Value of DNA Repair Gene and TP53 Co-mutation in Predicting Effect of Immunotherapy on Lung Adenocarcinoma / 肿瘤防治研究

Objective To explore the value of DNA repair genes (DRGs) in predicting the effect of immunotherapy on lung adenocarcinoma based on second-generation sequencing technology. Methods The data of lung adenocarcinoma were obtained from the Cancer Genome Atlas, including the testing cohort and the validation cohort. In the testing set, according to the cut-off value of tumor mutational burden (TMB) score 15, the patients with lung adenocarcinoma were divided into two groups: the low TMB score group and the high TMB score group. And we analyzed the relation between TMB and the overall survival of lung adenocarcinoma patients. KRAS and TP53 co-mutation was used as the standard control, the differences in the mutation count and TMB score between only DRGs mutation group and KRAS or TP53 co-mutation groups were analyzed. In the validation cohort, the differences between DRGs and KRAS or TP53 co-mutation groups in TMB, tumor neoantigen burden and PFS were analyzed. Results The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with only TP53 or DRGs mutation (P < 0.05). The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with KRAS/TP53 co-mutation (P=0.037, P=0.044). In validation cohort analysis, the TP53/DRGs co-mutation patients also showed higher tumor neoantigens, higher TMB and longer progression-free survival than those patients with only TP53 or DRGs or KRAS/TP53 co-mutation groups. Conclusion TP53/DRGs co-mutation may be served as a pair of potential biomarkers for predicting the efficacy of immunotherapy on lung adenocarcinoma.

Associação da imunoexpressão das proteínas XRCC1, TFIIH E XPF com características clinicopatológicas e sobrevida em carcinoma epidermoide de língua oral / Association of immunoexpression of XRCC1, TFIIH and XPF proteins with clinicopathological characteristics and survival in oral tongue squamous cell carcinoma

Sistemas de reparo do DNA, genes e proteínas, são essenciais para manutenção da integridade do genoma, evitando graves doenças como o câncer. Desrregulação na expressão destas proteínas vem sendo associado tanto ao risco do desenvolvimento, como na evolução de variados cânceres humanos com destaque para o carcinoma epidermoide oral. O objetivo deste trabalho foi analisar a imunoexpressão das proteínas de reparo do DNA, XRCC1, THIIF e XPF em carcinoma epidermoide de língua oral (CELO) e investigar associação com parâmetros clínicos, histopatológicos, de desfecho e sobrevida em cinco anos. Setenta e quatro casos de CELO foram analisados por meio da técnica da imuno-histoquímica de forma semiquantitativa. Observou-se alta expressão das proteínas pesquisadas nas células parenquimatosas, identificando associação significativa da elevada expressão de XRCC1 com melhor estadiamento clínico (p=0,02). A regressão de Cox revelou tamanho do tumor (p<0,01), comprometimento linfonodal (p=0,04), estágio do tumor (p=0,02) e profundidade de invasão >4mm (p=0,05) como fatores prognósticos para CELO. Os resultados deste experimento sugerem que as proteínas XRCC1, TFIIH e XPF participam do processo de tumorigênese, entretanto a imunoexpressão das mesmas não pode ser utilizada como indicador independente de prognóstico para CELO (AU).

DNA repair systems, genes and proteins are essential for genome integrity maintenance, avoiding serious diseases such as cancer. Deregulation in the expression of those proteins has been associated with both the risk of development and evolution of various human cancers, including oral squamous cell carcinoma. The purpose of this study was to analyze the immunoreactivity of the DNA repair proteins XRCC1, THIIF and XPF in oral tongue squamous cell carcinoma (OTSCC) and to investigate its association with clinical and histopathological parameters, outcome and 5-year survival rate. Seventy-four cases of OTSCC were analyzed semi-quantitatively through immunohistochemistry. We observed that DNA repair proteins were highly expressed in parenchymal cells; however, we only observed a significant association between XRCC1 high expression and better clinical staging (p=0,02). Cox regression showed that tumor size (p<0,01), lymph node involvement (p=0,04), tumor stage (p=0,02) and depth of invasion> 4mm (p=0,05) were prognostic factors. The results of this experiment suggest that XRCC1, TFIIH and XPF participate in the tumorigenic process, however, their immunoexpression may not be used as an independent prognostic indicator for OTSCC (AU).

Avaliação de polimorfismos funcionais nos genes de reparo XRCC1, APEX1, XPD e XPF em carcinomas de células escamosas orais / Evaluation of functional polymorphisms in the repair genes XRCC1, APEX1, XPD and XPF in oral squamous cell carcinomas

As vias de reparo por excisão de base (BER) e por excisão de nucleotídeo (NER) desempenham um papel crucial na manutenção da integridade genômica. Polimorfismos em genes das vias BER e NER, que modulam a capacidade de reparo do DNA, podem estar relacionados ao risco de desenvolvimento e prognóstico do câncer oral. O presente trabalho teve como objetivo investigar a frequência de polimorfismos de nucleotídeos simples, em dois genes da via de reparo do DNA por excisão de base (XRCC1 ­ rs25487 e APEX1 ­ rs1130409) e dois genes da via de reparo por excisão de nucleotídeo (XPD ­ rs13181 e XPF ­ rs1799797), em pacientes com carcinoma de células escamosas oral (CCEO), buscando associações com o risco de desenvolver esta neoplasia maligna e o seu prognóstico. Um total de 92 amostras de DNA de pacientes com CCEO e 130 controles foram genotipadas utilizando o método da reação em cadeia da polimerase em tempo real. O software estatístico GraphPad Prism version 6.0.1. foi utilizado para a aplicação dos testes apropriados. Odds ratio (OR) e hazard ratio (HR), e seus intervalos de confiança (IC) de 95%, foram calculados pela regressão logística. A avaliação do prognóstico foi realizada por meio da curva de Kaplan-Meier e análise multivariada de Cox. A presença das variantes polimórficas nos genes XRCC1, APEX1, XPD, e XPF não foram associadas ao risco de desenvolver CCEO. A interação da presença da variante polimórfica com o hábito de fumar não foi significativa para nenhum dos polimorfismos analisados. Já a presença do polimorfismo em XPD, somada ao hábito de beber, aumentou o risco de desenvolver CCEO (OR 1,86, 95% IC: 0,86 ­ 4,01, p=0,03). Apenas o SNP do APEX1 (rs1130409) esteve associado a uma diminuição da sobrevida específica (HR 3,94, 95% IC: 1,31 ­ 11,88, p=0,01). O presente estudo sugere uma interação entre o consumo de álcool e a presença do polimorfismo estudado no gene XPD. Além disso, indica um pior prognóstico para pacientes que possuem o polimorfismo estudado em APEX1 (AU).

Base excision repair (BER) and nucleotide excision repair (NER) pathways play critical role in maintaining genome integrity. Polymorphisms in BER and NER genes which modulate the DNA repair capacity may affect the susceptibility and prognosis of oral cancer. This study was conducted with genomic DNA from 92 patients with oral squamous cell carcinomas (OSCC) and 130 controls. The cases were followed up to explore the associations between BER and NER genes polymorphisms and the risk and prognosis of OSCC. Four single-nucleotide polymorphisms (SNPs) in XRCC1 (rs25487), APEX1 (rs1130409), XPD (rs13181) and XPF (rs1799797) genes were tested by polymerase chain reaction ­ quantitative real time method. The GraphPad Prism version 6.0.1 statistical software was applied for statistical analysis of association. Odds ratio (OR), hazard ratio (HR), and their 95 % confidence intervals (CIs) were calculated by logistic regression. Kaplan-Meier curve and Cox proportional hazard model were used for prognostic analysis. The presence of polymorphic variants in XRCC1, APEX1, XPD and XPF genes were not associated with an increased risk of OSCC. Gene-environment interactions with smoking were not significant for any polymorphism. The presence of polymorphic variants of the XPD gene in association with alcohol consumption conferred an increased risk of 1.86 (95% CI: 0.86 ­ 4.01, p=0.03) for OSCC. Only APEX1 was associated with decreased specific survival (HR 3.94, 95% CI: 1.31 ­ 11.88, p=0.01). These results suggest an interaction between polymorphic variants of the XPF gene and alcohol consumption. Additionally APEX1 may represent a prognostic marker for OSCC (AU).

Polymorphisms in base-excision & nucleotide-excision repair genes & prostate cancer risk in north Indian population.

Background & objectives: Genetic variation in the DNA repair genes might be associated with altered DNA repair capacities (DRC). Reduced DRC due to inherited polymorphisms may increase the susceptibility to cancers. Base excision and nucleotide excision are the two major repair pathways. We investigated the association between two base excision repair (BER) genes (APE1 exon 5, OGG1 exon 7) and two nucleotide excision repair (NER) genes (XPC PAT, XPC exon 15) with risk of prostate cancer (PCa). Methods: The study was designed with 192 histopathologically confirmed PCa patients and 224 age matched healthy controls of similar ethnicity. Genotypes were determined by amplification refractory mutation specific (ARMS) and PCR-restriction fragment length polymorphism (RFLP) methods. Results: Overall, a significant association in NER gene, XPC PAT Ins/Ins (I/I) genotype with PCa risk was observed (Adjusted OR- 2.55, 95%CI-1.22-5.33, P=0.012). XPC exon 15 variant CC genotypes presented statistically significant risk of PCa (Adjusted OR- 2.15, 95% CI-1.09-4.23, P=0.026). However, no association was observed for polymorphism with BER genes. Diplotype analysis of XPC PAT and exon 15 revealed that the frequency of the D-C and I-A diplotype was statistically significant in PCa. The variant genotypes of NER genes were also associated with high Gleason grade. Interpretation & conclusions: The results indicated that there was a significant modifying effect on the association between genotype XPC PAT and exon 15 polymorphism and PCa risk which was further confirmed by diplotype analysis of XPC PAT and exon 15 in north Indian population.

Investigation of lung cancer susceptibility correlated with polymorphism of DNA repair gene XRCC and hOGG1 / 肿瘤研究与临床

DNA repair gene polymorphism can change the functions and efficiency of DNA repair,influence cancer susceptibility.Many studies have been reported that DNA damage repair gene polymorphisms may be related to cancer susceptibility mutation in a variety of tumors and plays an important role in the pathological process.In addition,DNA damage repair genes may interact with other genes,the combined effect of tumor occurrence,development.Lung cancer is the well-studied tumor in this respect.In this paper,DNA damage repair gene XRCC and hOGG1 polymorphisms biological characteristics,these gene single nucleotide polymorphisms as well as cancer susceptibility were reviewed to provide a theoretical basis for the tumor prevention,diagnosis and treatment.

Association of genetic polymorphisms in the DNA repair gene XRCC1 and XPD with risk of prostate cancer / 中华泌尿外科杂志

Objective To explore the relationship between DNA repair gene XRCC1 and XPD polymorphisms and individual susceptibility to prostate cancer. Methods PCR-restriction fragment length polymorphism assay was used to analyze the XRCC1 (C26304T and G28152A) and XPD A35931C polymorphisms in 358 prostate cancer patients and 312 healthy controls. Unconditional logistic regression analysis was performed to calculate odd ratio (OR) and 95% confidence interval (CD for estimating the correlation between different genotypes and prostate cancer risks. Results Forty-seven(13.1%) cases present XRCC1 28152AA genotype in prostate cancer group, while 24 cases in the control group (7. 1%), individuals with this genotype had a significantly increased risk for prostate cancer (OR 1. 924, 95%CI=1.126 - 3. 288, P=0. 017). There was no significant difference between two groups at XRCC1 C26304T and XPD A35931C sites. Combined analysis of the three sites polymorphisms showed that individuals with XRCC1 28152 AA and XPD 35931AC+CC genotype had a higher risk of prostate cancer than those with three wild genotypes (OR = 3. 087,95%CI 1. 081 - 8.813;OR = 3. 376,95%CI 1.067-10.683;OR 3. 216,95%CI=1. 439-7.188,P = 0. 004). Analysis stratified by age of onset, PSA, Gleason score and T stage revealed that XRCC1 28152AA and XPD 35931 AC+CC high-risk genotype was especially associated with early age at onset of prostate cancer (P<0. 05). Conclusions The XRCC1 and XPD genotypes may be contributed to the risk of developing prostate cancer, particularly for younger patients.

The Effect of Genetic Variation in The Dna Base Repair Genes on the Risk of Head and Neck Cancer

DNA damage accumulates in cells as a result of exposure to exogenous agents such as benzopyrene, cigarette smoke, ultraviolet light, X-ray, and endogenous chemicals including reactive oxygen species produced from normal metabolic byproducts. DNA damage can also occur during aberrant DNA processing reactions such as DNA replication, recombination, and repair. The major of DNA damage affects the primary structure of the double helix; that is, the bases are chemically modified. These modification can disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. DNA repair genes and proteins scan the global genome to detect and remove DNA damage and damage to single nucleotides. Direct reversal of DNA damage, base excision repair, double strand break. DNA repair are known relevant DNA repair mechanisms. Four different mechanisms are distinguished within excision repair: direct reversal, base excision repair, nucleotide excision repair, and mismatch repair. Genetic variation in DNA repair genes can modulate DNA repair capacity and alter cancer risk. The instability of a cell to properly regulate its proliferation in the presence of DNA damage increase risk of gene mutation and carcinogenesis. This article aimed to review mechanism of excision repair and to understand the relationship between genetic variation of excision repair genes and head and neck cancer.

Application of multifactor dimensionality reduction on the interactions between gene-gene,geneenvironment and the risk sporadic colorectal cancer in Chinese population / 中华流行病学杂志

Objective To identify the association between risk of sporadic colorectal cancer and the common single nucleotide polymorphisms (SNPs) in DNA repairs genes, gene to gene interactions among them and their gene to environment interactions with common environmental factors. Methods In this population-based case-control study, 206 primary colorectal cancer cases and 845 cancer-free healthy controls were enrolled. Genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, with the status of subjects case or controls unknown.Multifactor dimensionality reduction (MDR) and logistic analysis were both used for association analysis.Results As compared to the younger age group (≥42,＜61 years), the risk of colorectal cancer in older age group (≥61 years) increased significantly ( OR = 2.04,95% CI: 1.49-2.80). Similar result was observed in the family cancer history ( OR = 1.51, 95% CI : 1.05-2.17 ). However, no significant association between any single DNA repair gene SNP and colorectal cancer risk was discovered. Results from MDR analysis only showed a significant interaction among the four following factors: age, alcohol drinking, XRCC1 Arg194Trp and OGG1 Ser326Cys (the cross-validation consistency = 10/10, the average testing accuracy = 0. 616, P=0.011 ). Using a logistic regression model, the"high-risk"individuals had a significantly elevated risk of colorectal cancer compared to those "low- risk" individuals classified by the above MDR model ( OR = 2.72,95% CI : 1.66-4.47 ). Conclusion The impact of polymorphisms in DNA repair genes on the risk of sporadic colorectal cancer exhibited a low-penetrance characteristics while the intricate interactions existing among them and with environmental factors.