Lung cancer is the most common cancer in the world due to its high incidence and recurrence. Genetic instability is one of the main factors leading to its occurrence, development and poor prognosis. Decreased xeroderma pigmentosum group C (XPC) expression notably enhances the stem cell properties of lung cancer cells and increases their proliferation and migration. Additionally, patients with lung cancer and low XPC expression had a poor prognosis. The purpose of the present study was to analyze the effect of XPC and IFN-γ on the clinical prognosis of patients with non-small cell lung cancer (NSCLC). Lung adenocarcinoma specimens were collected from a total of 140 patients with NSCLC. Additionally, from these 140 patients, 48 paracarcinoma tissue specimens were also collected, which were later used to construct tissue microarrays. The expression of XPC and IFN-γ in cancer tissues and in paraneoplastic tissues was detected using immunohistochemistry. The prognosis and overall survival of patients were determined through telephone follow-up. The results showed a positive correlation between expression of XPC and IFN-γ in NSCLC. Additionally, high expression of both markers was associated with a favorable prognosis in patients with NSCLC. The aforementioned findings suggest that the expression of XPC and IFN-γ has prognostic value in clinical practice and is expected to become a marker for clinical application.

Advances in genetic technologies have made genetic testing more accessible than ever before. However, depending on national, regional, legal, and health insurance circumstances, testing procedures may still need to be streamlined in real-world clinical practice. In cases of autosomal recessive disease with consanguinity, the mutation locus is necessarily isodisomy because both alleles originate from a common ancestral chromosome. Based on this premise, we implemented integrated genetic diagnostic methods using SNP array screening and long range PCR-based targeted NGS in a Japanese patient with xeroderma pigmentosum (XP) under the limitation of the national health insurance system. SNP array results showed isodisomy only in XPC and ERCC4 loci. NGS, with a minimal set of long-range PCR primers, detected a homozygous frameshift mutation in XPC; NM_004628.5:c.218_219insT p.(Lys73AsnfsTer9), confirmed by Sanger sequencing, leading to a rapid diagnosis of XP group C. This shortcut strategy is applicable to all autosomal recessive diseases caused by consanguineous marriages, especially in scenarios with a moderate number of genes to test, a common occurrence in clinical genetic practice.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent\'s SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5\'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

The aim of the present study was to evaluate the association between xeroderma pigmentosum group C (XPC) polymorphisms and pancreatic cancer (PC) risk. A total of 7 XPC tagging SNPs (tag-SNPs) were selected from the International HapMap Project Databases (rs2228001A/C, rs2470353G/C, rs2228000C/T, rs3731114C/G, rs3729587G/C, rs2607775C/G and rs3731055G/A) and were genotyped in 205 patients with PC and 230 non-cancer control subjects using a SNaPshot assay. The C allelic gene frequency of rs2470353 was higher in patients with PC compared with that in the control group (P=0.003). Compared with the GG gene type, PC risk was increased in subjects with GC and GC+CC gene types (P=0.012 and P=0.006, respectively). PC risk increased 3.505-fold for the subjects who were heavy smokers (tobacco, ≥25 packets/year) with the GC+CC gene type (P=0.008). The G allelic gene frequency of rs2607775 was higher in PC patients compared with that in the control group (P=0.003). Compared with the CC gene type, PC risk increased in subjects with CG and CG+GG gene types (P=0.013 and P=0.005, respectively). Furthermore, PC risk increased 3.950-fold in subjects who were heavy smokers (tobacco, ≥25 packets/year) with the CG+GG gene type (P=0.001). Haplotype analysis further revealed that the CCC haplotype of rs2228000, rs3731114 and rs3729587 increased PC risk (odds ratio, 1.610; 95% confidence interval, 1.035-2.481; P=0.034). The present study revealed that XPC gene polymorphisms could increase the risk of PC in the study population, particularly among heavy smokers.

Xeroderma pigmentosum (XP) is a rare autosomal recessive hereditary disease characterized by hyperphotosensitivity, DNA repair defects and a predisposition to skin cancers. The most frequently occurring type worldwide is the XP group A (XPA). There is a close relationship between the clinical features that ranged from severe to mild form and the mutational site in XPA gene. The aim of this study is to carry out the mutational analysis in Egyptian patients with XP-A. This study was carried out on four unrelated Egyptian XP-A families. Clinical features were examined and direct sequencing of the coding region of XPA gene was performed in patients and their parents. Direct sequencing of the whole coding region of the XPA gene revealed the identification of two homozygous nonsense mutations: (c.553C >T; p.(Gln185)) and (c.331G>T; p.(Glu111)), which create premature, stop codon and a homodeletion (c.374delC: p.Thr125Ilefs 15) that leads to frameshift and premature translation termination. We report the identification of one novel XPA gene mutation and two known mutations in four unrelated Egyptian families with Xermoderma pigmentosum. All explored patients presented severe neurological abnormalities and have mutations located in the DNA binding domain. This report gives insight on the mutation spectrum of XP-A in Egypt. This would provide a valuable tool for early diagnosis of this severe disease.

XPC is one of the key DNA damage recognition proteins in the global genome repair route of the nucleotide excision repair (NER) pathway. Previously, we demonstrated that NER-deficient mouse models Xpa(-/-) and Xpc(-/-) exhibit a divergent spontaneous tumor spectrum and proposed that XPC might be functionally involved in the defense against oxidative DNA damage. Others have mechanistically dissected several functionalities of XPC to oxidative DNA damage sensitivity using in vitro studies. XPC has been linked to regulation of base excision repair (BER) activity, redox homeostasis and recruitment of ATM and ATR to damage sites, thereby possibly regulating cell cycle checkpoints and apoptosis. XPC has additionally been implicated in recognition of bulky (e.g. cyclopurines) and non-bulky DNA damage (8-oxodG). However, the ultimate contribution of the XPC functionality in vivo in the oxidative DNA damage response and subsequent mutagenesis process remains unclear. Our study indicates that Xpc(-/-) mice, in contrary to Xpa(-/-) and wild type mice, have an increased mutational load upon induction of oxidative stress and that mutations arise in a slowly accumulative fashion. The effect of non-functional XPC in vivo upon oxidative stress exposure appears to have implications in mutagenesis, which can contribute to the carcinogenesis process. The levels and rate of mutagenesis upon oxidative stress correlate with previous findings that lung tumors in Xpc(-/-) mice overall arise late in the lifespan and that the incidence of internal tumors in XP-C patients is relatively low in comparison to skin cancer incidence.