4例着色于皮病伴发鳞状细胞癌临床病理分析

目的：探讨着色干皮病（xeroderma pigmentosum，XP）伴发鳞状细胞癌（squamous cell careinoma，SCC）的临床病理特点。方法：采用组织病理学方法对1993年～2004年间收集的XP伴发SCC患者进行分析。结果：4例中，男性1例，女性3例。发病年龄最小1岁，最大4岁，平均2．5岁。并发肿瘤年龄，最小7岁，最大18岁，平均12．8岁。其中有明确近亲婚配者2例（50％）。4例患者临床症状及病理结果均典型。结论：XP为常染色体隐性遗传性皮肤病，是一种癌前病变，以早年并发恶性肿瘤为其特征，其中以鳞状细胞癌和基底细胞癌最为常见。与皮肤损害和紫外线损伤程度密切相关。     

Influence of environmental and genetic factors on variation in human response to DNA damaging agents

Exogenous DNA damaging agents must be considered in the context of endogenous reactive species which have the potential to damage DNA. Although a no-effect level for a DNA-damaging compound may not exist, it may be feasible to define a level where reducing exposure to the compound is no longer the most effective way of reducing human risk. Modifying environmental factors which affect human response to damage may be the better strategy. Although a number of rare human syndromes are associated with a reduced ability to repair DNA damage, it is not clear how wide is the range of genetic variation in repair capacity among normal individuals. Studies with DNA repair-deficient human syndromes indicate that processes other than mutation and DNA repair must be involved in the development of cancer, and these processes may represent new sources of variation in human response to genotoxic agents.     

Two children with xeroderma pigmentosum developing two different types of malignancies simultaneously

Patients with xeroderma pigmentosum (XP) are highly sensitive to ultraviolet radiation and prone to develop multiple skin malignancies. We report two children under 6 years of age with XP who each developed two histologically different types of malignancies simultaneously. We conclude that it is of importance to be aware of the possibility of multiple malignancies of different types, even in young children. Accepted: 16 December 1996     

Whole‐exome sequencing and host cell reactivation assay lead to a diagnosis of xeroderma pigmentosum group D with mild ultraviolet radiation sensitivity

A case of xeroderma pigmentosum (XP) group D in a 39‐year‐old Japanese man is reported. The patient had suffered from moderate to severe solar sensitivity and freckle‐like pigmented macules in sun‐exposed areas since 6 years of age, and developed skin malignancies such as squamous cell carcinoma, actinic keratosis, Bowen’s disease and basal cell carcinoma. The minimal erythema dose for ultraviolet (UV) radiation was decreased with a delayed peak reaction. The level of unscheduled DNA synthesis of fibroblasts from the patient was 70% of normal, while they expressed POLH, a gene product responsible for the XP variant. Whole‐exome sequencing indicated that the patient harbored a homozygous mutation of c.1802G>T, p.Arg601Leu in ERCC2. A genetic complementation test was carried out by host cell reactivation assay, which showed that the patient’s fibroblasts recovered only when they were transfected with XPD cDNA, confirming the diagnosis of XP‐D. Arg601Leu mutation in ERCC2 may be related to mild UV radiation sensitivity and moderate skin lesions.     

Xeroderma pigmentosum genes and melanoma risk

Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA–XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility.     

氢醌对K562细胞着色性干皮病基因D甲基化的影响

目的：了解不同剂量苯代谢物氢醌（ HQ）对人白血病细胞株K562细胞着色性干皮病基因D（ XPD）甲基化水平的影响。方法：分别以终浓度为0、15、30和60μmol/L HQ溶液重复处理K562细胞48 h,采用MTT比色法检测K562细胞增殖能力,采用亚硫酸氢盐处理后测序法检测XPD甲基化水平;观察各组细胞存活率及甲基化率。结果：HQ 0、15、30、60μmol/L 处理后,K562细胞存活率分别为（100.00±0.00）％、（85.46±0.60）％、（63.46±7.02）％和（51.20±6.49）％,15μmol/L 组与0μmol/L 组比较,差异无统计学意义（ P ＞0.05）,30μmol/L和60μmol/L组与0μmol/L组比较,差异有统计学意义（P＜0.05）;XPD基因甲基化水平分别依次为1.03％（3/290）、0.34％（1/290）、0.34％（1/290）和0.70％（2/290）,15、30、60μmol/L组与0μmol/L组比较,差异无统计学意义（χ2=1.531,P＞0.05）。结论：HQ对K562细胞生长有明显的抑制作用,但对细胞中XPD基因甲基化水平无影响。     

A meta-analysis of xeroderma pigmentosum gene D Ls751Gln polymorphism and susceptibility to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I²) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC.     

The oxidatively induced DNA lesions 8,5'-cyclo-2'-deoxyadenosine and 8-hydroxy-2'-deoxyadenosine are strongly resistant to acid-induced hydrolysis of the glycosidic bond

The 8,5'-cyclopurine-2'-deoxynucleosides (cPu) are unique oxidatively induced DNA lesions in that they are specifically repaired by NER. In the absence of NER, a possible mechanism for cPu removal is spontaneous glycosidic bond hydrolysis followed by enzymic processing. Such a mechanism could be significant if the glycosidic bond in cPu were substantially destabilized, as shown for other DNA lesions. Therefore, we investigated the stability of the glycosidic bond in a cPu, (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) against acid hydrolysis. For comparison, we also studied 8-hydroxy-2'-deoxyadenosine (8-OH-dA). We found that the glycosidic bond in S-cdA is approximately 40-fold more resistant to glycosidic bond hydrolysis compared to dA. Interestingly, under the same conditions, the glycosidic bond in 8-OH-dA was even more stable than in S-cdA. These studies effectively rule out any mechanism for the removal of S-cdA or 8-OH-dA from DNA that requires spontaneous glycosidic bond hydrolysis, and further support the proposed role of cPu in the neurodegeneration observed in xeroderma pigmentosum patients who lack NER. Of broader significance, since NER does not function in non-transcribed DNA sequences of terminally differentiated cells, including neurons, cPu are expected to accumulate in such sequences even in individuals with normal NER, which could be important in the ageing process.     

着色性干皮病两例ERCC2和ERCC5基因突变分析

【摘要】 目的 分析2例着色性干皮病患儿基因突变。方法 收集2例着色性干皮病患儿临床资料,提取患儿及其父母外周血DNA,采用高通量全外显子组测序方法对患儿进行全外显子组测序,确定致病基因突变位点,再用Sanger测序法对患儿及其父母的DNA进行双向验证,重点关注着色性干皮病相关候选基因XPA、ERCC3、XPC、ERCC2、DDB2、ERCC4、ERCC5及POLH的变异。结果 例1为3岁男孩,面、耳、颈、双手背散发褐色斑点伴色素减退斑2年,步态不稳1年,皮疹夏季加重,以光暴露部位为主。例2为1岁5月龄男孩,面部散发褐色斑点伴少许色素减退斑1年。基因检测显示,例1 ERCC2基因发生复合杂合突变,即父源c.1805G>A（p.Gly602Asp）和母源c.586C>T（p.Arg196Ter）突变,为XPD型。例2 ERCC5基因发生复合杂合突变,即父源c.2533+2T>C和母源c.2453C>T（p.Ala818Val）突变,为XPG型。c.586C>T（p.Arg196Ter）和c.2533+2T>C既往未见报道。嘱防晒、避光,随访2年,患儿皮损较前有所增多,未出现恶性肿瘤。结论 ERCC2基因复合杂合突变可导致XPD型着色性干皮病,表现出皮肤和神经症状;ERCC5基因复合杂合突变可导致XPG型着色性干皮病,表现为轻症表型。早期临床特点结合基因检测有助于着色性干皮病患者的准确诊断及分型。