The role of XPC exon 15 gene in cancer development of the head and neck region

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ABSTRACT

Genetic variation in DNA repair gene can may be linked with altered DNA repair capacities (DRC). Decrease in DRC is due to inherited polymorphism and it can increase the susceptibility to cancer. The two major repair pathways are Base excision and Nucleotide excision. Genes of the Base excision repair (BER) pathway has been studied in association with various human cancers. In my term paper I have given a brief and precise description about the role of XPC exon 15 gene in cancer development of the head and neck region. The xeroderma pigmentosum complementation group C (XPC) protein plays a very important role in the nucleotide excision repair (NER) pathway[1].Deficiency in the XPC has been implicated in tumourigenesis.XPC DNA repair gene mutations results in the cancer-prone disorder like xeroderma pigmentosum. The XPC gene spans 33 kb and it has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Head and neck cancer is becoming very common now a days as today’s generation has a different type of lifestyles in which alcohol consumption, smoking ,sexually transmitted infections etc is very common and is considered as fashion. In my term paper I have inserted some of the images to make my view more clearly about the topic.

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INTRODUCTION

CANCER also known as malignantneoplasia, is a group of diseases including unregulated cell growth. In cancer cells divide and grow uncontrollably, forming malignant tumors, which may also affect the nearby parts of the body. Cancer may also spread to more distant parts of our body through the lymphatic system or through the bloodstream. There are about 200 different known cancers that affect humans[2]. Cancer is mainly treated with chemotherapy, radiation therapy and surgery. The chances of surviving the diseaseonly depends on the type and location of the cancer and the extent of disease at the start of the treatment. As cancer can affect people of all the different ages, and few types of cancer are more common in children, the risk of developing cancer generally increases with the age. In 2007, cancer caused about 13% of all human deaths worldwide.

Cancer prevention is defined as active measures to decrease the risk of cancer. Greater than 30% of the cancer deaths could be prevented by avoiding risk factors involvingtobacco,obesity, an insufficient diet, physical inactivity, alcohol, sexually transmitted infections.Not all environmental causes are although controllable, such as naturally occurring background radiation, and other cases of cancer are caused by hereditary genetic disorders, and hence it is not possible to prevent all cases of cancer.

HEAD AND NECK CANCER

Head and neck cancer refers to a group of biologically similar cancers that start in the lip, oral cavity, nasal cavity,paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas (HNSCC), Squamous cell carcinoma (SCC) is the most frequent malignant tumor ofthe head and neck region.Head and neck cancers often spread to the lymph nodes of the neck,this is often the first and sometimes the only sign of the disease at the time of diagnosis. Head and neck cancer is associated strongly with certain environmental and lifestyle risk factors, including tobacco smoking.There are 0.5 million new cases per year worldwide. Two thirds occurs in industrialized nations. HNSCC usually develops in males in the 6th and 7th decade. The five-year survival rate of patients with HNSCC is nearly about 40-50%[3][4].

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Figure 1

Showing the parts in the head and neck region which gets affected by cancer

REVIEW OF LITERATURE

Head and neck squamous cell carcinoma (HNSCC) comprise nearly about 6% of all malignant neoplasm. Overall survival is very low especially in the developing countries and the major risk factors of HNSCC became the smoking or the alcohol consumption[5]. Although the functional significance of XPC polymorphism has not yet been fully developed, due to smoking and alcohol consumption but it may increase the risk of head and neck cancer occurrence.

The xeroderma pigmentosum complementation group C (XPC) protein has a important role in nucleotide excision repair (NER) pathway. The functional DNA-binding domains of XPC interact with the HR23B to form a complex which recognizes and binds to the sites of the DNA damage. More than 100 polymorphic variables in theXPC gene have been identified and the two most common polymorphisms are Lys939Gln (XPC A33512C, rs2228001) and poly (AT) insertion/deletion polymorphism (XPC PAT I/D) in intron 9 which has been associated with risks of many of the human malignancies, involving cancers of lung, bladder, oesophagus, oral cavity, and head and neck[6].A potential rationale behind these gene-cancer risk is that these genetic variables may result in the alterations in phenotypes like of the DNA repair capacity (DRC).

Genome integrity is maintained generally by an internal network of DNA repair proteins[7][8]. Organisms have developed many DNA repair pathways and DNA damage checkpoints. Although each pathway is addressed individually, the cross link exists between repair pathways, and there are instances in which the DNA-repair protein is involved in more than one pathway. Single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with differences in the repair efficiency of DNA damage and it may influence an individual's risk of cancer. By establishing this connection, it has been a challenge due to the complexity of interactions that affect the repair pathways .Increasing environmental exposures, subtle modification in DNA repair efficiency, and the cancer risk .To date, there are ample of evidences indicating that HNC is a complex multifactorial disorder involving genetic factors, tobacco smoke, alcohol consuming, and environmental factors and some low-penetrant genes have been identified as the potential HNC susceptibility genes .Among them, an important one is xeroderma pigmentosum group D(XPD) gene, which is located on chromosome 19q13.3. XPD gene, also known as excision repair cross-complementing group 2 (ERCC2) gene, encodes XPD protein, one ATP-dependent helicase within the multi subunit transcription repair factor complex,TFIIH, participates in DNA unwinding during the nucleotide excision repair (NER) pathway and plays a vital role in the recognition and the repairment of structurally unrelated DNA lesions including bulky adducts and thymidine dimmers .Dysregulation of DNA repair proteins in NER pathways may be involved in pathogenesis of cancers .

Figure 2 Figure 3

Showing the throat cancer in various ways in the head and neck region.

ROLE OF XPC EXON 15 GENE

XPC gene encodes a component of the nucleotide excision repair (NER) pathway. There are several multiple components included in the NER pathway, including Xeroderma pigmentosum A-G and V, Cockayne syndrome (CS) A and B, and etc. XPC plays a key role in early steps of the global genome NER, generally in the damage recognition, open complex formation, and in repair protein complex formation. Mutations in XPC or other NER components result in Xeroderma pigmentosum, rare autosomal recessive disorder characterized by the increased sensitivity to sunlight with the development of carcinomas at an early age. Also spliced transcript variants has been found for this gene.

This gene is involved in the global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. It has a preference to bind DNA containing a short single-stranded segment but not to damagedoligonucleotides.

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The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and it togetherwith other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision complex. The XPC complex generally recognizes the wide spectrum of damaged DNA characterized by distortion of the DNA helix such as single-stranded loops. The orientation of theXPC complex binding appears to be crucial for inducing the productive NER. XPC complex is proposed to recognize and to interact with the unpaired bases on the undamaged DNA strand which is followed by the recruitment of the TFIIH complexand subsequent scanning for opposite strand in a 5'-to-3' direction by the NER machinery to-3' direction by the NER machinery.

DISCUSSION

Genome integrity is maintained by an internal network of DNA repair proteins.Organisms have developed some DNA-repair pathways and DNA-damage checkpoints. Defects in this complex machinery are associated generally with genotoxic susceptibility to cancer. XPC participates in DNA single strand break and in the base excision repair to protect genome stability in the mammalian cells. One of the most common polymorphisms of XPC the Arg399Gln is located in the BRCT1 domain, responsible for interacting with the other repair components of BER. It is important to implicate DNA-repair process with DNA-damage checkpoints and cell survival, to evaluate the role of DNA repair at both the cellular and the organismic levels.

Qiao et al studied XPC genotype-related DRC using a host-cell re-activation assay and it was found that the healthy subjects with the homozygous variant genotype of the PAT polymorphism exhibited the lower DRC as compared to the wild-type carriers (D/D), and it has been declared as a useful biomarker to identify the individuals at increased risk for developing cancer[9]. Blankenburg et al reported that XPCPAT and exon 15 polymorphisms are associated with the risk of melanoma[10].

The higher risk of head and neck cancer occurrence was associated with the combined Arg194Trp-Arg399Arg genotype but there was no altered risk associated with others haplotypes.

The XPC gene polymorphisms has been studied in the association with various human cancers mostly head and neck carcinomas. Major studies of head and neck cancer has been focused on polymorphisms of genes encoding the enzymes of xenobiotic metabolism and the DNA repair . Despite of large number of studies, in good-characterized populations, results from HNSCC patients are still very confusing. There was a marginally mark risk of HNSCC observed in variants of XPC genotype with Trp194 allele in population of Thiland[11], however smokers carrying the risk genotype of XRCC1 with dominant Gln399 allele were represented in head and neck cancer populations from eastern region of India. Recently, combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with HNSCC cancer in Taiwan has been explored. Except for XRCC2, none of the other SNPs was found to contribute to cancer risk. Finally, no association was found for either analyzed SNPs .

Figure 4

Graph showing cumulative survival growth after the diagnosis

Figure 5

CONCLUSION

Head and neck cancer patients have variable prognoses even within the similar clinical stage and while getting similar treatments. The number of studies of the genetic polymorphisms as the prognostic factors of HNSCC outcomes is expanding as the time passes. Candidate polymorphisms have been evaluated in the DNA repair, cell cycle, xenobiotic metabolism, and growth factor pathways growing.

Many different preventions and therapies are used in the treatment of head and neck cancer. The type of the treatment and therapies used generally depend on the location of the cancer in the head and neck area and also on the extent to which the cancer has spread during diagnosis. Patients’ also have the authority to decide whether they wish to go for a particular treatment or not. For example, some patients may decide to not to undergo radiation therapy which has serious side effects if it means they will be extending their lives by only a few months. Others may feel that the extra time is worth it and they wish to go for the treatments. Finally I conclude that HNSCC cancer risk may have an huge effect on the identification of a high-risk population worldwide.

REFERENCES

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2. Winn D (1992). "Smokeless tobacco and aerodigestive tract cancers: recent research directions". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 320: 39–46. doi:10.1007/978-1-4615-3468-6_6. ISBN 978-0-306-44244-5. PMID 1442283.

3.http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Headneck/Aboutheadneckcancers/Typesofheadneckcancer.aspx

4.NCI fact sheet on head and neck cancer

5. Genet Mol Res 2008, 1;7(3):574-582. Publisher

6. Zhang D, Chen C, Fu X, Gu S, Mao Y, Xie Y, et al. A meta-analysis of DNA repair gene XPC polymorphisms and cancer risk. J Hum Genet. 2008;53:18–33.

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Science 1999, 286:1897-1905. OpenURL

8.Hoeijmakers JH: Genome maintenance mechanisms for preventing cancer.

9. Qiao Y, Spitz MR, Shen H, Guo Z, Shete S, Hedayati M, et al. Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. Carcinogenesis. 2002;23:295–9

10. . Blankenburg S, König IR, Moessner R, Laspe P, Thoms KM, Krueger U, et al. Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case-control study. Carcinogenesis. 2005;26:1085–90 .

11. Kietthubthew S, Sriplung H, Au WW, Ishida T: Polymorphism in DNA repair genes and oral squamous cell carcinoma in Thailand.