7515

XRCC1

X-ray repair complementing defective repair in Chinese hamster cells 1;XRCC1;X-ray repair complementing defective repair in Chinese hamster cells 1

DNA repair protein XRCC1|X-ray repair cross-complementing protein 1

19q13.2

protein-coding

PURPOSE: Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays. RESULTS: For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases. CONCLUSION: XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

Preclinical data indicate that alpha6beta4 integrin signaling through Ras homolog gene family, member A, plays an important role in tumor cell motility. The objective of this study was to determine whether the combined expression of alpha6beta4 integrin and neuroepithelioma transforming gene 1 (Net1), a guanine nucleotide exchange factor specific for Ras homolog gene family member A, is associated with adverse clinical outcome in breast cancer patients. Immunohistochemical expression of each protein was evaluated in a tumor tissue microarray prepared from the primary tumors of 94 node-positive patients with invasive breast carcinoma treated with total mastectomy and doxorubicin-based chemotherapy without radiation with a median follow-up of 12.5 years. Associations between staining results and multiple clinicopathologic variables were investigated. Although there was no significant association between alpha6beta4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of alpha6beta4 and Net1 was associated with decreased distant metastasis-free survival (P = 0.030). In the subset of patients with hormone receptor-positive tumors, coexpression of alpha6beta4 and Net1 was associated with a decrease in distant metastasis-free and overall survival (P < 0.001 and P = 0.006, respectively). Although an association between human epidermal growth factor receptor 2 expression and coexpression of alpha6beta4 and Net1 (P = 0.008) was observed, coexpression of alpha6beta4 and Net1 (hazard ratio, 1.63; P = 0.02) and lymphovascular invasion (hazard ratio, 2.35; P = 0.02) were the only factors independently associated with the development of distant metastasis in multivariate analysis. These findings suggest that coexpression of alpha6beta4 integrin and Net1 could be a useful biomarker for aggressive disease in node-positive breast cancer patients.

BACKGROUND: DNA repair gene polymorphisms can contribute to susceptibility of human cancer, including gastric cancer. Three single nucleotide polymorphisms (SNPs) of xeroderma pigmentosum group D (XPD) and X-ray repair cross complement 1 (XRCC1) genes were genotyped in gastric cancer and control subjects in a population from Southwestern China for their association with susceptibility of gastric cancer risk. METHODS: 190 hospital-based cases and 180 matched controls were recruited and blood samples were collected from each of them and amplified with a PCR and DNA sequenced for XPD Asp312Asn, XRCC1 Arg194Trp, and XRCC1 Arg280Gln genotyping. RESULTS: Allelic association analysis of these three SNPs showed that the frequency of XRCC1 194Trp in gastric cancer case and the control was 17.2% and 7.3%, respectively, which was significantly associated with gastric cancer risk (OR=2.72, 95% CI: 1.04-7.24, p=0.027). Furthermore, XRCC1 194Trp allele increased gastric carcinoma risk in male patients with older age and distant metastasis of gastric cancer. In addition, XRCC1 Trp allele but not XRCC1 Arg allele was closely associated to development of gastric cardia carcinoma. However, other SNPs did not show an association with gastric cancer risk or other clinicopathologic data of the patients. CONCLUSION: XRCC1 194Trp allele significantly increased the risk of gastric cancer and also associated with risk of gastric cardia carcinoma and promoted distant metastasis of gastric cancer. Future study will verify these findings for use of this SNP as biomarker in gastric cancer.

Ultraviolet (UV) radiation-induced DNA damage and genomic instability is one of the leading causes for melanoma. X-ray repair cross-complementary protein 1, XRCC1, plays a critically important role in base excision repair pathway. This study was therefore performed to analyze the correlation between XRCC1 expression, melanoma progression, and patient survival. Using a tissue microarray with a total of 119 patients with melanoma, we demonstrate that loss of XRCC1 expression is associated with the progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma. We found that the loss of XRCC1 was correlated with the progression of melanoma from AJCC stage II to stage III and with worse overall and disease-specific 5-yr and 10-yr survival of patients with melanoma. Furthermore, we also illustrate the inhibitory effect of XRCC1 on melanoma cell invasion and migration, which are the regulatory events in melanoma metastasis.