.2393T>C, leading to a change in 798th isoleucine to tryptophan. All the results were summarized in [Table 1] and [Table 2].
|Table 1: Clinical, hematologic, morphologic and immunophenotypic features of three acute myeloid leukemia patients with variant t (8;21)|
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|Table 2: Summary of conventional and molecular cytogenetic findings and KIT mutation status|
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| > Discussion|| |
In 1973, when Janet Rowley reported t(8;21) in two patients, it became the first recurrent translocation identified in leukemia. t(8;21)-AML is a distinct subtype having specific morphological and clinical features. Several studies have long been reported the role of breakpoint regions, 8q22 and 21q22, in the formation of these clinical phenotypes.,,, Foremost significance of this translocation lies in its association with favorable prognosis. It is believed that RUNX1/RUNX1T1 fusion gene on the der(8) has a fundamental role in the onset of leukemogenesis. Hence, the precise detection of this chimeric gene is vital, which, in turn, helps to assign patients to the appropriate risk group.,
When compared to t(15;17) and inv (16), t(8;21) is most frequently associated with additional chromosomal abnormalities or unusual translocations involving chromosomes 8, 21, and 3 or 4, which is about 3%–4% of AML M2 with t(8;21). It was Lindgren and Rowley in 1977 who reported the first variant t(8;21) involving a third chromosome, t(8;11;21) and t(8;17;21), in two AML patients. Thereafter, there have been many such variant abnormalities reported. To the best of our knowledge, only four cases have been reported in literature as variant t(8;21) from India till date.,,, Here, we report three cases of AML with novel variants of the t(8;21), two three-way translocations and an isodicentric derived chromosome 8 with translocated 21st chromosome.
In patient #1, a novel variant translocation involving chromosomes 8, 13, and 21 was identified. t(8;13;21) has so far been reported in three patients with the involvement of 13q33, 13q12, and 13q14 along with 8q22 and 21q22.,, In contrast to the previous reports, in our case, fusion gene was located on chromosome 13, thus adding a novel t(8;13;21) variant to the literature. As the chromosomal preparations were suboptimal, the exact breakpoint regions were not able to identify. The precise characterization of the abnormality was made possible by FISH and SKY analysis, but the fusion gene could not be confirmed as RUNX1/RUNX1T1. Outcomes for previously reported variant cases are heterogeneous, both favorable , and unfavorable prognoses were reported. When comparing to these cases, our patient is survived for the most prolonged period of time. As per her last follow-up on January 2021, disease-free survival was 59 months.
In patient #2, the abnormality identified was an unusual isodicentric derivative chromosome 8. Isochromosome rarely occurs in AML with an overall frequency of 3.6% and the more common were i(11) q(10), i(17) q(q10), and i(21) q(10). i(8) is most often seen in ALL as a secondary abnormality to t(9;22). More than 50 cases have been reported in AML as per the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. It is notable that i(8)(q10) most frequently occurs in complex karyotypes, thus the prognostic significance is uncertain. No reports are available regarding the involvement of chromosome 21 and i(8)(q10) yet. In our study subject, one of the 21st chromosomes was completely translocated to the isochromosome 8 and thus forms an isodicentric derived chromosome 8 and monosomy 21. Fusion gene could not be found on both the chromosomes. Along with this highly rearranged isodicentric derived chromosome 8, the patient possesses monosomy 17. Autosomal monosomies such as −5, −7, and −17 have been recognized for many years as cytogenetic parameters conferring negative prognostic impact and are incorporated into the European Leukemia Network criteria (2017) of risk stratification. In a recent publication, Strickland AS reported monosomy 17 occurred predominantly in complex karyotypes (≥5) and is an independent prognostic marker predicting worse survival among monosomal karyotype patients as well as those with highly complex karyotypes. At the time of diagnosis itself, increased age, performance status, and later, the complex nature of the karyotype indicated the adverse prognosis of the patient and she succumbs to the disease after 2 months of diagnosis.
Patient 3 harbors another three-way translocation involving chromosomes 8, 12, and 21. In this case, conventional karyotype identified 50% of normal clone and abnormal clones with t(8;21) and loss of X chromosome, but in 70% of abnormal cells, del(12q) was also detected. FISH analysis on metaphase spreads identified the presence of RUNX1/RUNX1T1 fusion gene on derived chromosome 8 and further SKY analysis identified the involvement of chromosome 12. This also an unbalanced translocation with no gain of chromosome material on chromosome 12. It is supposed that 8q22 region was translocated to 12q. Along with the region from 12q, q22 region of chromosome 8 was translocated to 21q22, thus the RUNX1 and RUNX1T1 did not get fuse each other on der (21) and the 21q22 was translocated to der(8). Combined reports of Karyotype, FISH and SKY failed to identify the involvement of any other chromosome, thus it is suspected that the remaining portion of 12q was deleted. Involvement of chromosome 12 in variant three-way/four-way translocations was previously reported in 4 cases.,,,, Furthermore, Minamihisamatsu and Ishihara reported a three-way translocation, t(1;8;21)(p36;q22;q22) with additional chromosome abnormalities, del (12)(p11) and loss of X chromosome. p12, p13, q13, and q24 regions of chromosome 12 were previously reported to be involved in variant t(8;21).
t(8;21) most frequently associated with additional chromosomal abnormalities such as loss of sex chromosome, trisomy 8 and del (9q). There are discrepancies in the previously reported studies regarding the prognostic significance of such secondary aberrations in AML. Being the most frequent additional abnormality, the prognostic role of loss of sex chromosomes was extensively studied. Both adverse and favorable roles of loss of X/Y in the clinical outcomes of t(8;21) AML patients were reported.,,,,, Notwithstanding, some studies showed no significant association between the loss of X chromosome and prognosis in t(8;21) patients.,,, Recently, the prognostic significance of loss of sex chromosome has been studied separately in male and female t(8;21) AML patients retrospectively in 15 Chinese AML study groups. According to Chen et al., loss of the X chromosome in t(8;21) female patients predicts a favorable prognosis. However, there is no accurate information on how these additional chromosomal abnormalities or variant translocations affect prognosis of the disease and still remains obscure.
In brief, when compared to other hematological malignancies, spectrum of chromosomal aberrations is broad and diverse in AML and so routine cytogenetic analysis of leukemic blast cells plays a pivotal role in diagnosis, prognostication, and guidance of treatment. Current banding techniques have provided evidence for nonrandom karyotypic changes; however, most of the cases of variant rearrangements can be cryptic and might be overlooked by G-banding. This study highlights the importance of complete cytogenetic profiling of t(8;21) AML patients, providing the allocation for a stratified treatment approach of the disease. Since all the variant abnormalities are single population studies, the role of variant/unusual translocations and additional chromosomal abnormalities in determining prognosis is disputable. Single case reports as well as large scale studies are necessary to provide further insights in understanding of the mechanism involved in these rearrangements and its impact on prognosis. Therefore, contribution to the registry of t(8;21) with abnormal variants and their proper follow-up is very important, which in future helps to clarify underlying molecular pathogenesis so that improved therapies might be developed.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We are thankful to patients for their kind cooperation. We would also like to thank Kerala State Council for Science Technology and Environment(KSCSTE), Thiruvananthapuram, Kerala, for awarding a research fellowship to Ms. Akhila Raj T V.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]