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ORIGINAL ARTICLE
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Association of MLH1-93G>A polymorphisms toward lung cancer susceptibility and its association with clinical outcome in North Indian patients treated with platinum-based chemotherapy


1 Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India
2 Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission19-Mar-2021
Date of Acceptance09-Sep-2021
Date of Web Publication14-Jan-2022

Correspondence Address:
Siddharth Sharma,
Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala - 147 004, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_465_21

 > Abstract 


Background: Lung cancer is one of the most prevalent and main causes of malignancy-related deaths worldwide, especially in developed countries. Epidemiological studies have demonstrated that individuals having alterations in a particular gene may have a high risk of developing certain types of cancer.
Materials and Methods: In the present study, 500 Indian lung cancer patients and 500 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism method was used to identify the genotype of enrolled individuals and MedCalc statistical package was used for carrying out statistical analysis.
Results: In this study, we found a reduced risk of developing adenocarcinoma in patients harboring variant (P = 0.0007) and combined type genotype (P = 0.008), whereas an increased risk for small-cell lung carcinoma (SCLC) development for those subject harboring GA genotypes (P = 0.03) was also observed. Further, heterozygous type and combined type genotype of heavy smokers for MLH1 polymorphism reported a 2-fold (P = 0.001) and 1.8-fold increased risk toward lung cancer development, respectively (P = 0.007). In case of females, the subjects harboring a variant allele have a significantly reduced risk for lung cancer development (P = 0.0001). For MLH1 polymorphism, reduced risk of developing tumor to T3 or T4 stage was observed (P = 0.04). Moreover, this is the first study reporting overall survival (OS) association for north Indian lung cancer patients with platinum-based doublet chemotherapy; for docetaxel, a three-fold increase in hazard ratio and corresponding low median standard survival time (8.4 months) for mutant and combined type genotype (P = 0.04) was observed.
Conclusions: These results suggest that MLH1-93G>A polymorphism is involved in modulating the risk toward lung cancer. Our study also concluded a negative association of OS in patients undergoing carboplatin/cisplatin and docetaxel chemotherapy.

Keywords: Chemotherapy, lung cancer, MLH1, overall survival, pack-years, polymorphism



How to cite this URL:
Singh S, Singh N, Baranwal M, Sharma S. Association of MLH1-93G>A polymorphisms toward lung cancer susceptibility and its association with clinical outcome in North Indian patients treated with platinum-based chemotherapy. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=335489




 > Introduction Top


Lung cancer has become the single most common cause of death occurring due to cancer and hence has become a big health problem all over the world.[1] Although a lot of studies suggest that smoking is the leading factor for the occurrence of cancer, only about 15% of lung cancer patients are smokers proposing that there might be some others factors involved in the development of cancer.[2],[3] Several Epidemiological studies have also reported that alteration in specific genes (DNA repair pathways) can increase the risk of developing different types of cancer.[4],[5] MMR is a DNA repair pathway which is responsible for recognizing and repairing the mismatches occurring due to insertion, deletion, and misincorporation of bases during the process of replication and recombination.[6] MLH1, a DNA repair protein helps fix errors that are made when DNA is copied in preparation for cell division. Any polymorphism in the MLH1 gene can lead to alteration in the structure of MLH1 protein due to which the resultant protein will become nonfunctional which further influences individual susceptibility toward the development of lung cancer. Currently, there are more than 1521 single-nucleotide polymorphisms (SNPs) which are clinically significant in the SNP database maintained by NCBI for the MLH1 gene. Out of these rs1800734-93G>A polymorphism is most extensively studied in different population and have been shown to be related with the increasing susceptibility toward lung cancer, prostate, colorectal, and colon cancer and squamous cell carcinoma in different populations.[7],[8],[9],[10] Hence, in this study, we have conducted a case–control study to investigate the association of rs1800734-93G>A polymorphism toward lung cancer in the north Indian population.


 > Materials And Methods Top


Patient recruitment

This is a hospital-based case-control study conducted on 500 lung cancer patients and 500 healthy controls. The ethical committee of PGIMER-Post Graduate Institute of Medical Education and Research, Chandigarh, India, has approved this study. The details about the demographics of patients and their smoking habits were recorded by the interviewer. The individuals recruited for this study were selected without any biasness toward gender, histology, age, smoking habits, and TNM staging. Other details such as tumor size, lymph node invasion, metastasis, and how the patient is responding toward chemotherapy were taken from the medical records of the patients at the hospital. Only those patients are recruited who meet the following criteria: (a) Confirmation of nonsmall-cell lung carcinoma (SCLC) or SCLC by the clinician (b) willing to undergo complete cycle of chemotherapy unless advised to stop (c) given written informed consent. The data about the smoking habits were also collected and based on that patients were stratified into “smokers” and “non-smokers.”

Chemotherapeutic regimen

The patients in this study were given platinum-based chemotherapy as these cases were inoperable. The chemotherapy drugs given included carboplatin or cisplatin along with and 3rd generation agents such pemetrexed, irinotecan, or docetaxel. The combinatorial therapy involved 500 mg/m2 pemetrexed, 100 mg/m2 irinotecan, or 75 mg/m2 docetaxel (administered as a 1-h infusion, followed by cisplatin 65 mg/m2 administered over 3-h as an intravenous infusion). Vitamin B12 and standard folate supplementation were given to all the patients. The treatment procedure was repeated every 3–4 weeks and the chemotherapeutic drugs were administered intravenously. The 4 cycles of chemotherapy were administered as per the standard protocol followed by PGIMER after which the tumor response is assessed.

The recruited patients were followed after every 2 months till the end of the study or the death of the patient. The survival time was calculated from the date when cancer was first diagnosed till the date of last follow-up or the death of the patient.

Genotyping of MLH1 variants

Phenol chloroform method for genomic DNA isolation was used to extract DNA from 4 ml of blood.[11] The genotype of MLH1 (-93G>A/rs1800734) was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.[12] MLH1 polymorphic site was further amplified by using the following primers: FP: 5'-TCT AAC AGG CAA GTA GGA AC-3' RP: 5'-TAG CCA CAT TTA ATC CAT AAC-3'. Following is the composition of PCR master mix (20 μl): 1X PCR buffer, 0.5 μM of forward and reverse primer, 200 μM dNTPs, 50 μg/ml BSA, 1.5 mM MgCl2, 1 Unit Taq polymerase and 50 ng template DNA. PCR reaction for MLH1 was set up as follows: One cycle of 5 min and 30 sec at 95°C and 94°C, 45s at 63°C, 30 cycles for 30 s each at 72°C and one cycle for 5 min at 72°C. PCR product of MLH1 is 387 bp long, which is further confirmed by running it on 1.5% agarose gel along with 100 bp ladder. RFLP method was used after digesting the PCR product with PvuII restriction enzyme at 37°C overnight. A single band of 387 bp was for mutant type genotype, two bands of size 207 and 180 bp belong to wild-type genotype and three bands corresponding to 387, 207 and 180 bp belongs to heterozygous type genotype [Figure 1].
Figure 1: Detection of the hMLH1-93G→A polymorphism by polymerase chain reaction and PvuII digestion. Polymerase chain reaction product was digested (+) or undigested (−) with PvuII for 24 h at 37°C. A single band of 387 bp was for mutant type genotype (AA), two bands of size 207 and 180 bp belongs to wild-type genotype (GG) and three bands corresponding to 387, 207, and 180 bp belongs to heterozygous type genotype (GA)

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Statistical analysis

The current study involves population living in the northern India region. To analyze if the cancer patients and control population follow Hardy–Weinberg equilibrium (HWE), we performed the goodness-of-fit Chi-square test. Odds ratio (OR) was calculated using the logistic regression method and taking gender, age, and smoking status as the confounding factors. Median standard time (MST) for overall survival (OS), unadjusted hazard ratio (HR), and adjusted HR were calculated by Univariate Kaplan–Meir and Multivariate Cox regression method utilizing Medcalc statistical software version 14.8.1. A P < 0.05 was considered significant.


 > Results Top


Patient characteristics and clinical predictors

The current study involves 500 cases and 500 controls and key features such as demographic information, age, gender, smoking characteristics, TNM, histology, and various other clinical data of cases and control are shown in [Supplementary Table 1]. The cases were further stratified based on histology and the bifurcation is as follows: Squamous-cell carcinoma (SQCC) −41%, adenocarcinoma (ADCC) −40.6% and SCLC −16.8%, others −1.2% and unknown −0.4%.



Association of the MLH1-93G>A polymorphism and risk towards lung cancer according to tumor histology

The distribution of both the allelic and genotypic frequencies of MLH1 polymorphic variant is shown in [Supplementary Table 2]. The frequencies of GG, GA, and AA genotypes were 45, 44.6, and 10.4%, respectively, in controls, and 47.2, 42.0, and 10.8% in cases. Thus, in both cases and controls, the genotypic frequencies of MLH1 (−93G>A/rs1800734) polymorphism did not exhibit any significant difference (χ2 = 0.69; df = 2; P = 0.70) as shown in [Supplementary Table 2]. No significant deviation from HWE was noticed for MLH1 genotype among cases (χ2 = 0.50; df = 1; P = 0.47) and controls (χ2 = 0.08; df = 1; P = 0.76), signifying no sample biasedness. The GG wild-type genotype was used as a reference and our results suggests no association between MLH1 variants and risk of lung cancer. However, when we further stratified our data on the basis of histology, reduction in risk was observed in heterozygous type genotype (GA) as compared to wild-type genotype (GG) (AOR = 0.48; 95% CI = 0.32–0.73, P = 0.0007) for the patients diagnosed with ADCC [Table 1]. The dominant model, also exhibited reduced risk towards lung cancer for combined genotype (GA + AA) (AOR = 0.88; 95% CI = 0.67–1.15; P = 0.008) [Table 1]. Similarly, in the co-dominant model we found an increased risk for SCLC development for those subjects harboring GA genotype (AOR = 1.78; 95% CI = 1.04–3.02; P = 0.03).

Table 1: Genotypic and allelic distribution of the MLH1 genetic variant and its association with risk of lung cancer according to tumor histology

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Association of the MLH1-93G>A polymorphism with smoking status

Out of 500 cases and controls, there were 398 and 449 smokers in our study. These were further analyzed by stratifying based on pack-years (number of cigarettes/bidis smoked per day/20) x number of years smoked). When the co-dominant model was evaluated it was observed that heavy smokers have a two-fold increased risk of lung cancer development for heterozygous type genotype (AOR = 2.18, 95%CI = 1.33–3.55, P = 0.001) [Table 2]. In dominant model for the same group combined genotype (GA + AA) also showed significant increase in risk for development of lung cancer (AOR = 1.83, 95% CI = 1.18–2.85, P = 0.007). No association of MLH1 polymorphism for smokers and nonsmokers toward the development of lung cancer was reported in our results [Supplementary Table 3].
Table 2: Relationship of different MLH1 genotypes with the smoking status of cases and controls

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Association of MLH1 rs1800734 polymorphism with gender and clinic-pathological features

To analyze any association of gender, various clinic-pathological features with rs1800734 (-93G>A) polymorphism and susceptibility toward lung cancer we employed logistic regression method. Our results showed that in the co-dominant model of female category there was a significant reduction in risk of developing lung cancer in subjects harboring a variant allele (AOR = 0.016; 95%CI = 0.002–0.12; P = 0.0001) and subjects having combined genotype (GA + AA) in dominant model (AOR = 0.02; 95%CI = 0.002-0.16; P = 0.0002) [Table 3]. Our results also showed heterozygous type genotype had significantly low chance of developing a T4 stage tumor (AOR = 0.64, 95% CI = 0.42–0.98, P = 0.04) [Supplementary Table 4].
Table 3: Relationship of different MLH1 polymorphisms on the basis of gender

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Association of rs1800734 polymorphism with OS and chemotherapy regimens

Out of 500 lung cancer patients almost, 354 patients were given chemotherapeutic drugs so we wanted to estimate if MLH1-93G>A polymorphism exerts any modulating effect and also if OS is associated with different chemotherapeutic drugs used in the treatment. The complete results of MLH1-93G>A polymorphism and OS are depicted in [Supplementary Table 5]. All patients received first-line chemotherapeutic drug viz. carboplatin/cisplatin along with the second line of chemotherapy drugs which includes paclitaxel, pemetrexed, irinotecan, and docetaxel. When we analyzed the data from patients receiving docetaxel, we found that there was a 3-fold increase in HR and an MST had significantly reduced (8.4 vs. 13.33 months, HR: 3.13, 95% CI = 0.90-10.9, P = 0.04) for both heterozygous type (GA) and combination of heterozygous and mutant type genotype (GA + AA) as shown in [Figure 2]. We did not find any significant association in OS of patients and second line of chemotherapeutic drug paclitaxel, irinotecan, pemetrexed [Supplementary Table 6].

Figure 2: Overall survival survival WRT to docetaxel therapy

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 > Discussion Top


The mismatch repair (MMR) pathway is responsible for recognizing and repairing the erroneous insertion, mis-incorporation, and deletion of the bases during the process of replication and recombination. Mutations in DNA repair pathways have been associated with the development of various types of cancer.[13],[14] Till date, several studies have addressed whether some genetic variation (SNPs) affects various clinical outcomes in lung cancer patients.[15],[16] This study is focused on finding whether MLH1 (rs1800734) polymorphism plays any role in modulating the risk for lung cancer and furthermore we also attempted to evaluate the impact of the MLH1-93G>A polymorphism on the outcome of lung cancer patients treated with platinum-based doublet chemotherapy.

Results from our study concluded that there is no significant association between MLH1-93G>A polymorphism and risk of developing lung cancer when all the three genetic models were evaluated. Our results are in accordance with earlier studies conducted which have also reported no association between the MLH1-93G>A genotype and risk of occurrence of prostate cancer in the Iranian population.[7] However, a study conducted by Slováková and colleagues on the Slovakia populace reported a 1.4-fold increased risk of lung cancer.[17] Furthermore, when we analyzed our data based on histology, we observed that lung cancer subjects were at a reduced risk for developing ADCC (OR = 0.48, P = 0.0007 and 0.88, P = 0.008) when the co-dominant and dominant models were applied. On the contrary, when the recessive model was evaluated, we observed a 1.8-fold risk for ADCC (P = 0.02). In the case of SCLC, subjects who were carrying a single copy of the variant allele had a higher propensity towards SCLC (P = 0.02). Our results were in accordance with the previous studies which reported an association for the occurrence of LC based on histology. Shih et al. have reported that individuals having MLH1 polymorphism have about two-fold increased risk of developing ADCC. In the same study, authors have reported a 1.5-fold increased risk for SQCC, but we failed to find any association for SQCC in our study.[18] The ambiguity in these studies may be due to differences in the selection of population under study, their ethnic composition, sample size, and exposure to other environmental pollutants.

Cigarette smoking is another risk factor which is related to the development of lung cancer. Hence, to understand if there is any association of smoking and its synergistic interaction with the MLH1-93G>A polymorphism for the development of lung cancer, we stratified the patients into two groups: “smokers” and “nonsmokers.” Further “smokers” group was divided into two subgroups: Light smokers and heavy smokers based upon the pack-years smoked. Our results suggest that there is no association for overall smokers and non-smokers in relation to the polymorphic variants of MLH1-93G>A and risk for lung cancer. On the contrary, when we estimated the role between heavy and light smokers, it was clearly evident that subjects who were smoking more than 25 pack-years and harboring a single copy of the variant allele (GA) for the MLH1-93G>A polymorphism had a two-fold high risk for lung cancer predisposition in the co-dominant model (P = 0.001). A similar observation was also evident in those subjects who were carrying a single variant allele for the-93G>A polymorphism where a 1.8-fold increase risk was observed. Earlier studies also showed similar results, Shih et al. reported a 1.5-fold increased risk of developing LC. However, Shih has also reported a four-fold increased risk for lung cancer with non-smokers for the above polymorphism.[18] Lo et al., in another study conducted on the Taiwanese population have also shown that the risk of developing LC for smokers was inclined to those subjects who were carrying the wild-type genotype (GG).[19] Yu et al., (2006) also corroborated our study; they have also reported an increased risk for developing lung cancer for patients belonging to the category of heavy smokers and light smokers, respectively, in colorectal cancer.[20]

We have also analyzed our data after dividing the study based on gender and our results clearly conclude that female subjects were at a low risk of developing lung cancer as compared to male (P = 0.0001). Our results were in accordance to a previous study done in Slovak population, where the authors have reported a significantly low risk of occurrence of LC in females.[17] It is very enticing to propose that reduced risk of LC in females is an indicator of a relation between rs1800734 polymorphism, lung cancer and hormonal stimulation. The MLH1-93G>A polymorphism lies in the promoter region which also have a semi-responsive estrogen element.[21] Further, Belcher et al., have shown a relationship between tumors not associated with reproductive organs and hormones especially estrogen.[22] Several other studies reported the role of estrogen in activation of MMR proteins and have tried to explain the role of estrogen in tumor.[23] However, a study conducted in Taiwan population contradicts our results they have reported that male population have slight risk whereas female have a very high risk of developing lung cancer approximately 8 times.[18]

We have also analyzed the implication of MLH1-93G>A polymorphism based on various clinical-pathological features like the clinical stage of tumor, its size, invasion in lymph node, and metastasis. Our data concludes that GA type genotype has decreased risk of developing Stage III or IV lung cancer, previous studies are not in accordance with our conclusion, Shih et al. have predicted a two-fold increased risk of developing stage III or IV lung cancer in the Taiwanese populace.[18] Furthermore, in the same study authors have shown 1.3 times increased chance for an individual to have stage I and II lung cancer, but our study does not show any association of such kind. We also did not find any association of MLH1 polymorphism with lymph node invasion and metastasis which is in accordance with the previous studies.[18]

In this study, we have also evaluated if there is any association between the MLH1-93G>A polymorphism and OS of lung cancer patients undergoing platinum-based chemotherapy. As far as our knowledge is concerned, we are the first to report the data of association of OS with platinum-based doublet chemotherapy and MLH1-93G>A polymorphism for the north Indian population. All the LC patients were either given docetaxel, paclitaxel, irinotecan or pemetrexed along with carboplatin/cisplatin as advised by the clinician. Our results showed that the patients who were given carboplatin/cisplatin and docetaxel and carrying the single variant allele for MLH1 polymorphism exhibited the worst prognosis (MST = 8.4; HR = 3.13; P = 0.04).

To the best of our knowledge, previous studies completed till date have very small sample size so an important strength of our current investigation is a huge sample size which will increase the reliability of our study. In the current study, we have focused particularly on three endpoints viz. OS, chemotherapy response, and clinic-pathological features in relation to MLH1 polymorphism. Moreover, we could not find any study analyzing the role of MLH1 polymorphism in relation to OS and platinum-based chemotherapy. However, our study too has certain limitations. First, even though, we have chosen large sample size but the number of subjects under subcategories is small which might be a limitation. Since smoking and its duration are also critical for this study, differences in smoking habits and pack-years in control and case subjects were also considered as a limitation. Further, the control population studied in our investigation is recruited from one particular area, so there might be a possibility of selection biasedness.


 > Conclusion Top


Our study on north Indian Lung cancer patients concluded that MLH1 -93G>A polymorphism is associated with modulating the susceptibility towards lung cancer. We have also reported decrease in overall survival for patients taking carboplatin/cisplatin and docetaxel chemotherapy.

Acknowledgement

We would like to express gratitude to all the subjects who participated in this study. The authors thanks to Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India for providing samples, and Thapar Institute of Engineering and Technology, Patiala, Punjab for providing the necessary infrastructure to carry out the research work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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