XRCC1 Arg194Trp polymorphism, risk of nonmelanoma skin cancer and extramammary Paget’s disease in a Japanese population

The X-ray repair cross-complementing groups 1 gene plays an important role in base excision repair. At least three common single nucleotide polymorphisms frequently occur in this gene (Arg399Gln, Arg194Trp and Arg280His). Recent studies reported that these polymorphisms were associated with not only risk of visceral malignancy but also that of skin cancer such as basal cell carcinoma and squamous cell carcinoma, whereas the results of previous study vary among races. In this case–control study, we investigated whether these single nucleotide polymorphisms were associated with the risk of skin cancer in a Japanese population. The study population was composed of 197 patients with skin cancer (27 actinic keratoses, 47 basal cell carcinomas, 27 squamous cell carcinomas, 29 Bowen’s diseases, 46 malignant melanomas and 21 extramammary Paget’s diseases) and 93 control subjects. We genotyped two single nucleotide polymorphisms (Arg194Trp and Arg399Gln) using polymerase chain reaction-restriction fragments length polymorphism analysis. We found a significantly increased risk for basal cell carcinoma, squamous cell carcinoma and extramammary Paget’s disease associated with Arg194Trp [adjusted odds ratio (AOR) = 2.347, 3.587, 3.741, 95 % confidence interval (CI) 1.02–5.39, 1.19–10.8, 1.15–12.2, respectively]. We also found a significantly decreased risk for basal cell carcinoma associated with Gln399Gln (AOR = 0.259, 95 % CI 0.07–0.96). Our data suggest that the Arg194Trp polymorphism could be associated with nonmelanoma skin cancer and extramammary Paget’s disease risk in a Japanese population

Conditional Gene Knockout in Human Cells with Inducible CRISPR/Cas9.

The advent of the easily programmable and efficient CRISPR/Cas9 nuclease system has revolutionized genetic engineering. While conventional gene knockout experiments using CRISPR/Cas9 are very valuable, these are not well suited to study stage-specific gene function in dynamic situations such as development or disease. Here we describe a CRISPR/Cas9-based OPTimized inducible gene KnockOut method (OPTiKO) for conditional loss-of-function studies in human cells. This approach relies on an improved tetracycline-inducible system for conditional expression of single guide RNAs (sgRNAs) that drive Cas9 activity. In order to ensure homogeneous and stable expression, the necessary transgenes are expressed following rapid and efficient single-step genetic engineering of the AAVS1 genomic safe harbor. When implemented in human pluripotent stem cells (hPSCs), the approach can be then efficiently applied to virtually any hPSC-derived human cell type at various stages of development or disease

A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes

Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes

BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFß1, IGFBP3) were evaluated. METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFß1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery).</p> <p>Methods</p> <p>A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis.</p> <p>Results</p> <p>A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant <it>GSTP1 </it>(Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, <it>p </it>= 0.047).</p> <p>Conclusions</p> <p>The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01316328">NCT01316328</a></p

Reflections on the ethics of recruiting foreign-trained human resources for health

<p>Abstract</p> <p>Background</p> <p>Developed countries' gains in health human resources (HHR) from developing countries with significantly lower ratios of health workers have raised questions about the ethics or fairness of recruitment from such countries. By attracting and/or facilitating migration for foreign-trained HHR, notably those from poorer, less well-resourced nations, recruitment practices and policies may be compromising the ability of developing countries to meet the health care needs of their own populations. Little is known, however, about actual recruitment practices. In this study we focus on Canada (a country with a long reliance on internationally trained HHR) and recruiters working for Canadian health authorities.</p> <p>Methods</p> <p>We conducted interviews with health human resources recruiters employed by Canadian health authorities to describe their recruitment practices and perspectives and to determine whether and how they reflect ethical considerations.</p> <p>Results and discussion</p> <p>We describe the methods that recruiters used to recruit foreign-trained health professionals and the systemic challenges and policies that form the working context for recruiters and recruits. HHR recruiters' reflections on the global flow of health workers from poorer to richer countries mirror much of the content of global-level discourse with regard to HHR recruitment. A predominant market discourse related to shortages of HHR outweighed discussions of human rights and ethical approaches to recruitment policy and action that consider global health impacts.</p> <p>Conclusions</p> <p>We suggest that the concept of corporate social responsibility may provide a useful approach at the local organizational level for developing policies on ethical recruitment. Such local policies and subsequent practices may inform public debate on the health equity implications of the HHR flows from poorer to richer countries inherent in the global health worker labour market, which in turn could influence political choices at all government and health system levels.</p

A Bioinformatics Filtering Strategy for Identifying Radiation Response Biomarker Candidates

The number of biomarker candidates is often much larger than the number of clinical patient data points available, which motivates the use of a rational candidate variable filtering methodology. The goal of this paper is to apply such a bioinformatics filtering process to isolate a modest number (<10) of key interacting genes and their associated single nucleotide polymorphisms involved in radiation response, and to ultimately serve as a basis for using clinical datasets to identify new biomarkers. In step 1, we surveyed the literature on genetic and protein correlates to radiation response, in vivo or in vitro, across cellular, animal, and human studies. In step 2, we analyzed two publicly available microarray datasets and identified genes in which mRNA expression changed in response to radiation. Combining results from Step 1 and Step 2, we identified 20 genes that were common to all three sources. As a final step, a curated database of protein interactions was used to generate the most statistically reliable protein interaction network among any subset of the 20 genes resulting from Steps 1 and 2, resulting in identification of a small, tightly interacting network with 7 out of 20 input genes. We further ranked the genes in terms of likely importance, based on their location within the network using a graph-based scoring function. The resulting core interacting network provides an attractive set of genes likely to be important to radiation response