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Vol. 27. Issue 2.
Pages 116-123 (March - April 2021)
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Vol. 27. Issue 2.
Pages 116-123 (March - April 2021)
Original article
DOI: 10.1016/j.pulmoe.2020.11.007
Open Access
Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome?
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Maria Joana Catarataa,b,c,d,e,
Corresponding author
mjcatarata@i3s.up.pt

Corresponding author at: i3S, Instituto de Investigação e Inovação em Saúde, Tumour & Microenvironment Interactions Group R. Alfredo Allen, 4200-135 Porto, Portugal.
, Margarida Lourençof, Maria Fátima Martinsf,g, João Fradef, Alice Pêgoc, Carlos Robalo Cordeiroc,g, Rui Medeirosd,e, Ricardo Ribeiroa,b,f,h
a i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
b Tumour & Microenvironment Interactions Group, INEB, Biomedical Engineering Institute, University of Porto, Portugal
c Department of Pulmonology, University Hospital of Coimbra, Portugal
d Faculty of Medicine, University of Porto, Portugal
e Molecular Oncology and Viral Pathology Group - Research Centre, Portuguese Institute of Oncology, Porto, Portugal
f Department of Clinical Pathology, University Hospital of Coimbra, Portugal
g Faculty of Medicine, University of Coimbra, Portugal
h Laboratory of Genetics, Faculty of Medicine, University of Lisbon, Portugal
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Figures (1)
Tables (3)
Table 1. Clinical and oncological characteristics of the patients (N=168).
Table 2. Univariate analyses of AGXT rs34116584 and clinical variables with time-to-progression and time-to-death.
Table 3. Multivariate Cox regression including only the significant covariates after empirical analysis, for PFS and OS.
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Abstract
Introduction

AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively.

Methods

Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis.

Results

Multivariate analysis showed shorter PFS for T carriers [HR=2.0, 95% CI, 1.4−3.0, p<0.0001] and shorter OS [HR=1.8, 95% CI, 1.1−3.0, p=0.017] globally, as well as in a subgroup of patients (n=144) treated with first line platinum-based chemotherapy [HR=2.0, 95% CI, 1.3–3.1, p=0.001] and [HR=1.8, 95% CI, 1.1–3.1, p=0.026], respectively.

Conclusion

This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy.

Keywords:
Non-small cell lung cancer
Single nucleotide polymorphism
Pharmacogenetics
Cohort study
Full Text
Introduction

Lung cancer is one of the most common malignancies worldwide and the most common cause of cancer deaths in the past few decades, with over one million subjects yearly diagnosed 1. The 5-year survival rate is the lowest compared with other frequent malignancies 2. Among all primary lung cancers, non-small cell lung cancer (NSCLC) represents approximately 85% of cases. The 5-year relative survival rate has been increasing over the last years, particularly due to progress in treatment over the years 3.

Although targeted therapies have redefined treatment options for patients with molecularly defined NSCLC (eg, epidermal growth factor receptor [EGFR]-mutant, anaplastic lymphoma kinase [ALK]-rearranged NSCLC), these therapies are ineffective in those whose tumours lack such genetic alterations, which comprise the majority of NSCLC patients 4.

Standard-of-care first-line chemotherapy for advanced NSCLC without actionable driver mutations or low expression of programmed death-ligand 1 (PD-L1) has historically been platinum-doublet, cisplatin or carboplatin, with or without maintenance therapy 5. Despite its wide acceptance and use, platinum-based chemotherapy presents poor clinical outcomes and efficacy varies across patients. Currently, the combination of immune checkpoint inhibitors with chemotherapy in advanced driver mutation-negative NSCLC and tumour PD-L1 expression under 50%, has replaced the regimen of only platinum-based chemotherapy in first line treatment 6.

Beyond clinical and pathologic features, genetic variation is also considered a factor associated with treatment efficacy and prognosis 7. Single-nucleotide polymorphisms (SNP), account for 90% of genetic polymorphisms, with some responsible for distinct molecular roles, contributing to inter-individual functional variability, correlating with relevant phenotypic variations in medicine 8. The AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, localized in hepatic peroxisomes, which is known to participate in glyoxylate detoxification 9. Mutations in this gene have been reported to alter subcellular targeting and have been associated with type I primary hyperoxaluria 10. A polymorphism in AGXT gene (rs34116584) is responsible for a C>T substitution at locus +32 that results in Pro-Leu substitution located at codon 11 of exon 1 11. The amino acid substitution at position 11 creates a conformational change that is related to decreased activity 11. The polymorphism AGXT rs34116584 was shown to be associated with progression-free survival (PFS) in patients with metastatic colorectal cancer in response to oxaliplatin 12. Here, we sought to evaluate whether this genetic variant was associated with clinical outcomes in NSCLC patients, under the platinum-based chemotherapy regimen.

Material and methodsPopulation

This study comprises a retrospective cohort of histologically confirmed NSCLC patients (n=168), which were recruited between August 2017 and October 2018 from Coimbra University Hospital. Subjects with concomitant primary tumour in another organ were excluded. Clinical information was retrieved from clinical charts on pathological background, medications, stage, Eastern Cooperative Oncology Group performance status (ECOG PS), tumour mutational status, type of cancer treatment and disease progression/death. Targeted therapies were administered to carriers of genetic alterations in EGFR and ALK, whereas checkpoint inhibitors were used as salvage therapy. Information on chemotherapy-related febrile neutropenia (grade 3–4) in patients admitted to hospital stay was retrieved from clinical charts. The primary endpoint was progression-free survival (PFS) and the time-to-disease progression was calculated in months from the date of first line chemotherapy until the date of progression according to RECIST criteria. Overall survival (OS) was included as secondary endpoint, and the time-to-death was computed in months from the date of first line chemotherapy until the date of death/date of last visit. The research was reviewed and approved by the Coimbra University Hospital’s Ethical Committee (ref. 0111/CES) and by the Portuguese National Committee for data protection (number 2588/2017). Informed consent was obtained from each participant in agreement with the Helsinki Declaration.

AGXT genetic polymorphism and genotyping

The single nucleotide polymorphism included in the present study (AGXT rs34116584) was selected after reviewing public databases, in silico analysis and review of scientific literature to identify this functional polymorphism with minor allele frequency above 1% 8,10,11. Each patient donated a sample of blood (∼8mL) for research, collected to EDTA-Vacutainer tubes, at the same time of blood collection for routine analytic follow-up. The collected blood was separated into plasma and buffy coat and stored at −80°C until further analysis. DNA was isolated and purified from diluted buffy coats, using EZ1 BioRobot and EZ1 DNA Blood kit (QIAgen). AGXT rs34116584 was genotyped using the Sequenom Mass ARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform (Sequenom, San Diego, CA, USA). Primers were designed using semi-automated Assay Design 3.1 Software (Sequenom).

Statistical analysis

Statistical analyses were performed on SPSS statistics software V.25.0 and P values below 0.05 were considered statistically significant. Continuous variables were depicted as average±standard deviation or median (interquartile range) according to departure from normality using Shapiro-Wilk test. Additive (CC vs. CT vs. TT), recessive (CC/CT vs. TT) and dominant (CC vs. CT/TT) genetic models were stratified according to wild type allele C. The time-to-outcome for AGXT genotypes was tested using Kaplan-Meier curves and Log-rank test in univariate and Cox proportional hazard model for multivariate analyses. The univariate empirical analyses included AGXT genetic models as well as other clinicopathological covariates. A p-value <0.05 was used as criteria for inclusion of a clinical variable in the multivariate Cox regression analysis, whereas the genetic model to include was determined using the likelihood ratio. The estimates of sample size, power, and effect size (regression coefficient) for survival analyses that use Cox proportional hazards models were conducted using STATA 16.0. It also reports the number of events (failures) required to be observed in the study. Sample size and number of events were calculated assuming alpha=0.05 and power>0.8. For both endpoints, the effect size was calculated from the resulting Hazard Ratio of AGXT variable in multivariate analysis. The minimal sample size for PFS was n=62 with an estimated number of events of n=50, whereas for OS, the calculated sample size was n=173 and the estimated number of events n=77.

Results

The clinicopathological characteristics of participating subjects are described in Table 1. The anatomical localization of distant metastases at diagnosis (n=94) was distributed as pleura and lung (62.8%), extra-thoracic (29.8%) and multiple (7.4%). Regarding mutational status, we observed that 8.3% of patients (n=14) had EGFR mutation (exon 19 deletions or exon 21 mutation), whereas 3.0% (n=5) had rearrangements in the gene encoding anaplastic lymphocyte kinase. Platinum-based doublet chemotherapy was administered to 85.7% of NSCLC patients, most frequently the cisplatin combination. Adjuvant chemotherapy was administered in twelve patients. In a subgroup of patients with chronic renal disease (n=24) the doublet chemotherapy with carboplatin was the first choice. Fifty-one patients underwent checkpoint inhibitors as second-, third- and fourth-line therapy. The median time-to-disease progression and the median time-to-death was 7.5 (CI 95%, 6.1–9.0) and 30.0 months (CI 95%, 16.9–43.2), respectively.

Table 1.

Clinical and oncological characteristics of the patients (N=168).

Clinical Variables   
Age, Mean ± SD  64.8±10.7 
Gender, N (%)   
Male  124 (73.8%) 
Female  44 (26.2%) 
Smoking history, N (%)   
No  31(18.5%) 
Smoker  13 (7.7%) 
Previous smoker  68 (40.5%) 
pTNM 8th edition, N (%)   
IIIA  20 (11.9%) 
IIIB  33 (19.6%) 
IIIC  21 (12.5%) 
IVA  65 (38.7%) 
IVB  29 (17.3%) 
ECOG performance status at diagnosis, N (%)   
39 (23.2%) 
86 (51.2%) 
39 (23.2%) 
4 (2.4%) 
0 (0%) 
Histology, N (%)   
Adenocarcinoma  117 (69.9%) 
Squamous cell carcinoma  42 (25.9%) 
Adenosquamous  6 (3.6%) 
Others  3 (1.8%) 
First line systemic therapy, N (%)   
Platinum-based doublet chemotherapy  144 (85.7%) 
Cisplatin  121 (84.0% 
Carboplatin  23 (16.0%) 
Targeted therapy  24 (14.3%) 

The AGXT rs34116584 genetic polymorphism distribution in this cohort of NSCLC patients was 71.7% C homozygous, 23.5% heterozygous and 4.8% T homozygous. Genotyping was successfully performed in 166 patients, with two missing genotyping. The median time-to-endpoint, hazard and survival univariate analyses of the empirical statistical procedure are depicted in Table 2. In the dominant genetic model, there was a significantly shorter PFS for T-allele carriers [5.4 months (CI 95% 4.3−6.4) versus 9.4 (CI 95%, 7.2−11.7), p<0.0001] and a shorter OS [22.2 months (CI 95% 13.6−30.8) versus 43.6 months (20.3−66.9), p=0.015] (Fig. 1). Notably, despite the AGXT rs34116584 T-carriers had shorter PFS than CC homozygous both in the subset of mutated (n=14, p=0.028) and wild-type (n=154, p<0.0001) EGFR, those AGXT carriers only presented shorter OS in wild-type (p=0.022) but not for mutated EGFR (p=0.692). Additionally, in a subset of patients with information on PD-L1 expression (n=98, 33.7% without and 66.3% with PD-L1 expression ≥1%), Kaplan-Meier plots with Log-Rank tests showed that T-carriers had shorter time-to-progression independently of PD-L1 positivity (p=0.010 and p=0.040, respectively).

Table 2.

Univariate analyses of AGXT rs34116584 and clinical variables with time-to-progression and time-to-death.

  Progression-free survivalOverall survival
  Median (95%CI)  P *  Median (95%CI)  P * 
Age           
<65.4  86  7.2 (5.8-8.7)    43.6 (8.5-78.7)   
>65.4  82  8.6 (5.1-12.1)  0.541  23.6 (15.3-31.8)  0.078 
Gender           
Male  124  7.2 (5.3-9.1)    28.1 (21.7-34.4)   
Female  44  8.9 (5.5-12.3)  0.547  82.5 (15.1-150.0)  0.102 
Histology           
Adenocarcinoma  117  7.8 (5.7-9.9)    44.0 (18.6-69.4)   
Squamous cell    5.7 (4.4-7.0)    24.6 (17.0-32.2)   
Others *  429  9.5 (3.4-15.7)  0.201  31.3 (19.3-43.4)  0.069 
         
26  10.2 (4.1-16.3)    30.0 (14.1-46.0)   
46  9.4 (4.0-14.9)    67.4 (46.7-88.2)   
18  4.7 (1.4-8.1)    26.9 (19.5-34.3)   
78  5.5 (4.0-7.1)  0.008  25.4 (16.7-34.2)  0.011 
         
N0  13  9.0 (4.2-13.8)    –   
N1  18  7.1 (2.3-12.0)    82.5 (22.9-142.1)   
N2  34  9.5 (2.8-16.2)    26.9 (18.5-35.3)   
N3  103  6.6 (4.6-8.6)  0.151  31.3 (12.9-50.0)  0.790 
         
no  74  9.6 (5.2-14.0)    78.7 (53.0-104.4)   
yes  94  5.4 (4.5-6.2)  0.003  22.2 (17.3-27.1)  <0.0001 
Type Therapy           
Surgery+CT  12  20.5 (0.0-49.2)    –   
CT  125  6.6 (4.9-8.2)    26.9 (21.0-33.0)   
CT+RT  31  8.9 (4.9-12.8)  0.024  34.9 (7.2-62.5)  0.188 
ECOG PS           
Good (0-1)  125  8.0 (6.1-9.9)    44.0 (21.2-66.8)   
Poor (2-4)  43  5.4 (2.7-8.1)  0.171  12.9 (9.8-16.0)  <0.0001 
Systemic Therapy           
Platinum based  144  6.2 (4.7-7.8)    28.1 (20.0-36.2)   
Target therapy  24  13.3 (0.2-26.3)  0.005  0.183 
AGXT rs34116584           
Additive model           
CC  119  9.4 (7.2-11.7)    43.6 (20.3-66.9)   
CT  39  5.7 (5.0-6.4)    17.8 (10.0-25.7)   
TT  4.0 (3.4-4.6)  <0.0001  24.6 (21.9-27.2)  0.009 
Dominant model           
CC  119  9.4 (7.2-11.7)    43.6 (20.3-66.9)   
CT/TT  47  5.4 (4.3-6.4)  <0.0001  22.2 (13.6-30.8)  0.015 
Recessive model           
CC/CT  158  7.8 (6.3-9.2)    31.3 (16.7-45.9)   
TT  4.0 (3.4-4.6)  0.025  24.6 (21.9-27.2)  0.615 

CT, chemotherapy; ECOG PS, ECOG performance status; OS, overall survival; PFS, progression-free survival; RT, radiotherapy. * Log-Rank test. ** others: pleomorphic, combined squamous and adenocarcinoma. 95%CI, 95% confidence interval.

Fig. 1.

Kaplan-Meier plots with Log-Rank tests for AGXT dominant genetic models in association with progression-free survival (PFS) and with overall survival (OS) for all NSCLC patients (n=168) and those treated with platinum-based chemotherapy (n=144).

(0.21MB).

The statistically significant covariates from univariate analysis were included in a Cox proportional-hazards multivariate model. This data showed for AGXT T-carriers an increased risk for progression (HR=2.0; 95% CI, 1.4−3.0; p<0.0001) and for cancer-specific death (HR=1.8; 95% CI, 1.1−3.0; p=0.017), regardless of tumour size, distant metastasis at diagnosis, type of systemic therapy and type of treatment modality (Table 3). To test the hypothesis that AGXT rs34116584 was associated with the response to platinum-based chemotherapy, the analysis was conducted in the group of patients treated with first line platinum-based doublet chemotherapy (n=144). In this subgroup, there were no identifiable actionable driver mutations at the diagnosis. Univariate analysis showed longer PFS in C homozygous (median 8.6, CI 95%, 6.1–11.1 months) in comparison with T-carriers (median 5.1, CI 95%, 4.2–6.0 months) (p<0.0001) (Fig. 1). Concordantly, the time-to-death was also longer in CC (median 34.9, CI 95%, 12.1–57.6 months) compared to T-carriers (median 19.8, CI 95%, 8.9–30.7 months) (p=0.037) (Fig. 1). On multivariate analysis T-carriers had higher risk for disease progression (HR=2.0, 95% CI, 1.3–3.1, p=0.001) independently of relevant clinicopathological covariates. In platinum-treated patients, those with febrile neutropenia (n=20) exhibited more frequently the T-allele compared to non-febrile neutropenia (35% versus 29%, respectively), despite the lack of association of the SNP with myelotoxicity (OR=1.34, 95% CI, 0.49–3.64, p=0.566).

Table 3.

Multivariate Cox regression including only the significant covariates after empirical analysis, for PFS and OS.

  Progression-free survivalOverall survival
  HR (95%CI)  HR (95%CI) 
cT (TNM)         
T1  Referent    Referent   
T2  1.6 (0.9-2.8)  0.131  0.6 (0.3-1.4)  0.278 
T3  2.2 (1.1-4.6)  0.026  0.9 (0.4-2.2)  0.856 
T4  2.1 (1.2-3.7)  0.007  1.6 (0.8-3.1)  0.159 
Distant metastasis         
No  Referent    Referent   
Yes  1.6 (1.5-2.3)  0.010  2.1 (1.3-3.7)  0.005 
Systemic Therapy         
Platinum  referent    –   
Target therapy  0.4 (0.2-0.8)  0.003  –  – 
ECOG PS         
Good (0-1)  –    Referent   
Poor (2-4)  –  –  2.3 (1.4-3.7)  0.001 
Type of therapy         
Surgery+CT  Referent    –   
CT  2.7 (1.1-6.7)  0.026  –   
CT+RT  2.8 (1.1-7.0)  0.027  –  – 
AGXT rs34116584         
Dominant model         
CC  Referent    Referent   
CT/TT  2.0 (1.4-3.0)  <0.0001  1.8 (1.1-3.0)  0.017 

CT, chemotherapy; ECOG PS, ECOG performance status; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; 95%CI, 95% confidence interval

Discussion

In the past, advances in genetic knowledge about lung cancer mutational landscape, together with development of targeted therapies, led to a paradigm shift in the treatment of NSCLC. Nevertheless, platinum-containing regimens remain the appropriate treatment for most patients 13. Clinical management of resistance or toxicity to chemotherapy in NSCLC patients would benefit from the identification of predictive and prognostic molecular biomarkers, including functional genetic polymorphisms.

The AGXT gene, located in chromosome 2q37.3 region, encodes the alanine-glyoxylate aminotransferase, whose activity is largely confined to peroxisomes in the liver 14. This enzyme catalyses the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate as cofactor 15. A missense genetic variant (AGXT rs34116584), with a proline-to-leucine substitution located at codon 11 of exon 1, occurs with a frequency of 15–20% in European and North American population 11. This polymorphism was primarily studied in primary hyperoxaluria type I 16–18. A recent report explored its role in cancer, showing an association with disease progression and death in metastatic colon cancer patients treated with oxaliplatin 12. Reports are sparse concerning the association of this SNP with cancer and have never been explored in lung cancer patients.

Herein, the AGXT-rs34116584 genetic polymorphism was analysed in locally advanced/metastatic NSCLC patients, using as outcomes the PFS and OS. Multivariate analyses revealed an independent increased risk for disease progression and for death in AGXT rs34116584 T-carriers, after adjustment for tumour size, distant metastasis, ECOG PS, treatment modality or systemic therapy. Previous molecular in vitro studies showed that the C-to-T substitution results in an amino acid modification at position 11 and creates a conformational alteration that ultimately leads to a significant decrease in alanine-glyoxylate aminotransferase´s activity and subsequent accumulation of oxalate 19,20. Both oxalate and glyoxylate generate reactive oxygen species (ROS) 21,22, which have been associated with increased mutational burden, tumour progression and dissemination 23. Since T-allele carriers have higher levels of oxalate 24 and consequently are prone to increased ROS production, the worst prognosis described for TT/TC might be an oxidative stress-mediated deregulation induced by AGXT rs34116584 SNP. This effect might be exponentiated upon exposure to hypoxia and oxidative stress causing DNA damage, or during concomitant administration to cytotoxic therapies 25.

Furthermore, a significantly shorter time-to-disease progression was found for T-allele carriers independent of EGFR mutational status, although no relation was observed with OS for subjects with EGFR tumour mutation. These findings could be aligned with a minor clinical relevance for AGXT rs34116584 SNP in comparison to EGFR mutation status that impacts a longer-term endpoint. Notably, tyrosine kinase inhibitors (TKIs) improve survival in NSCLC patients with EGFR mutation 26, modifying the natural history of disease, and possibly impacting the association of the genetic polymorphism.

In patients under first line platinum-based doublets, we verified that T-allele carriers had shorter PFS and OS; regardless of tumour size, distant metastasis, ECOG PS and treatment modality. These well-established prognostic covariates, were shown to influence NSCLC clinical outcomes 27. Here, the AGXT rs34116584 association with response to platinum-based chemotherapy remained significant, despite adjustment for these factors, suggesting that this SNP might add significant information to traditional clinical predictive and prognostic factors. The AGXT rs34116584 C>T substitution, induces a decrease of alanine-glyoxylate aminotransferase activity and is responsible for the mistargeting of the enzyme from the peroxisomes to the mitochondria, where the enzyme cannot work properly 10. These changes were predicted to have significant effects in oxalate synthesis and excretion, and the deposition of insoluble calcium oxalate in the kidney and urinary tract 28, which could be associated with increased toxicity and lesser efficacy of platinum based chemotherapy.

Moreover, cisplatin causes a number of significant side effects including nausea and vomiting, neutropenia, ototoxicity, neurotoxicity, and renal function impairment 29. Despite efforts to identify genetic predictors of the effectiveness and toxicity of cytotoxic therapies, up to now there are no robust data that can be used in clinical practice to guide the best subgroup of patients to receive cisplatin 29. Although carboplatin induces nephrotoxicity to a lesser extent, it induces more myelotoxicity 30. No association was found in our study for the AGXT rs34116584 SNP with febrile neutropenia, although the low number of subjects included in this analysis limits its conclusions.

To the best of our knowledge, this is the first report describing the prognostic impact of functional AGXT polymorphism in lung cancer patients. As such, further studies in larger independent populations are required to confirm these results. Despite inherent size limitations, in this study patients were recruited from a homogeneous cohort, the analysed SNP was selected based on functional biological relevance, and the study design and statistics accounted for important risk factors in NSCLC.

Conslusion

The functional impact of the AGXT rs34116584 SNP in decreasing the peroxisomal activity of the enzyme alanine glyoxylate aminotransferase influence oxalate accumulation. This effect might have an influence in platinum metabolization, with impact on toxicity and tumour aggressiveness, being associated with worse prognosis. This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a biomarker or as a pharmacogenetic predictor of response to platinum-based chemotherapy.

Funding

MJ Catarata was supported by the Portuguese Pulmonology Society.

Ethics approval

This project has been reviewed and approved by Coimbra University Hospital’s Ethical Committee (reference number 0111/CES; date of approval: 27th July 2017) and was also approved by the National Committee for data protection (number 2588/2017; date of approval: 6th March 2017).

Conflicts of interest

All authors declare that they have no conflict of interest.

Acknowledgments

The authors would like to acknowledge the lab technician’s Dr Elisabete Camilo, Dr Isabel Marques and Dr Andreia Coelho for their invaluable support for DNA extraction.

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