Biomarkers Of Cancer Susceptibility Research Articles

Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study.

Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

Association of Polymorphisms in Vitamin D-Metabolizing Enzymes DHCR7 and CYP2R1 with Cancer Susceptibility: A Systematic Review and Meta-Analysis.

The deficiency of vitamin D has been reported to be relevant to cancer risk. DHCR7 and CYP2R1 are crucial components of vitamin D-metabolizing enzymes. Thus, accumulating researchers are concerned with the correlation between polymorphisms of DHCR7 and CYP2R1 genes and cancer susceptibility. Nevertheless, the conclusions of literatures are inconsistent. We conducted an integrated review for the correlation of DHCR7 and CYP2R1 SNPs with cancer susceptibility. In the meanwhile, a meta-analysis was performed using accessible data to clarify the association between DHCR7 and CYP2R1 SNPs and overall cancer risk. Literatures which meet the rigid inclusion and exclusion criteria were involved. The association of each SNP with cancer risk was calculated by odds ratios (ORs). 12 case-control designed studies covering 23780 cases and 27307 controls were ultimately evolved in the present meta-analysis of five SNPs (DHCR7 rs12785878 and rs1790349 SNP; CYP2R1 rs10741657, rs12794714, and rs2060793 SNP). We found that DHCR7 rs12785878 SNP was significantly related to cancer risk in the whole population, Caucasian subgroup, and hospital-based (HB) subgroup. DHCR7 rs1790349 SNP was analyzed to increase cancer risk in Caucasians. Moreover, CYP2R1 rs12794714-A allele had correlation with a lower risk of colorectal cancer. Our findings indicated that rs12785878, rs1790349, and rs12794714 SNPs might potentially be biomarkers for cancer susceptibility.

Meta-analysis of the association between MBD4 Glu346Lys polymorphism and cancer risk.

The purpose of this study was to systematically evaluate the association between methyl-CpG binding domain 4, DNA glycosylase (MBD4) Glu346Lys polymorphism and cancer risk. A comprehensive document retrieval from the Chinese National Knowledge Infrastructure (CNKI), EMBASE, and PubMed databases was performed through 1 September 2019. The strength of the correlation was assessed using the pooled odds ratio (ORs) and 95% confidence interval (CIs). Five relevant studies were retrieved following screening, including 1804 cases and 2193 controls. We found no association between MBD4 Glu346Lys polymorphism and cancer risk under all genetic models. Nevertheless, a subgroup analysis based on country showed a strong association in the Chinese population. Under the recessive model, Chinese individuals with the Lys/Lys genotype had a higher risk of cancer (OR = 1.37, 95% CI = 1.11-1.70). Analysis of the MBD4 Glu346Lys polymorphism in different populations will help to elucidate the pathogenesis of cancer. The polymorphism can be utilized as a biomarker for cancer susceptibility among Chinese people.

A comprehensive evaluation for polymorphisms in let-7 family in cancer risk and prognosis: a system review and meta-analysis

miRNA polymorphisms had potential to be biomarkers for cancer susceptibility and prognosis. The mature miRNA-let-7 family was considered as the most important miRNA for the cancer incidence and progression. Recently, the promising let-7 miRNAs were reported to be associated with various cancers, but the results were inconsistent. We performed a first-reported systematic review with a meta-analysis for the association of let-7 family single nucleotide polymorphisms (SNPs) with cancer risk/prognosis. Ten studies were included with a total of 3878 cancer cases and 4725 controls for the risk study and 1665 cancer patients for the prognosis study in this meta-analysis. In the risk study, the let-7i rs10877887 and let-7a-1/let-7f-1/let-7d rs13293512 were shown no significant association for the overall cancer risk. In the stratified analysis, the rs10877887 variant genotype was significantly associated with a decreased cancer risk in head and neck cancer (TC compared with TT: P=0.017; odds ratio (OR) = 0.81; TC + CC compared with TT: P=0.020; OR = 0.82). In the prognosis study, the let-7i rs10877887 SNP was shown to be associated with a higher risk for cancer prognosis in the dominate model (P=0.004; hazard ratio (HR) = 1.32). The other two SNPs (let-7a-1 rs10739971 and let-7a-2 rs629367) were not found to be associated with cancer survival. None of the let-7 family polymorphisms had potential to be biomarkers for cancer susceptibility but let-7i rs10877887 SNP had potential to be predicting markers for cancer prognosis. In the future, large-sample studies are still needed to verify our findings.

DNA mismatch repair and its many roles in eukaryotic cells.

DNA mismatch repair (MMR) is an important DNA repair pathway that plays critical roles in DNA replication fidelity, mutation avoidance and genome stability, all of which contribute significantly to the viability of cells and organisms. MMR is widely-used as a diagnostic biomarker for human cancers in the clinic, and as a biomarker of cancer susceptibility in animal model systems. Prokaryotic MMR is well-characterized at the molecular and mechanistic level; however, MMR is considerably more complex in eukaryotic cells than in prokaryotic cells, and in recent years, it has become evident that MMR plays novel roles in eukaryotic cells, several of which are not yet well-defined or understood. Many MMR-deficient human cancer cells lack mutations in known human MMR genes, which strongly suggests that essential eukaryotic MMR components/cofactors remain unidentified and uncharacterized. Furthermore, the mechanism by which the eukaryotic MMR machinery discriminates between the parental (template) and the daughter (nascent) DNA strand is incompletely understood and how cells choose between the EXO1-dependent and the EXO1-independent subpathways of MMR is not known. This review summarizes recent literature on eukaryotic MMR, with emphasis on the diverse cellular roles of eukaryotic MMR proteins, the mechanism of strand discrimination and cross-talk/interactions between and co-regulation of MMR and other DNA repair pathways in eukaryotic cells. The main conclusion of the review is that MMR proteins contribute to genome stability through their ability to recognize and promote an appropriate cellular response to aberrant DNA structures, especially when they arise during DNA replication. Although the molecular mechanism of MMR in the eukaryotic cell is still not completely understood, increased used of single-molecule analyses in the future may yield new insight into these unsolved questions.

Decreased Risk of Developing Cancer in Subjects Carrying SLC52A3 Rs13042395 Polymorphism: Proof from a Meta-Analysis

This study aimed to conduct a meta-analysis to explore the association between SLC52A3 rs13042395 polymorphism and cancer risk. A comprehensive literature search was performed to confirm the relationship evaluated using STATA 12.0 software. Overall, SLC52A3 rs13042395 C>T polymorphism was associated with cancer risk in two genetic models (TT vs CC: odds ratio: 0.86; 95% CI: 0.80-0.93; p < 0.001, TT vs CC + CT: odds ratio: 0.88; 95% CI: 0.82-0.95; p = 0.001). Significant associations were found between SLC52A3 rs13042395 polymorphism and decreased cancer risk among esophageal cancer, Asians, female, normal BMI and old age groups. No significant associations were observed in alcohol and smoking groups. SLC52A3 rs13042395 C>T polymorphism might be a potential biomarker for cancer susceptibility.

Abstract 5147: Characterization of the tissue-specific properties of cancer driver mutations suggests spontaneous mutation in normal tissues drives tumor susceptibility

Abstract Cancer driver mutations (CDMs) are being developed as theranostic biomarkers. This study used high-sensitivity quantification by ACB-PCR, with a sensitivity of 10−5, to elucidate the tissue-specific properties of CDMs. We employed the paradigm of comparing levels of specific hotspot CDMs in normal human tissues and tumors. Specifically, we measured KRAS G12D, KRAS G12V, PIK3CA E545K, and PIK3CA H1047R mutant fractions (MFs) in normal breast, colon, lung, and thyroid and quantified the same mutations in mammary ductal carcinomas (DCs), colonic adenocarcinomas, lung adenocarcinomas, and papillary thyroid carcinomas. Three major findings were: 1) these mutations occur in normal human tissues at relatively high frequencies, 2) there is considerable variability in CDM MFs in normal tissues across individuals, and 3) tumors frequently carry CDMs at levels greater than that present in normal tissue, but below that detected by standard DNA sequencing. Understanding the prevalence of mutant subpopulations is important because they can drive resistance to molecularly-targeted therapies. The PIK3CA H1047R profile for normal breast and DC were similar, with large mutant subpopulations present in both tissue types. Because the PIK3CA H1047R mutation is the most prevalent point mutation reported in breast cancer, we conclude that it can drive breast carcinogenesis as a subpopulation, potentially through a paracrine mechanism, and may be a useful biomarker of breast cancer susceptibility. Other properties of CDMs elucidated were gender differences, the accumulation of mutation with donor age, and the correlation between MF and maximum tumor dimension (MTD). Male lung had significantly greater PIK3CA H1047R MFs than female lung. The PIK3CA H1047R MF in normal breast was positively correlated with donor age, and the mutation in DCs was positively correlated with MTD. By contrast, KRAS MFs showed non-significant decreases in normal lung with increasing donor age. For colorectal adenocarcinomas, KRAS G12V MF was negatively correlated with MTD, consistent with previous findings that KRAS G12V MF decreases during adenoma to adenocarcinoma progression. This suggests that the selective advantage provided by KRAS G12V mutation is context-dependent and can be either positive or negative. Across the four mutational targets and four tissue types, a significant positive correlation was observed between the variability (Log10 standard deviation) of MF measured in normal tissues and the prevalence with which the mutation reportedly occurs in tumors, as per The Cancer Genome Atlas database. This suggests that level and inter-individual variation in CDMs can be used to identify promising tissue-specific, mutational biomarkers of cancer susceptibility. This is not a formal dissemination of information by FDA and does not represent agency position or policy. Citation Format: Barbara L. Parsons, Meagan B. Myers, Karen L. McKim, Malathi Banda. Characterization of the tissue-specific properties of cancer driver mutations suggests spontaneous mutation in normal tissues drives tumor susceptibility. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5147.

Abstract A68: Does genetic ancestry influence the metabolic response to a traditional Mexican versus U.S. diet? A randomized crossover feeding trial among first and second generation women of Mexican descent

Abstract Background: Greater acculturation to the U.S. dietary habits has been suggested to contribute to the high rates of obesity, insulin resistance, and therefore, potential risk of type 2 diabetes (T2D) and breast cancer. Mexican immigrants may be evolutionary adapted to traditional diets high in legumes and complex carbohydrates. When consuming an inexpensive, readily available U.S. diet high in refined carbohydrates and added sugars they may experience a detrimental metabolic and/or inflammatory response, placing them at a disproportionately higher risk of certain cancers. To better understand these biological mechanisms that may underlie immigrant-related health disparities, we tested whether genetic ancestry modified the metabolic response to a traditional Mexican versus U.S. diet in a controlled feeding trial. Methods: First and second generation, female, Mexican immigrants (n=53) completed a randomized, crossover feeding trial testing the response to a Mexican versus U.S. diet for 24 days each, separated by a 28-day washout period. The trial diets were designed to provide energy content for weight maintenance and were similar in macronutrient composition. Participants were instructed to consume only study provided foods. The traditional Mexican diet was high in corn tortillas, beans, Mexican soups, fruits, vegetables, animal fats, full-fat milk, and Mexican cheeses; in contrast, the U.S. diet was high in refined carbohydrates, vegetable oils, nonfat or low-fat milk, processed foods, processed meats and sugar-sweetened beverages. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6), and the calculated homeostasis model assessment of insulin resistance (HOMA-IR) at the beginning and end of each feeding period. DNA was extracted from baseline blood for genotyping and estimation of each participant's proportion of genetic ancestry from four populations – Indigenous American (IA), European, African, and Asian – with the use of 218 Informative Ancestry Markers. Linear mixed models were adjusted for diet sequence, feeding period, baseline and washout biomarker concentrations, age, body weight, and acculturation. Results: The overall genetic ancestral background of the study sample was 53% IA and 36% European ancestry. In general, genetic ancestry did not modify the metabolic responses to the Mexican versus U.S. diet. However, genetic ancestry was associated with some baseline participant's characteristics and measures. Greater IA ancestry trended toward a positive association with waist-to-hip ratio (P=0.08) and was inversely associated with both education and acculturation (P&amp;lt;0.05). Further, greater IA ancestry was positively associated with baseline fasting serum concentrations of glucose, CRP, IL-6, and calculated HOMA-IR (P&amp;lt;0.05), and was inversely associated with circulating concentrations of IGF-1 and IGFBP-3 (P&amp;lt;0.05). Conclusions: Genetic ancestry suggested differences in baseline measures of several biomarkers that have been identified as cancer susceptibility biomarkers. Although, we found a significant metabolic response to the traditional Mexican versus U.S. diet, overall, we did not observe correlations between genetic ancestry and this response. Nonetheless, the results from the study may inform our understanding of variation in cancer susceptibility biomarkers in vulnerable populations. Additional research is needed to further investigate whether genetic ancestry modifies the associations of other lifestyle exposures, such as physical activity or smoking, with cancer susceptibility biomarkers in Mexican immigrants and other minority groups. Citation Format: Margarita Santiago-Torres, Jean De Dieu Tapsoba, Mario Kratz, Johanna W. Lampe, Kara L. Breymeyer, Lisa Levy, Xiaoling Song, Adriana Villaseñor, Ching-Yun Wang, Christopher Carlson, Marian L. Neuhouser. Does genetic ancestry influence the metabolic response to a traditional Mexican versus U.S. diet? A randomized crossover feeding trial among first and second generation women of Mexican descent. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A68.

Impact of DCC (rs714) and PSCA (rs2294008 and rs2976392) Gene Polymorphism in Modulating Cancer Risk in Asian Population.

Multiple studies have investigated the association of gene variant of Deleted in colorectal carcinoma (DCC) and Prostate Stem cell antigen (PSCA) with various cancer susceptibility; however, the results are discrepant. Since SNPs are emerging as promising biomarker of cancer susceptibility, here, we aimed to execute a meta-analysis of DCC (rs714 A > G) and PSCA (rs2294008 C > T, rs2976392 G > A) polymorphism to demonstrate the more accurate strength of these associations. We followed a rigorous inclusion/exclusion criteria and calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Overall, the pooled analysis showed that the DCC rs714 conferred increased risk of cancer only in Asians (AA vs. GG: OR = 1.86, p ≤ 0.0001; AG vs. GG: OR = 1.43, p = 0.005; GA + AA vs. GG: OR = 1.66, p ≤ 0.0001; AA vs. GG + GA; OR = 1.52, p ≤ 0.004, A vs. G allele: OR = 1.41, p ≤ 0.0001). PSCA rs2294008 was associated with increased overall cancer risk (TT vs. CC: OR = 1.28, p = 0.002; CT vs. CC: OR = 1.21, p ≤ 0.0001; CT + TT vs. CC: OR = 1.24, p ≤ 0.0001; TT vs. CC + CT; OR = 1.17, p ≤ 0.005, T vs. C allele: OR = 1.16, p ≤ 0.0001); however, in stratified analysis this association was limited only to gastric and bladder cancer and the strength was more prominent in Asians. In contrast, the PSCA rs2976392 SNP did not modulate the cancer risk. Therefore, we concluded that rs714 and rs2294008 polymorphism may represent a potential genetic biomarker for cancer risk in Asians and gastric as well as bladder cancer, respectively. However, since our study is limited to Asians and cancer types, further larger studies involving other cancers and/or population, gene-environment interactions and the mechanism of DCC and PSCA gene deregulation are desired to define the role of genotype with overall cancer risk.

Involvement of cysteine proteases in cancer.

The cysteine protease family members play important roles in various pivotal cellular processes. The difficulty in the analysis of the effects of cysteine protease aberrations in cancer comes as a result of the fact that they take part in complex proteolytic pathways. Nevertheless, there is a vast amount of data regarding the involvement of distinct members of this family in divergent types of cancer. Cysteine proteases assist migration and development of the disease, as well as increase the invasiveness of particular kinds of tumors. They are designated as both drug targets, as well as cancer susceptibility biomarkers. This implies that the abnormalities in their activity and expression patterns may be associated with the hallmarks of cancer. This review demonstrates that the influence of cysteine proteases on different mechanisms underlying cancer is undisputable. Thus, they are potent targets for future study and should be recognized as key players in the fight against cancer.

Abstract 1517: Detection of SMAD4, MAP2K4, RB1 and CDKN2A gene deletions in human tumor cells by multiplex qPCR

Abstract Gene duplications and deletions are critical to understanding cancer biology. Deletion in SMAD4, MAP2K4, RB1 and CDKN2A genes are known to play important roles in certain types of cancer or cancer states. Characterization of such mutations in different tumor cells provide insight into the study of novel biomarkers of cancer susceptibility, initiation, progression and metastases and help identify them as risk factors for various types of cancer. We demonstrated a quantitative method to detect multiple gene deletions in human tumor cells by multiplex PCR. We designed four TaqMan® Copy Number Assays to interrogate common deletion mutations in SMAD4, MAP2K4, RB1 and CDKN2A genes and performed multiplex PCR alongside with endogenous controls on representative human tumor and normal cells in different tissues. Since the detection of multiple deletion targets were performed in one single reaction, we were able to profile multiple deletion mutations in one single sample. This method can potentially be applied to the study of Copy Number Variations (CNV) on biological samples with limited quantity such as FFPE samples, as well as enables the characterization of multiple targets on samples in exactly the same condition and state. Citation Format: Cora Woo, Joyce Wilde, Sunali Patel. Detection of SMAD4, MAP2K4, RB1 and CDKN2A gene deletions in human tumor cells by multiplex qPCR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1517. doi:10.1158/1538-7445.AM2014-1517

Abstract 306: DNA Repair Enzyme Signature of a cohort of 100 healthy individuals using peripheral blood mononuclear cells: In the search of cancer susceptibility biomarkers

Abstract It is well established that mutations and combinations of polymorphisms in DNA Repair genes contribute to cancer occurrence. However the relationship between genotypes and cancer is not straightforward. As a matter of fact, individuals’ cancer susceptibility also depends on their genotoxic exposure history, age and lifestyle. In this context, functional DNA-repair tests better account for DNA Repair complexity and constitute powerful strategies to characterize effective individuals DNA Repair capacity. Currently available tools interrogate very limited aspects of DNA Repair mechanism and more informative assays are urgently needed. In humans Base Excision Repair (BER) involves several glycosylases that have the ability to recognize and cleave a set of small base lesions resulting from oxidation, alkylation, or deamination of normal bases, with the help of an AP endonuclease (APE1) that removes abasic sites. To precisely characterize the BER pathway and offer better chance to identify individuals with altered DNA repair capacities, we developed a comprehensive approach that quantifies simultaneously several BER repair enzymes in cell extracts. This multiplexed biochip version of the well-known oligonucleotide cleavage assay was implemented to characterize the DNA Repair Enzyme Signature of a cohort of 100 healthy individuals (50% males and 50% females, ranging in age from 18 to 70 years). All were non-smokers. Two 8 mL blood samples were taken the first day and another one one week apart. Whole cell extracts were prepared from the subjects Peripheral Blood Mononuclear Cells (PBMCs) and protein concentration was determined. Assay robustness was assessed and the inter- and intra-individual BER variability was also determined. We observed a large inter-individual variability in DNA repair capacities. We demonstrated that there was a gender-specific impact of aging on certain DNA Repair activities. Thanks to the multiplexed approach, using hierarchical clustering and principal component analysis, we gained new information on the different glycosylase activities co-regulations and assigned the samples to distinct subpopulation clusters characterized by their DNA Repair Signature. Here again, males and females exhibited different features. We demonstrated that our powerful assay is robust, can be implemented on a large scale and could be used for population studies to identify biomarkers of exposure and biomarkers of cancer susceptibility. We thank GRAVIT and CEA program Technologies for Health for financial support. Citation Format: Sylvie Sauvaigo, Lise Jacqueroux, Benoit Pitiot, Sylvain Caillat, Nicolas Gonnet, Jean-Luc Cracowski. DNA Repair Enzyme Signature of a cohort of 100 healthy individuals using peripheral blood mononuclear cells: In the search of cancer susceptibility biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 306. doi:10.1158/1538-7445.AM2014-306

The significance of Exo1 K589E polymorphism on cancer susceptibility: evidence based on a meta-analysis.

The exonuclease1 (Exo1) gene is a key component of mismatch repair (MMR) by resecting the damaged strand, which is the only exonuclease involved in the human MMR system. The gene product is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. However, whether Exo1 is required to activate MMR-dependent DNA damage response (DDR) remains unknown, the conclusions of the Exo1 polymorphisms on cancer susceptibility studies were not consistent. We carried out a meta-analysis of 7 case-control studies to clarify the association between the Exo1 K589E polymorphism and cancer risk. Overall,a significant association of the Exo1 K589E polymorphism with cancer risk in all genetic models (Lys vs Glu: OR = 1.51, 95%CI:1.39–1.99, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.43, 95%CI:1.28–1.60, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.45, 95%CI:1.90–3.17, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.53, 95%CI:1.38–1.71, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.27, 95%CI:1.79–2.89, P<0.01). In the stratified analysis by ethnicity, significantly increased risk was observed in Asian population (Lys vs Glu: OR = 1.53, 95%CI:1.39–1.69, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.50, 95%CI:1.34–1.69, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.48, 95%CI:1.84–3.34, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.58, 95%CI:1.41–1.78, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.18, 95%CI:1.62–2.93, P<0.01). Subgroup analysis based on smoking suggested Exo1 K589E polymorphism conferred significant risk among smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 2.16, 95%CI:1.77–2.63, P<0.01), but not in non-smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 0.89, 95%CI:0.64–1.24, P = 0.50). In conclusion, Exo1 K589E Lys allele may be used as a novel biomarker for cancer susceptibility, particularly in smokers.

The effect of MUC1 rs4072037 functional polymorphism on cancer susceptibility: evidence from published studies.

Genome-wide association studies have identified a susceptibility variation MUC1 rs4072037 for gastric cancer in Chinese population. Subsequent case-control studies have reported this association in other populations. However, the results remain controversial and ambiguous. The aim of this study is to provide a precise quantification for the association between MUC1 rs4072037 variation and the risk of cancer. We performed pooled analysis of 10 case-control designed studies including 4,220 cases and 6,384 controls. Odds ratios (OR) and 95% confidence interval (95%CI) were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity and cancer types. All statistical analyses were performed by Manager 5.0 and Stata 12.0 software. Overall, the MUC1 rs4072037 polymorphism was associated with risk of cancer in all genetic models (G vs A: OR = 0.71, 95%CI: 0.63–0.80, p<0.01; GA vs AA: OR = 0.61, 95%CI:0.55–0.67, p<0.01; GG vs AA: OR = 0.58, 95%CI: 0.47–0.71, p<0.01; AG+AA vs GG: OR = 0.60, 95%CI: 0.55–0.60, p<0.01; GG vs AG+AA: OR = 0.70, 95%CI: 0.58–0.85, p<0.01). Further, subgroup analysis based on ethnicity suggested MUC1 rs4072037 polymorphism had a subtly reduced cancer risk among Asian population, and stratified analysis by cancer types showed significantly decreased risk of gastric cancer in all genetic models. In conclusion, MUC1 rs4072037 polymorphism may be used as potential biomarker for cancer susceptibility particularly for gastric cancer and for Asian population.

SNP rs10248565 in HDAC9 as a novel genomic aberration biomarker of lung adenocarcinoma in non-smoking women

BackgroundNumerous efforts have been made to elucidate the etiology and improve the treatment of lung cancer, but the overall five-year survival rate is still only 15%. Although cigarette smoking is the primary risk factor for lung cancer, only 7% of female lung cancer patients in Taiwan have a history of smoking. Since cancer results from progressive accumulation of genetic aberrations, genomic rearrangements may be early events in carcinogenesis.ResultsIn order to identify biomarkers of early-stage adenocarcinoma, the genome-wide DNA aberrations of 60 pairs of lung adenocarcinoma and adjacent normal lung tissue in non-smoking women were examined using Affymetrix Genome-Wide Human SNP 6.0 arrays. Common copy number variation (CNV) regions were identified by ≥30% of patients with copy number beyond 2 ± 0.5 of copy numbers for each single nucleotide polymorphism (SNP) and at least 100 continuous SNP variant loci. SNPs associated with lung adenocarcinoma were identified by McNemar’s test. Loss of heterozygosity (LOH) SNPs were identified in ≥18% of patients with LOH in the locus. Aberration of SNP rs10248565 at HDAC9 in chromosome 7p21.1 was identified from concurrent analyses of CNVs, SNPs, and LOH.ConclusionThe results elucidate the genetic etiology of lung adenocarcinoma by demonstrating that SNP rs10248565 may be a potential biomarker of cancer susceptibility.

Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses

BackgroundThe circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems.MethodsTo assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS-targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis.ResultsTIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate.ConclusionsOur results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome.

PLCE1 rs2274223 A&gt;G polymorphism and cancer risk: a meta-analysis

Phospholipase C epsilon 1 gene (PLCE1) encodes a phospholipase enzyme which regulates various physiological processes (cell growth, differentiation, and apoptosis) and is supposed to play a critical role in carcinogenesis. Recently, a single nucleotide polymorphism (rs2274223 A>G) in PLCE1 was reported as a novel susceptibility locus for esophageal and gastric cancers by genome-wide association studies performed in Chinese population. However, individual association studies replicating this finding showed inconclusive results. Therefore, we performed a meta-analysis of eligible studies to derive precise estimation of the association of PLCE1 rs2274223 A>G polymorphism with cancer risk. We performed pooled analysis of 12 case–control studies including 7,622 cases and 9,555 controls. Odds ratios and 95 % confidence interval were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity, cancer types, and source of controls. All statistical analyses were performed by MIX 2.0 software. We found that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of cancer in log additive/dominant model and at allele level (GG vs. AA: OR = 1.24, 95 % CI = 1.01–1.53, P = 0.039; AG vs. AA: OR = 1.24, 95 % CI = 1.16–1.32, P < 0.001; AG + GG vs. AA: OR = 1.22, 95 % CI = 1.12–1.34, P < 0.001; and G vs. A allele: OR = 1.15, 95 % CI = 1.05–1.25, P = 0.002). Further, stratified analysis showed elevated risk of only gastric and esophageal tumors. Sub-group analysis based on ethnicity suggests PLCE1 polymorphism conferred significant risk among Asian (Chinese) but not in Caucasian. In conclusion, PLCE1 rs2274223 polymorphism may be used as potential biomarker for cancer susceptibility particularly for esophageal/gastric cancer and for the Chinese population.

Genome-Wide Small RNA Sequencing and Gene Expression Analysis Reveals a microRNA Profile of Cancer Susceptibility in ATM-Deficient Human Mammary Epithelial Cells

Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a syndrome characterized by neurological, motor and immunological defects, and a predisposition to cancer. MicroRNAs (miRNAs) are useful tools for cancer profiling and prediction of therapeutic responses to clinical regimens. We investigated the consequences of ATM deficiency on miRNA expression and associated gene expression in normal human mammary epithelial cells (HME-CCs). We identified 81 significantly differentially expressed miRNAs in ATM-deficient HME-CCs using small RNA sequencing. Many of these have been implicated in tumorigenesis and proliferation and include down-regulated tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as over-expressed pro-oncogenic miRNAs, such as hsa-miR-93 and hsa-miR-221. MicroRNA changes were integrated with genome wide gene expression profiles to investigate possible miRNA targets. Predicted mRNA targets of the miRNAs significantly regulated after ATM depletion included many genes associated with cancer formation and progression, such as SOCS1 and the proto-oncogene MAF. While a number of miRNAs have been reported as altered in cancerous cells, there is little understanding as to how these small RNAs might be driving cancer formation or how they might be used as biomarkers for cancer susceptibility. This study provides preliminary data for defining miRNA profiles that may be used as prognostic or predictive biomarkers for breast cancer. Our integrated analysis of miRNA and mRNA expression allows us to gain a better understanding of the signaling involved in breast cancer predisposition and suggests a mechanism for the breast cancer-prone phenotype seen in ATM-deficient patients.

MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies

Cumulative evidence suggests that MLH1, the key component in the mismatch pathway, plays an important role in human cancers. Two potential functional polymorphisms (-93G>A and I219V) of MLH1 have been implicated in cancer risk. The aim of this meta-analysis was to summarize the evidence for associations. Eligible studies were identified by searching the electronic literature PubMed, ScienceDirect and Embase databases for relevant reports and bibliographies. Studies were included if of case-control design investigating MLH1 polymorphisms (-93G>A and I219V) and cancer risk with sufficient raw data for analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to evaluate the strength of associations. Our meta-analysis from 33 published case-control studies showed the variant A allele of -93G>A polymorphism to be associated with increased risk in all genetic models (AA vs. GG: OR = 1.22, 95% CI: 1.03-1.44), especially among non-Asians (AA vs. GG: OR = 1.28, 95% CI: 1.04-1.58). For the I219V polymorphism, however, there was no main effect associated with overall cancer risk in any genetic model. The meta-analysis suggested that the MLH1 -93G>A polymorphism may be a biomarker of cancer susceptibility. Large sample association studies and assessment of gene-to-gene as well as gene-to-environment interactions are required to confirm these findings.

LINE-1 Methylation Levels in Leukocyte DNA and Risk of Renal Cell Cancer

PurposeLeukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.Experimental DesignLINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.ResultsLINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84–83.47) compared to 81.67% (IQR: 80.35–83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20−2.81), OR(Q3) = 1.72(1.11−2.65) and OR(Q4) = 2.06(1.34−3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.ConclusionsHigher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.