Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children:A five-center case-control study

Objective:Nucleotide excision repair(NER)plays a vital role in maintaining genome stability,and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation.This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.Methods:In this five-center case-control study,we enrolled 966 subjects from East China(193 hepatoblastoma patients and 773 healthy controls).The TaqMan method was used to genotype 19 single nucleotide polymorphisms(SNPs)in NER pathway genes,including ERCC1,XPA,XPC,XPD,XPF,and XPG.Then,multivariate logistic regression analysis was performed,and odds ratios(ORs)and 95%confidence intervals(95%CIs)were utilized to assess the strength of associations.Results:Three SNPs were related to hepatoblastoma risk.XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model(adjusted OR=1.49,95%CI=1.07−2.08,P=0.019;adjusted OR=1.66,95%CI=1.12−2.45,P=0.012,respectively).However,XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model(adjusted OR=0.68,95%CI=0.49−0.95;P=0.024).Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups.Moreover,there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci(eQTLs)and splicing quantitative trait loci(sQTLs)analysis.Conclusions:In summary,NER pathway gene polymorphisms(XPC rs2229090,XPD rs3810366,and XPD rs238406)are significantly associated with hepatoblastoma risk,and further research is required to verify these findings.

Transcription-coupled nucleotide excision repair in mammalian cells： molecular mechanisms and biological effects

The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPⅡo-blocking DNA lesions by transcription-coupled repair （TC-NER）, a specialized subpathway of nucleotide excision repair （NER）. Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects （cancer） of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome （CS）. Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER： CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPⅡo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFⅡS. The emerging picture of TC-NER is complex： repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPⅡo, and requires at least two essential assembly factors （CSA and CSB）, the core NER factors （except for XPC-RAD23B）, and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.

Eukaryotic nucleotide excision repair： from understanding mechanisms to influencing biology

Repair of bulky DNA adducts by the nucleotide excision repair （NER） pathway is one of the more versatile DNA repair pathways for the removal of DNA lesions. There are two subsets of the NER pathway, global genomic-NER （GG- NER） and transcription-coupled NER （TC-NER）, which differ only in the step involving recognition of the DNA lesion. Following recognition of the damage, the sub-pathways then converge for the incision/excision steps and subsequent gap filling and ligation steps. This review will focus on the GGR sub-pathway of NER, while the TCR sub-pathway will be covered in another article in this issue. The ability of the NER pathway to repair a wide array of adducts stems, in part, from the mechanisms involved in the initial recognition step of the damaged DNA and results in NER impacting an equally wide array of human physiological responses and events. In this review, the impact of NER on carcinogenesis, neurological function, sensitivity to environmental factors and sensitivity to cancer therapeutics will be discussed. The knowledge generated in our understanding of the NER pathway over the past 40 years has resulted from advances in the fields of animal model systems, mammalian genetics and in vitro biochemistry, as well as from reconstitution studies and structural analyses of the proteins and enzymes that participate in this pathway. Each of these avenues of research has contributed significantly to our understanding of how the NER pathway works and how alterations in NER activity, both positive and negative, influence human biology.

Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer

BACKGROUND Single nucleotide polymorphisms(SNPs)are universally present in nucleotide excision repair(NER)pathway genes,which could make impacts on colorectal carcinogenesis and prognosis.AIM To explore the association of all tagSNPs in NER pathway genes with colorectal cancer(CRC)risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage.METHODS Genotyping for NER SNPs was performed using kompetitive allele specific PCR.In the discovery stage,39 tagSNPs in eight genes were genotyped in 368 subjects,including 184 CRC cases and 184 individual-matched controls.In the validation stage,13 SNPs in six genes were analyzed in a total of 1712 subjects,including 854 CRC cases and 858 CRC-free controls.RESULTS Two SNPs(XPA rs10817938 and XPC rs2607775)were associated with an increased CRC risk in overall and stratification analyses.Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk.Another two SNPs(ERCC2 rs1052555 and ERCC5 rs2228959)were newly found to be associated with a poor overall survival of CRC patients.CONCLUSION Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population.The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

DNA Repair Gene Polymorphisms in the Nucleotide Excision Repair Pathway and Lung Cancer Risk: A Meta-analysis

Objective： A number of studies have reported the association of ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂ gene polymorphisms with lung cancer risk. However, the results were conflict. To clarify the impact of polymorphisms of ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂, on lung cancer risk, a meta-analysis was performed in this study. Methods： The electronic databases PubMed and Embase were retrieved for studies included in this meta-analysis by ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂, ＂lung＂, ＂cancer/neoplasm/tumor/carcinoma＂, ＂polymorphism＂ （An upper date limit of October, 31, 2009）. A meta-analysis was performed to evaluate the relationship among XPA, XPC and XPD polymorphism and lung cancer risks. Results： A total of 31 publications retrieved from Pubmed and Embase included in this study. XPC A939C CC genotype increased lung cancer risk in total population （recessive genetic model： OR=1.23, 95% CI：1.05-1.44; homozygote comparison： OR=1.21,95%CI：1.02-1.43and CC vs. CA contrast： OR=1.25,95%CI：1.06-1.48）, except in Asians. XPD A751C, 751C allele and CC genotype also increased lung cancer risk in total population and in Caucasians （recessive genetic model： Total population： OR=1.20, 95%CI：1.07-1.35）. No significant correlation was found between XPD A751C and lung cancer risk in Asians and African Americans. XPD G312A AA genotype increased lung cancer risk in total population, in Asians and Caucasians（recessive genetic model： Total population： OR=1.20, 95%CI： 1.06-1.36）. No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk. Conclusion： Our results suggest that the polymorphisms in XPC and XPD involve in lung cancer risks. XPA polymorphisms is less related to lung cancer risk.

Diffusion of nucleotide excision repair protein XPA along DNA by coarse-grained molecular simulations

Protein XPA plays critical roles in nucleotide excision repair pathway.Recent experimental work showed that the functional dynamics of XPA involves the one-dimensional diffusion along DNA to search the damage site.Here,we investigate the involved dynamical process using extensive coarse-grained molecular simulations at various salt concentrations.The results demonstrated strong salt concentration dependence of the diffusion mechanisms.At low salt concentrations,the one-dimensional diffusion with rotational coupling is the dominant mechanism.At high salt concentrations,the diffusion by three-dimensional mechanism becomes more probable.At wide range of salt concentrations,the residues involved in the DNA binding are similar and the one-dimensional diffusion of XPA along DNA displays sub-diffusive feature.This sub-diffusive feature is tentatively attributed to diverse strengths of XPA-DNA interactions.In addition,we showed that both binding to DNA and increasing salt concentration tend to stretch the conformation of the XPA,which increases the exposure extent of the sites for the binding of other repair proteins.

The Timing of Primary Neurosurgical Repair and Wound-Site Infection in Children with Myelomeningocele

Background: The optimal time to closure of a newborn with a myelomeningocele has been the focus of a number of evaluations. The Timing of primary surgery has received significant attention due to its relationship to repair-site infection that can lead to increased morbidity and prolonged hospital stays. It is on this basis that recommendations have utilized 48 - 72 hours post birth as ideal time of closure. This is not only prevent infection at the site but also prevent ventriculitis and neural structure damage. We therefore, hypothesized an increase in wound infection rates in those patients with delays in myelomeningocele repair. Methods: We retrospectively reviewed the records of 103 children with myelomeningocele treated between 2016 and 2023. At discharge the patients were followed up at the post-operative clinic visit 2 weeks later. Children were assigned to 1 of 2 groups, those who underwent primary neurosurgical repair within 72 hours of delivery (Group 1) and those undergoing repair after 72 hours (Group 2). We compared the infection rates. Results: 103 children who underwent myelomeningocele repair were identified, with a median time from birth to treatment of 1 day. Eight (7.8 %) patients were noted to have post-repair surgical site complications. There was no significant difference in rates of infection between Group 1 and Group 2 repair times. The presence of infection was associated increased length of stay when compared to neonates without infection. Conclusion: In children with myelomeningocele, the timing of primary neurosurgical repair appears not to have a significant impact on surgical site infection. Closure of the spinal lesion within the first 72 hours of life may be more favorable for neural damage prevention. These results suggest that early myelomeningocele repair may not impart significantly on the rate of wound-site infection.

Excision repair cross complementation group 1 polymorphisms and lung cancer risk： a meta-analysis

Background Several studies have evaluated the association between polymorphisms of encoding excision repair cross complementation group 1 （ERCC1） enzyme and lung cancer risk in diverse populations but with conflicting results.By pooling the relatively small samples in each study, it is possible to perform a meta-analysis of the evidence by rigorous methods.Methods Embase, Ovid, Medline and Chinese National Knowledge Infrastructure were searched. Additional studies were identified from references in original studies or review articles. Articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using the statistical techniques of meta-analysis.Results We found 3810 cases with lung cancer and 4332 controls from seven eligible studies. T19007C polymorphism showed no significant effect on lung cancer risk （C allele vs. T allele： odds ratio （OR）=0.91, 95% confidence interval （CI）=0.80-1.04; CC vs. TT： OR=0.76, 95% CI=0.56-1.02; CC vs. （CT＋TT）： OR=0.96, 95% CI=-0.84-1.10）. Similarly,there was no significant main effects for T19007C polymorphism on lung cancer risk when stratified analyses by ethnicity （Chinese or Caucasian）. No significant association was found between C8092A polymorphism （3060 patients and 2729 controls） and the risk of lung cancer （A allele vs. C allele： OR=1.03, 95% CI=0.95-1.11; AA vs. CC： OR=1.08, 95% CI=-0.88-1.33; AA vs. （AC＋CC）： OR=1.08, 95% CI=-0.88-1.31）.Conclusion We found little evidence of an association between the T1900C or C8092A polymorphisms of ERCC 1 and the risk of lung cancer in Caucasian or Han Chinese people.

Excision Repair Cross-complementation Group 1 is a Prognostic Biomarker in Patients with Colorectal Cancer Receiving Chemotherapy

Background：Conflicting results about the association between expression level of excision repair cross-complementation group 1 （ERCC1） and clinical outcome in patients with colorectal cancer （CRC） receiving chemotherapy have been reported.Thus,we searched the available articles and performed the meta-analysis to elucidate the prognostic role of ERCC1 expression in patients with CRC.Methods：A thorough literature search using PubMed （Medline）,Embase,Cochrane Library,Web of Science databases,and Chinese Science Citation Database was conducted to obtain the relevant studies.Pooled hazard ratios （HRs） or odds ratios （ORs） with 95% confidence intervals （CIs） were calculated to estimate the results.Results：A total of 11 studies were finally enrolled in this meta-analysis.Compared with patients with lower ERCC1 expression,patients with higher ERCC1 expression tended to have unfavorable overall survival （OS） （HR =2.325,95% CI：1.720-3.143,P 〈 0.001）,progression-free survival （PFS） （HR =1.917,95% CI：1.366-2.691,P 〈 0.001） and poor response to chemotherapy （OR =0.491,95% CI：0.243-0.990,P =0.047）.Subgroup analyses by treatment setting,ethnicity,HR extraction,detection methods,survival analysis,and study design demonstrated that our results were robust.Conclusions：ERCC1 expression may be taken as an effective prognostic factor predicting the response to chemotherapy,OS,and PFS.Further studies with better study design and longer follow-up are warranted in order to gain a deeper understanding of ERCC 1＇s prognostic value.

Association of Base Excision Repair Gene Polymorphisms with the Response to Chemotherapy in Advanced Non-Small Cell Lung Cancer

Background： Base excision repair （BER） plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer （NSCLC） patients treated with platinum-based chemotherapy. Methods： During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G. and PARPI T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P 〈 0.05 was considered statistically significant. Results： The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype （odds ratio [OR]： 5.216, 95% confidence interval [CI]： 1.568-17.352, P = 0.007）, TC genotype （OR： 2.692, 95% C1：1.007-7.198, P = 0.048）, as well as the genotype of TC together with CC （OR： 3.178, 95% CI： 1.229-8.219, P = 0.017） were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGGI C1245G gene polymorphisms and chemosensitivity. Conclusions： The PARPI 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.

Base excision repair accessory factors in senescence avoidance and resistance to treatments

Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.

18F-fluorodeoxyglucose Uptake with Expression of Excision Repair Cross-complementary Group I and Ribonucleotide Reductase Subunit M1 in Non-small Cell Lung Cancer

Fluorodeoxyglucose positron emission tomography/conlputed tomography （FDG PET/CT） is widely applied in non-small cell lung cancer （NSCLC）. The standardized uptake value （SUV）, a semi-quantitative index, plays an essential role in NSCLC tbr diagnosis, staging, and efficacy evaklation. It has been px3posed that the SUV of tumors may correlate with the presence or absence of chemotherapy resistance-associated biomarkers based on studies that have displayed a close correlation between SUV and the expression levels of excision repair cross-complementary Group 1 （ERCC 1 ）1~1 and Tp53-induced glycolysis and apoptosis regulator.121 FDG avidity of NSCLC and ERCC 1 and ribonucleotide reductase subunit M 1 （RRM 1 ） levels have not been as extensively investigated. Based on these findings, we looked tbr correlations among metabolic parameters （SUVm,,. metabolic tumor volume [MTV], and total lesion glycolysis [TLG]） and ERCC1 and RRM1 expression in patients with NSCLC, to investigate whether FDG uptake reflects the presence or absence ofchemoresistance proteins （ERCC1 and RRM 1 ） within tumor cells.

A brief history of the DNA repair field

The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has been studied. This article briefly recounts the early history of this field.

XRCC1 and DNA polymerase β in cellular protection against cytotoxic DNA single-strand breaks

Single-strand breaks （SSBs） can occur in cells either directly, or indirectly following initiation of base excision repair （BER）. SSBs generally have blocked termini lacking the conventional 5＇-phosphate and 3＇-hydroxyl groups and require further processing prior to DNA synthesis and ligation. XRCC1 is devoid of any known enzymatic activity, but it can physically interact with other proteins involved in all stages of the overlapping SSB repair and BER pathways, including those that conduct the rate-limiting end-tailoring, and in many cases can stimulate their enzymatic activities. XRCC1^-/- mouse fibroblasts are most hypersensitive to agents that produce DNA lesions repaired by monofunctional glycosylase-initiated BER and that result in formation of indirect SSBs. A requirement for the deoxyribose phosphate lyase activity of DNA polymerase β （pol β） is specific to this pathway, whereas pol β is implicated in gap-filling during repair of many types of SSBs. Elevated levels of strand breaks, and diminished repair, have been demonstrated in MMS- treated XRCC1^-/-, and to a lesser extent in pol β^-/- cell lines, compared with wild-type cells. Thus a strong correlation is observed between cellular sensitivity to MMS and the ability of cells to repair MMS-induced damage. Exposure of wild-type and polβ^-/- cells to an inhibitor of PARP activity dramatically potentiates MMS-induced cytotoxicity. XRCC1^-/- cells are also sensitized by PARP inhibition demonstrating that PARP-mediated poly（ADP-ribosyl）ation plays a role in modulation of cytotoxicity beyond recruitment of XRCC 1 to sites of DNA damage.

APE1 polymorphisms are associated with colorectal cancer susceptibility in Chinese Hans

AIM: To study the association between four base excision repair gene polymorphisms and colorectal cancer risk in a Chinese population.

ERCC1 polymorphism, expression and clinical outcome of oxaliplatin-based adjuvant chemotherapy in gastric cancer

AIM： TO determine the influence of excision repair cross complementing group 1 （ERCC1） codon 118 polymorphism and mRNA level on the clinical outcome of gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy. METHODS： Eighty-nine gastric cancer patients treated with oxalipatin-based adjuvant chemotherapy were included in this study. ERCC1 codon 118 C/T polymorphism was tested by polymerase chain reaction-ligation detection reaction （PCR-LDR） method in peripheral blood lymphocytes of those patients; and the intratumoral ERCC1 mRNA expression was measured using reverse transcription PCR in 62 patients whose tumor tissue specimens were available. RESULTS： No significant relationship was found between ERCC1 codon 118 polymorphism and ERCC1 mRNA level. The median relapse-free and overall survival period was 20.1 mo and 28.4 too, respectively. The relapse-free and overall survivals in patients with lOW levels of ERCC1 mRNA were significantly longer than those in patients with high levels （P 〈 0.05）, while there was no significant association found between ERCC1 118 genotypes and the disease prognosis. Multivariate analysis also showed that ERCC1 mRNA level was a potential predictor for relapse and survival in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy （P 〈 0.05）. CONCLUSION： ERCC1 codon 118 polymorphisrn has no significant impact on ERCC1 rnRNA expression, and the intraturnoral ERCC1 rnRNA level but not codon 118 polymorphisrn may be a useful predictive parameter for the relapse and survival of gastric cancer patients receiving oxaliplatin-based adjuvant chemotherapy.

Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer

Aim： This study explored the correlation between the expression of excision repair cross-complementation group 1 （ERCC1） and the prognosis of gastric cancer patients. Methods： From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry （IHC） was used to assess the expression of ERCCI in resected samples. The relationship between ERCCI expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time （MST） and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis. Results： ERCC1 expression was positive in 412 patients （68.1%）. There is no significant difference between ERCCl-positive group and ERCCl-negative group in terms of the MST and 5-year survival rate （P=0.455）. The MST and 5-year survival rate have no significant difference （P=0.162） between group with chemotherapy and group with no chemotherapy in patients with ERCCl-positive expression. However, the MST and 5-year survival rate in patients with ERCCl-negative expression benefited more from with chemotherapy （P=0.019）. The ERCCl-positive patients survived longer than those ERCCl-negative patients （P=0.183） in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC 1 expression had no significant relationship with overall survival in patients with stage II or llI gastric cancer （P〉0.05）. Conclusions： ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCCl-negative expression could benefit more from adjuvant chemotherapy.

Features of trinucleotide repeat instability in vivo

Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurode-generative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Studies of bacteria, yeast, mice and man have helped to unravel some features of the mechanism of trinucleotide expansion. Looped DNA structures comprising trinucleotide repeats are processed during replication and/or repair to generate deletions or expansions. Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms. In mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.

MUTYH:Not just polyposis

MUTYH is a base excision repair enzyme,it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor.In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine(8-oxoG)pairs,inducing G:C to T:A transversions.MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production.MUTYH mutations have been linked to MUTYH associated polyposis syndrome(MAP),an autosomal recessive disorder characterized by multiple colorectal adenomas.MAP patients show a greatly increased lifetime risk for gastrointestinal cancers.The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases.This review evaluates the role of MUTYH,focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer.This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis.Furthermore,we describe the association between MUTYH single nucleotide polymorphisms(SNPs)and different cancer and non-cancer diseases.We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets.Considering the multiple functions and interactions of MUTYH protein,its involvement in pathologies based on oxidative stress damage could be hypothesized.Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined,the risk for malignancies of the duodenum,ovary,and bladder is also increased as well as the onset of benign and malignant endocrine tumors.The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma,while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells.Furthermore,some MUTYH SNPs have been associated with lung,hepatocellular and cervical cancer risk.An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis,including neurological and ocular diseases.Finally,it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.

腹壁硬纤维瘤的治疗

探讨自体阔筋膜移植或结合腹直肌前鞘翻转成形加自体阔筋膜移植，在修复硬纤维瘤切除后腹壁大缺损的作用。方法：在大腿外侧面作平行的二个皮肤纵形切口，皮下潜行分离后用切割器切除阔筋膜，并进行0．5厘米重叠的褥式缝合修补缺损。腹直肌前鞘翻转成形可补充修补巨大缺损。结果：11例直径大于3厘米的硬纤维瘤切除后，5例直接缝合腹壁缺损的有3例局部肿瘤复发，而6例用自体阔筋膜修补的无一例复发。结论：扩大腹壁硬纤维瘤的切除是防止局部复发的有效手段，而自体阔筋膜修补腹壁缺损为扩大切除肿瘤提供安全保证。