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Decoding the Genetic Alteration in Genes of PARP Family and the Possible Association with HNSCC

Introduction: Genetic alterations have long been associated with the transformation of normal cells into malignant cells. Several genes are related to exhibiting the phenotype. The PARP gene family is mainly involved in maintaining genome stability. They play an important role in DNA repair and the programmed cell death process. Aim: To analyse the genetic alteration in PARP family and to determine its association with HNSCC. Materials and Methods: Cbioportal was used as the primary database for identifying the mutations and variations. The data generated in the form of oncoprint was further assessed for frequency of occurrence, type and novelty. Results and Discussion: It can be observed that greater amplification was found in the TIPARP gene which is 14% among all the 17 genes of the family. Also to add on, PARP 14 and PARP 15 show amplification patterns in similar groups of patients. Several types of mutations such as truncated, splicing deep deletion were found in most of the genes. The TIPARP gene was upregulated in HNSCC patients. The Caucasians experiencing low/medium expression of TIPARP Original Research Article Ravikumar et al.; JPRI, 33(64A): 307-317, 2021; Article no.JPRI.74420 308 showed greater rates of survival than highly expressed African Americans. Similarly, males presenting with low or medium expression of TIPARP showed a greater rate of survival than the highly expressed females. Conclusion: TIPARP could be a promising prognostic marker for screening populations vulnerable


INTRODUCTION
Head and neck squamous cell carcinoma (HNSCC) which is the major type of cancer that is most common world wide. Mutation in the TP53 gene sequence which is the somatic genomic alteration that potentially gives rise to HNSCC. Several other gene mutations have also been implicated in the development of oral cancer. The treatment procedure involves surgery, chemotherapy, radiotherapy etc. [1]. HNSCC occurs majorly in 5 anatomical sites which consist of oral cavity, oropharynx, Nasopharynx, hypopharynx and larynx. HNSCC is the cancer that can be cured if it is detected early and often there won't be any symptoms visible, hence it can be avoided at the earliest and detected only when it becomes severe [2]. Tobacco smoking is the primary reason for HNSCC and it is mainly seen in males rather than females. The detection and the diagnosis involves immunohistochemistry, PCR, in situ hybridisation [3].
Poly (ADP-ribose) polymerases (PARPs) are a family of enzymes that exhibit the ability to catalyze the transfer of ADP-ribose to target proteins. Cellular processes, transcription, replication, recombination and DNA repair are a few pathways to mention where PARPs play a vital role. With a special emphasis on the involvement of PARP proteins in DNA repair is of great interest, because certain transformed cells principally rely on PARP mediated DNA repair for survival. Several reports on PARP inhibitors have been shown to increase tumor sensitivity to DNAdamaging agents [3,4]. It is seen that among PARP, PARP1 and PARP2 has a catalytic activity and is useful when there is DNA breakage [5]. Genetic alteration has a different pathway and is seen when there is high DNA damage and it is also the multistep accumulation in the genomic landscapes which develops into HNSCC due to overexpression of oncogenes, silenced tumor suppressor [6].
Numerous in silico methods have been used to identify potential variations or mutations in the genome, which could act as potential drivers in triggering disease phenotypes. In the study conducted by Aparna et al, it was seen that matrix metalloproteinases and their association in HNSCC since MMP are involved in malignant transformation of a tumor and studied the expression of MMP in HNSCC patients [7]. The PARP inhibitors have been found to be useful in HNSCC treatment and the study conducted by Wurtser showed the association of the PARP gene family with HNSCC [8]. Based on the previous research it can be seen that there was very little study on the PARP gene family and also negligible research done on its association with HNSCC.Our team has extensive knowledge and research experience that has translate into high quality publications [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]26,27,28]. This research aims to decode the genetic alteration in the genes of the PARP gene family and their association with HNSCC.

Data Source
It is a retrospective study and the patient's data has been derived from cBioportal [29] which contains all the patient's details obtained from different cohorts. Information about the genetic alterations throughout the genomic landscape of HNSCC patients are deposited in the repository [30]. The complete profiling of each case in the data set and the demographic details are given in Table 1

Oncoprint Data Analysis
The information obtained includes the allele frequency, variation, protein coding, amino acid, deletion, insertion etc. the putative association involving the variations, genome, novel variation and the disease phenotype [29,31].

gnomAD Data Analysis
This type of investigation involves the large scale sequencing projects and the dataset containing unrelated sequences and public release and compares the variants documented and reported gnomAD repository [29,31].

Gene Expression and Survival Analysis
The expression of the gene presenting with highest frequency of gene alteration in HNSCC was analysed using the UALCAN (http://ualcan.path.uab.edu/cgi-bin/TCGAsurvival) database. Survival curve analysis based on the tumor grade and expression profile was performed to demonstrate the putative role of PARP family of genes with HNSCC. Combined survival effect analysis of gene expression and other clinical parameters such as race, gender, tumor grade, cancer subtypes were assessed using a log-rank test that generated a p value which was further used to indicate statistical significance of survival correlation between groups. The test that was used is log rank test [32].

RESULTS
cBioportal database was the primary source to obtain the information of patients with head and neck squamous cell carcinoma. The Table 1 shows the demographic details of the patients and the age group of patients was between 19-90 years. Table 2   The expression of TIPARP was upregulated in HNSCC individuals in comparison to normal individuals. The p value was found to be 1.82 x 10 -1 which was found to be insignificant (Fig. 2). Upon analysing survival probability based on the Kaplan Meier analysis of TIPARP gene expression classified based on race, it was found that low/medium expression in caucasian individuals showed maximum survival rate when compared to the high expression African-American, the p value was found to be p = 0.045 (Fig. 3a). The Kaplan Meier analysis of TIPARP expression level classified based on gender showed that low/medium expression male have greater survival rate when compared to high expression females and the p value was found to be p = 0.027 (Fig. 3b).

DISCUSSION
Head and neck squamous cell carcinoma is the most common type of cancer which is diagnosed every year [33]. The study is done to understand the alterations that were observed in the PARP gene family and their involvement in HNSCC.
This study provides us with information that is already not available and usage of data sources to easily obtain information about patients and perform basic research to accumulate preliminary data. Genetic alteration is a very time consuming procedure when done manually and expensive too. PARP plays an important role in DNA repair pathways (Vyas et al., 2013), with a special emphasis on base excision repair (BER), which is involved in DNA repair of single strand breaks (SSBs). Since in most of the cancer types BER is impaired eventually leading to inhibition of poly (ADP-ribose) polymerase (PARP). This results in the conversion of SSBs to double strand breaks (DSBs).
The expression of PARP1 is increased in oral squamous cell carcinoma. The expression of PARP was seen at subcellular level. The overexpression in premalignant tumors also paved the way for diagnosed OSCC in the future [34]. According to the study conducted by Maria et al, it was found that the expression of PROX1 gene was found to be expressed as tumor suppressor gene [35]. A study conducted by Gesche indicated that XIAP is involved in the oral squamous cell carcinoma and also the Kaplan Meier curve indicated the XIAP association in unfavourable prognosis of oral squamous cell carcinoma and other curve showing the survival rate that was insignificant [35,36]. The study that was conducted by Yao et al, found that usage of microRNAs in association with OSCC and observed that fibroblast transfers microRNA to oral squamous cell carcinoma cells. Overexpression of miR-34a-5p could lead to tumorigenesis and contribute to the aggressiveness of the cells [37]. Usage of Rab5a was seen in many different types of cancer. A study conducted by Dizhang et al. showed that in 49.3% of OSCC patients Rab5a was overexpressed [37,38]. The gene alteration studies on various genes have also been done for HNSCC and other cancers as well [39,40,41,42,43,44,45].

CONCLUSION
The present study brings in a conclusion that TIPARP could be considered as a prognostic marker in the case of HNSCC. Although the gene expression pattern between normal and tumor tissues do not produce a significant variation, the expression level in different races and genders contributed to significant change in the survival of HNSCC patients. More clinical studies have to be carried out to derive an association between TIPARP and HNSCC.

CONSENT
As per international standard or university standard, patients' written consent has been collected and preserved by the author(s).

ETHICAL APPROVAL
As per international standard or university standard written ethical approval has been collected and preserved by the author(s).