Chronological difference in walking impairment among Japanese group A xeroderma pigmentosum (XP-A) patients with various combinations of mutation sites

Almost all Japanese group A xeroderma pigmentosum (XP-A) patients have nonsense and/or nonsense codon-leading mutations in the XP group A (XPA) gene, and develop neurological abnormalities. Walking ability is one of the most important neuromuscular functions of the patients, because it determines their daily activities. We studied the correlation between the various combinations of mutations found by PCR-RFLP in Japanese XP-A patients and their chronological walking impairment. We classified these patients into six groups. Group I: A patient who was homozygous for the mutation at codon 116 in exon 3 (Type 1 mutation) could never walk unaided. Group III: Typical patients who were homozygous for the mutation at intron 3 (Type 2 mutation) could walk unaided till 7–16 years of age. Group V: Patients who were compound heterozygous for Type 2 mutation and for the mutation at codon 228 in exon 6 (Type 3 mutation) began to develop some walking difficulty at 5–13 years of age and became unable to walk at 25–28 years of age. Group VI: A patient who was homozygous for Type 3 mutation could walk unaided without any difficulty till the age of 21. The walking ability of group II and IV patients is not known yet.     

XPC Lys939Gln(A/C)基因多态性与胃癌易感性的Meta分析

目的 探讨着色性干皮病C(XPC)基因939氨基酸位点Lys/Gln多态性与胃癌易感性的关系.方法 计算机检索PubMed、Cochrane Library、Elsevier、Springer-Verlag、中国期刊全文数据库(CNKI)、中国生物医学文献数据库(CBM)、维普中文科技期刊数据库(VIP)及万方医药期刊全文数据库,检索时间为建库至2015年9月,收集有关XPC Lys939Gln(A/C)基因多态性与胃癌易感性的病例对照研究.由两名评价员按照纳入、排除标准独立筛选文献,进行质量评价.采用STATA 12.0软件进行Meta分析,计算比值比(OR)及95％可信区间(CI)进行关联强度评价,并进行亚组、敏感性分析和发表偏倚的检测.结果 本研究共纳入7个病例对照研究,包括2 336例胃癌患者和3 502例健康对照.Meta分析结果显示,与等位基因A比较,等位基因C可增加胃癌的风险(OR=1.09,95％ CI为1.01 ～1.18,Z=2.12,P=0.034);与基因型AA相比,纯合子模型(CC)和显性模型(CC+ AC)基因型可增加罹患胃癌风险(CC vs.AA:OR=1.19,95％ CI为1.00 ～1.42,Z=2.00,P=0.046;CC+ AC vs.AA:OR=1.12,95％ CI为1.00～1.25,Z=2.03,P=0.042).对研究人群和对照来源进行亚组分析结果显示,在亚洲人群和社区来源的对照中,XPC Lys939Gln(A/C)基因多态性与胃癌风险有关.亚洲人群中,C vs.A:OR=1.10,95％ CI为1.01 ～ 1.20,Z=2.28,P=0.023;CC vs.AA:OR =1.21,95％ CI为1.01 ～1.46,Z =2.02,P=0.043;CC+AC vs.AA:OR=1.13,95％ CI为1.01 ～ 1.27,Z=2.11,P=0.035.社区来源的对照组中,C vs.A:OR =1.11,95％ CI为1.01 ～1.21,Z=2.25,P=0.024;CC vs.AA:OR =1.23,95％ CI为1.02 ～ 1.50,Z=2.12,P=0.034.结论 XPC Lys939Gln(A/C)基因多态性可能与罹患胃癌的易感性有关.等位基因C、基因型CC和CC +AC可能增加胃癌的风险.     

Neurochemistry evaluated by MR spectroscopy in a patient with xeroderma pigmentosum group A

MRI of a female patient with xeroderma pigmentosum group A (XP-A) showed progressive cerebral atrophy, but no disease-specific lesion. MR spectroscopy with short TE sequences in the bilateral white matter revealed decreased N-acetyl aspartate (neuro-axonal marker) and increased myo-inositol (astroglial marker) with a normal concentration of choline (membrane marker), which are compatible with the neuropathology of XP-A, consisting of a reduced number of neurons, and fibrillary astrogliosis with preservation of myelinated fibers. MR spectroscopy reveals neurochemical derangement in XP-A, which cannot be observed on conventional MRI, and will be useful to monitor the neurochemical derangements of XP-A.     

Low-dose levodopa is effective for laryngeal dystonia in xeroderma pigmentosum group A

Xeroderma pigmentosum (XP), a genetic disorder in DNA nucleotide excision repair, is characterized by skin hypersensitivity to sunlight and progressive neurological impairment. Laryngeal dystonia and vocal cord paralysis are complications that can arise in older XP group A (XPA) patients. We report three patients with XPA being administered low-dose levodopa (0.3–1.5 mg/kg/day) for laryngeal dystonia. Patients were aged from 13 to 18 years, exhibited paroxysmal choking and inspiratory stridor, and were diagnosed with laryngeal dystonia. Two XPA patients responded to low-dose levodopa, and paroxysmal choking and involuntary movements resolved, although one of the two patients showed incomplete resolution due to suspected vocal cord paralysis. The other patient was unable to tolerate the medication because of a transient decrease of muscle tone in the extremities. We previously reported a decreased immunostaining of dopaminergic (DA) terminals in the basal ganglia of XPA patients, which may be involved in laryngeal dystonia. Low-dose levodopa has been reported to alleviate DA receptor supersensitivity in tic patients, while laryngeal dystonia occurs in patients with tardive dyskinesia caused by DA receptor supersensitivity. Thus, low-dose levodopa may improve laryngeal dystonia by alleviating DA receptor supersensitivity in XPA patients. We recommend that low-dose levodopa be used for treatment of paroxysmal respiratory disturbances and/or involuntary movements in XPA patients.     

XPC Lys939Gln polymorphism,smoking and risk of sporadic colorectal cancer among Malaysians

AIM: To investigate the risk association of xeroderma pigmentosum group C (XPC ) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition. METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI. RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032). CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians.     

Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non–Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery

ObjectiveThe aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non–small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery.Materials and MethodsA total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (−37 C/A) polymorphisms with response and survival.ResultsThe median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03).ConclusionThe XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients.     

Oncolytic Vaccinia virus safely and effectively treats skin tumors in mouse models of xeroderma pigmentosum

Xeroderma pigmentosum (XP) is an orphan autosomal recessive disorder of DNA repair. When exposed to genotoxic stress, XP patients have reduced capacity to remove bulky adducts by nucleotide excision repair and are thus greatly predisposed to cancer. Unfortunately, given the nature of their underlying genetic defect, tumor‐bearing XP patients cannot be treated with conventional DNA damaging therapies. Engineered strains of the poxvirus Vaccinia have been shown to cure cancer in numerous preclinical models, and based on promising Phase I/II clinical trials have recently been approved for late phase evaluation in humans. As poxviruses are nongenotoxic, we investigated whether clinical‐candidate strains of Vaccinia can safely and effectively treat cancers arising from XP. In vitro, Vaccinia virus was highly cytotoxic against tumor‐derived cells from XP patients, on average 10‐ to 100‐fold more so than on nontumor derived control cells from similar patients. In vivo, local or systemic administration of Vaccinia virus led to durable tumor resolution in both xenograft and genetic models of XP. Importantly, Vaccinia virus was well tolerated in the genetic models, which are each null for a critical component of the DNA repair process. Taken together, our data suggest that oncolytic Vaccinia virus may be a safe and effective therapy for cancers arising from XP, and raise the possibility of similar therapeutic potential against tumors that arise in patients with other DNA repair disorders.