XPG is Predictive Gene of Clinical Outcome in Advanced Nonsmall-cell Lung Cancer with Platinum Drug Therapy

Polymorphisms in XPG are considered to contribute to the clinical outcome of patients receiving platinumdrug chemotherapy. We aimed to investigate the role of five potential SNPs of XPG gene on the responseto platinum-based chemotherapy in advanced Chinese NSCLC patients. A total of 451 patients with newlydiagnosed and histopathologically confirmed primary NSCLC were consecutively collected. XPG rs2296147,rs4150261, rs17655, rs1047768 and rs2094258 were genotyped by the Taqman real-time polymerase chain reaction(PCR). In our study, we found patients carrying rs1057768 TT genotype had a significantly lower treatmentresponse when compared with the CC genotype (OR=0.38, 95% CI=0.18-0.78). Patients carrying rs1047768 TTgenotype showed a significantly short median PFS (11.2 months) and OS (13.6 months) than CC genotype, andthe hazard ratios (HR) for PFS and OS were 2.06 (1.01-4.50) and 2.29 (1.21-2.49), respectively. Moreover, wefound a significant decreased risk of death from NSCLC among patients carrying the rs2296147 TT genotypewhen compared with the CC genotype, the HR (95% CI) for OS being 0.50 (0.27-0.95). In conclusion, our studyfound that polymorphisms in rs1047768 C/T and rs2296147 C/T are associated with response to platinum-basedchemotherapy in advanced NSCLC, and XPG polymorphisms could be predictive of prognosis.     

Xeroderma Pigmentosum Complementation Group F Polymorphisms Influence Risk of Glioma

We conducted an exploratory investigation of whether variation in six common SNPs of xerodermapigmentosum complementation group F (XPF) is associated with risk of glioma in a Chinese population. Sixsingle nucleotide polymorphisms (SNPs) were genotyped in 207 glioma cases and 236 cancer-free controls by a384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). The rs1800067G and rs2276466 G allele frequencies were significantly higher in the glioma group than controls. Individualswith the rs1800067 GG genotype were at greater risk of glioma when compared with the A/A genotype in thecodominant model, with an OR (95% CI) of 2.63 (1.04-7.25). The rs2276466 polymorphism was significantlyassociated with moderate increased risk of glioma in codominant and dominant models, with ORs (95% CI) of1.90 (1.05-3.44) and 1.55 (1.07-2.47), respectively. The combination genotype of rs1800067 G and rs2276466 Galleles was associated with a reduced risk of glioma (OR=0.44, 95% CI=0.19-0.98). These findings indicate thatgenetic variants of the XPF gene have critical functions in the development of glioma.     

Xeroderma pigmentosum group C in a French Caucasian patient with multiple melanoma and unusual long-term survival

We report the case of an 83-year-old French woman with multiple melanomas showing a severe DNA repair deficiency, corrected after transfection by XPC cDNA. Two biallelic mutations in the XPC gene are reported: an inactivating frameshift mutation in exon 15 (c.2544delG, p.W848X) and a missense mutation in exon 11 (c.2108 C>T, P703L). We demonstrate that these new mutations are involved in the DNA repair deficiency and confirm the diagnosis of xeroderma pigmentosum from complementation group C (XP-C). We speculate that the coexistence of a MC1R variant may be involved in the phenotype of multiple melanomas and that the unusual long-term survival may be related to a lower ultraviolet radiation exposure and to a regular clinical follow-up. This patient appears to be the first French Caucasian XP-C case and one of the oldest living patients with XP reported worldwide.     

着色性干皮病基因D多态性与慢性苯中毒发病风险

目的探讨XPD的基因多态性与个体慢性苯中毒发病风险的关系。方法采用病例-对照设计,以152名苯中毒工人为病例组,152名接触苯而没有中毒表现的工人为对照组。应用聚合酶链反应-限制性片断长度多态性分析技术(PCR-RFLP)检测XPDc.199、XPDc.201、XPDc.312和XPDc.751位点的多态性。结果未检测到XPDc.199、XPDc.201位点的突变基因型;与携带XPDc.312Asp/Asp基因型的个体相比,调整性别、工龄和暴露强度后,携带XPDc.312Asp/Asn+Asn/Asn基因型的个体的慢性苯中毒的发病风险降低(ORadj=0.59,95%CI=0.35～0.99,χ2=3.99,P0.05),在低强度苯接触组,该突变基因型的保护作用更为显著(ORadj=0.15,95%CI=0.04～0.51,χ2=8.93,P0.01)。结论XPDAsp312Asn基因多态可能与个体慢性苯中毒发病风险的改变有关。     

The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells

Targeting synthetic lethality in DNA repair pathways has become a promising anti-cancer strategy. However little is known about such interactions with regard to the nucleotide excision repair (NER) pathway. Therefore, cell lines with a defect in the NER genes ERCC6 or XPC and their normal counterparts were screened with 53 chemically defined phytochemicals isolated from plants used in traditional Chinese medicine for differential cytotoxic effects. The screening revealed 12 drugs that killed NER-deficient cells more efficiently than proficient cells. Five drugs were further analyzed for IC₅₀ values, effects on cell cycle distribution, and induction of DNA damage. Ascaridol was the most effective compound with a difference of > 1000-fold in resistance between normal and NER-deficient cells (IC₅₀ values for cells with deficiency in ERCC6: 0.15 μM, XPC: 0.18 μM, and normal cells: > 180 μM). NER-deficiency combined with ascaridol treatment led to G2/M-phase arrest, an increased percentage of subG1 cells, and a substantially higher DNA damage induction. These results were confirmed in a second set of NER-deficient and -proficient cell lines with isogenic background. Finally, ascaridol was characterized for its ability to generate oxidative DNA damage. The drug led to a dose-dependent increase in intracellular levels of reactive oxygen species at cytotoxic concentrations, but only NER-deficient cells showed a strongly induced amount of 8-oxodG sites. In summary, ascaridol is a cytotoxic and DNA-damaging compound which generates intracellular reactive oxidative intermediates and which selectively affects NER-deficient cells. This could provide a new therapeutic option to treat cancer cells with mutations in NER genes.     

人剪切修复基因XPD对人肝癌SMMC-7721细胞中Ets-1和Cdk6基因的调控作用

目的:观察野生型人剪切修复基因XPD转染入人肝癌细胞SMMC-7721后,细胞内Ets-1和Cdk6基因的表达变化及对SMMC-7721肝癌细胞增殖的影响。方法:将人工合成的pEGFP-N2-XPD重组质粒通过Lipofectamine 2000TM转染SMMC-7721细胞。设重组质粒转染细胞SMMC-7721-pEGFP-N2-XPD(XPD)组、空载质粒转染细胞SMMC-7721-pEGFP-N2(N2)组、脂质体组、无转染空白对照组。分别用逆转录-聚合酶链反应(RT-PCR)和蛋白印迹法(Western blot)检测细胞中XPD、Ets-1、Cdk6基因mRNA和蛋白质的表达量,并用流式细胞仪检测细胞周期变化,四甲基偶氮唑盐微量酶反应比色法(MTT)检测各组细胞的增殖活力。结果:XPD组中的XPD的mRNA和蛋白质表达较其他3组明显增高(P<0.001),而Ets-1、Cdk6 mRNA和蛋白质表达较其他3组明显减少(P<0.001)。转染pEGFP-N2-XPD重组质粒后细胞停滞在G1期,难于进入S期。转染了野生型XPD的SMMC-7721细胞增殖能力减弱。结论:XPD基因可能通过抑制Ets-1、Cdk6基因的表达影响肝癌细胞的生长。     

着色性干皮病继发眼部恶性肿瘤的临床特点及其手术治疗

目的 探讨着色性干皮病继发眼部恶性肿瘤的临床、病理、手术治疗方法及预后.方法 回顾性病例研究.1999-2008年间收治的着色性干皮病继发眼部恶性肿瘤患者5例,平均年龄(44.6±4.9)岁,采用手术治疗,并对这些患者的手术方式、肿瘤病理学检查和免疫组化检查结果进行分析.结果 病理学及免疫组化检查显示结膜角膜黑色素瘤1例,基底细胞癌3例,恶性神经鞘瘤1例.5例患者随访3～6年、2例术后再发肿瘤,l例为毛发上皮瘤,1例为鳞状细胞癌.结论 继发于着色性干皮病的眼部肿瘤多为恶性,有复发倾向,虽然眼部并发的恶性肿瘤发病进展快、预后差,但及时的手术干预,可以明显改善预后.术中可根据冰冻病理检查,对已发生癌变者行大面积切除、植皮,手术治疗范围要足够大.     

Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells

DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, such drugs induced DNA damages as well as DNA repair are important in mediating drug resistance to cancer treatments. To evaluate changes in DNA repair proteins that occur in DNA damage agent treatment, we challenged human A549 lung adenocarcinoma cells with cisplatin. hHR23/RAD23, an accessory protein involved in nucleotide-excision repair (NER) at an early lesion-recognition step, was upregulated by cisplatin in a dose- and time-dependent manner. Upregulation of hHR23 expression by low-dose cisplatin was accompanied by an increase in p53, p21, and XPC protein levels. Importantly, knockdown of hHR23B by RNA interference decreased DNA repair activity, cell survival, and induction of p53 and XPC following treatment with cisplatin. Conversely, overexpression of hHR23B enhanced repair activity towards cisplatin-damaged DNA. Inhibition of MEK/ERK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways attenuated cisplatin-induced hHR23 expression, indicating that these pathways are involved in the process. The increase in hHR23 protein expression mediated by MEK/ERK signaling was due to increased translational efficiency resulting from phosphorylation/activation of the translation-initiating factor eIF-4B. Taken together, these results suggest that cisplatin-induced increases in hHR23 levels are regulated by proliferative signaling pathways and important for DNA repair.     

Re-irradiation of metastatic disease in the neck from xeroderma pigmentosum

Background

Xeroderma pigmentosum, an autosomal recessive disease that occurs with a frequency of 1:250,000, is caused by a genetic defect in nucleotide excision repair enzymes. Mutation of these enzymes leads to the development of multiple basal cell and squamous cell carcinomas.

Objectives

We present a case of xeroderma pigmentosum in a patient with cervical and intraparotid metastatic disease from recurrent cutaneous squamous cell carcinomas of the face and scalp, treated with neck dissection and re-irradiation. With the illustrative case report, we include a literature review of diagnosis, prognostic factors, and treatment, with emphasis on surgical and radiation treatment of cervical metastatic disease from recurrent skin carcinomas.

Case Presentation

A xeroderma pigmentosum patient presented to our clinic with a 2-cm right submental and 1-cm right infra-auricular mass after resection of multiple squamous cell carcinomas of the scalp and face, and external-beam radiation therapy to the right face and neck. Fine-needle aspiration biopsy of the submental mass revealed poorly differentiated squamous cell carcinoma. The patient was brought to the operating room for a right modified radical neck dissection and excision of the right submental and intraparotid mass. Surgical pathology revealed 3 level ia and supraclavicular lymph nodes that were positive for metastatic squamous cell carcinoma. Re-irradiation to the entire right hemi-neck and left submandibular nodal region was performed using opposed oblique portals for the upper neck and a low anterior en face hemi-neck portal. The left parotid region was also included in the re-irradiation volume. Treatment was completed without delayed complications or recurrences to date.

Conclusions

To our knowledge, this is the first case report in the literature of a patient with xeroderma pigmentosum who subsequently developed metastatic disease from recurrent cutaneous squamous cell carcinoma. Because of the rarity of xeroderma pigmentosum, this case report is also the first to describe re-irradiation to treat cervical and intraparotid metastatic disease in a xeroderma pigmentosum patient.     

Xeroderma pigmentosum clinical practice guidelines

Xeroderma pigmentosum (XP) is a genetic photosensitive disorder in which patients are highly susceptibe to skin cancers on the sun‐exposed body sites. In Japan, more than half of patients (30% worldwide) with XP show complications of idiopathic progressive, intractable neurological symptoms with poor prognoses. Therefore, this disease does not merely present with dermatological symptoms, such as photosensitivity, pigmentary change and skin cancers, but is “an intractable neurological and dermatological disease”. For this reason, in March 2007, the Japanese Ministry of Health, Labor and Welfare added XP to the neurocutaneous syndromes that are subject to government research initiatives for overcoming intractable diseases. XP is one of the extremely serious photosensitive disorders in which patients easily develop multiple skin cancers if they are not completely protected from ultraviolet radiation. XP patients thus need to be strictly shielded from sunlight throughout their lives, and they often experience idiopathic neurodegenerative complications that markedly reduce the quality of life for both the patients and their families. Hospitals in Japan often see cases of XP as severely photosensitive in children, and as advanced pigmentary disorders of the sun‐exposed area with multiple skin cancers in adults (aged in their 20–40s), making XP an important disease to differentiate in everyday clinical practice. It was thus decided that there was a strong need for clinical practice guidelines dedicated to XP. This process led to the creation of new clinical practice guidelines for XP.