It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.

The DNA repair machinery plays a key role in maintaining genomic stability by preventing the emergence of mutations. Furthermore, the -93G>A polymorphism in the MLH1 gene has been associated with an increased risk of developing colorectal cancer. Therefore, the aim of this study was to examine the expression pattern and effect of this polymorphism in normal and tumour samples from patients with colorectal cancer. The MLH1 -93G>A (rs1800734) polymorphism was detected by PCR-RFLP in 49 cases of colorectal cancer. MLH1 expression was investigated using real-time quantitative PCR. The results indicate a significant decrease in MLH1 expression in tumour samples compared to their normal counterparts. The MLH1 gene was also significantly repressed in samples from patients who had some degree of tumour invasion into other organs. Similarly, those patients who were in a more advanced tumour stage (TNM III and IV) exhibited a significant reduction in MLH1 gene expression. Finally, the mutant genotype AA of MLH1 was associated with a significant decrease in the expression of this gene. This finding suggests that this polymorphism could increase the risk of developing colorectal cancer by a defective mismatch repair system, particularly through the loss of MLH1 expression in an allele-specific manner.

Survivin is a small protein member of the inhibitor of apoptosis protein family. Its expression occurs in G2/M phase of cell cycle, acting inhibiting apoptosis blocking caspases cascade directly or indirectly, and also controlling cell division. Survivin was found to be overexpressed in breast cancer, and its expression have been associated mostly with poor outcome. The aim of this case-control study was to evaluate the prognostic value of Survivin immunoexpression in early stage (pT1pN0 or pT2pN0) breast cancer. The study was conducted collecting data from 170 women with invasive breast carcinoma. The case group (n=57) and control group (n=113) consisted of patients with and without tumor recurrence, respectively. Immunohistochemical Tissue Microarray analyses were conducted to detect Survivin expression. In addition, molecular classification was done based on immunohistochemistry, and classic clinical and histological breast cancer variables were collected. The findings were submitted to the chi-square test and Fisher’s exact test, followed by multivariate analysis with multinomial logistic regression. The level of statistical significance was set at 5% (p<0.05). Median follow-up time was 6 years, ranging from 4 to 13 years. In the univariate analysis, patients with recurrence presented a higher histologic grade (p=0.005), percentage of tumor cells expressing survivin (p=0.006) and stronger immunostaining for this protein (p=0.021). In the multivariate analysis, stronger immunostaining for survivin (OR 1.850; p=0.023) and greater percentage of survivin expression (OR 2.290; p=0.016) persisted independently associated which higher rates of recurrence. Higher immunoexpression of survivin was independently associated with recurrence in early stage invasive breast tumors. Multinomial logistic regression model. In the first model, variables with p <0.200 were used in order to highlight the first order factors independently associated with disease-free survival. In the second model, variables with a significant association in model 1 were excluded in order to highlight second order factors independently associated with disease-free survival. In the third model, there were no factors independently associated with disease-free survival. Table 1 - Clinical-pathological characterization of the 170 cases of early stage breast cancer patients with and without recurrence.RecurrenceTotalNoYespAge≤ 55 years8658280,78650,6%51,3%49,1%> 55 years84552949,4%48,7%50,9%Histological subtypeDuctal158104540,24492,9%92,0%94,7%Lobular5502,9%4,4%,0%Others7434,1%3,5%5,3%StagespT1a7520,9024,1%4,4%3,5%pT1b2113812,4%11,5%14,0%pT1c65452038,2%39,8%35,1%pT277502745,3%44,2%47,4%Histological gradeI332850,00519,4%24,8%8,8%II75492644,1%43,4%45,6%III41192224,1%16,8%38,6%Ignored2117412,4%15,1%7,0%Breast surgeryMastectomy8557281,00050,0%50,4%49,1%Conservative85562950,0%49,6%50,9%Sentinel lymph node biopsyNo3220120,35318,82%17,7%18,2%Yes137934481,5%82,3%80,0%Ignored1010,6%0,0%1,8%ChemotherapyNo5135160,69730,0%31,0%28,1%Yes119784170,0%69,0%71,9%TrastuzumabNo156105510,76192,3%92,9%91,1%Yes13857,7%7,1%8,9%Hormone therapyNo2918110,58117,1%15,9%19,3%Yes141954682,9%84,1%80,7% Table 2 - Patterns of Survivin expression in tumors of patients with breast cancer with and without recurrence.RecurrenceTotal**NoYespSubcellular localizationAbsent4220,9422,7%2,1%3,8%Cytoplasmic89573260,1%60,0%60,4%Nuclear2315815,5%15,8%15,1%Cytoplasmic and Nuclear32211121,6%22,1%20,8%IntensityAbsent4220,0212,7%2,1%3,8%Weak7353*2049,3%55,8%37,7%Moderate62382441,9%40,0%45,3%Strong927*6,1%2,1%13,2%Percentage of expression≤ 50%10977320,00673,6%81,1%60,4%> 50%39182126,4%18,9%39,6%*p<0,05** 22 patients (12,9%) of sample loss in tissue microarray. Table 3 - Cox survival regression model of patients diagnosed and treated for invasive breast carcinoma.p-ValorAdjusted ORModel 1Histological grade*0,0072,108Survivin - intensity*0,0231,850Survivin - percentage of expression0,1001,876Breast cancer subtype classified by immunohistochemistry0,2631,126Model 2Survivin - percentage of expression*0,0162,290Breast cancer subtype classified by immunohistochemistry0,0931,170Model 3Breast cancer subtype classified by immunohistochemistry0,2411,107 Citation Format: Heloisa OM Belchior, Victor P Andrade, Marcos VA Lima, Maria do PSS Cunha, Monique BC Lemos, Paulo GB Silva, Isabelle JL Silva-Fernandes. Survivin immunoexpression: An independent prognostic marker of recurrence in early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-61.