NAT1

Gene Summary

Gene:NAT1; N-acetyltransferase 1
Aliases: AAC1, MNAT, NATI, NAT-1
Location:8p22
Summary:This gene is one of two arylamine N-acetyltransferase (NAT) genes in the human genome, and is orthologous to the mouse and rat Nat2 genes. The enzyme encoded by this gene catalyzes the transfer of an acetyl group from acetyl-CoA to various arylamine and hydrazine substrates. This enzyme helps metabolize drugs and other xenobiotics, and functions in folate catabolism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:arylamine N-acetyltransferase 1
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Carcinogens
  • Biomarkers, Tumor
  • Pancreatic Cancer
  • Cancer Gene Expression Regulation
  • Diet
  • DNA Primers
  • NAT1
  • Acetyltransferases
  • Xanthines
  • Glutathione Transferase
  • Sequence Homology, Nucleic Acid
  • Enzyme Inhibitors
  • Phenotype
  • Acetylation
  • Pharmacogenetics
  • Polymerase Chain Reaction
  • Risk Factors
  • Genotype
  • Cohort Studies
  • Cytochrome P-450 CYP1A1
  • Cervical Cancer
  • Alleles
  • Arylamine N-Acetyltransferase
  • Up-Regulation
  • Meat
  • Cytochrome P-450 CYP1A2
  • Small Molecule Libraries
  • Chromosome 8
  • Cytochrome P-450 Enzyme System
  • Transcription
  • DNA Adducts
  • Bladder Cancer
  • Lung Cancer
  • Breast Cancer
  • Colorectal Cancer
  • Isoenzymes
  • Base Sequence
  • Genetic Predisposition
  • Genetic Variation
  • Case-Control Studies
  • Postmenopause
  • Odds Ratio
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NAT1 (cancer-related)

Savci-Heijink CD, Halfwerk H, Koster J, van de Vijver MJ
A novel gene expression signature for bone metastasis in breast carcinomas.
Breast Cancer Res Treat. 2016; 156(2):249-59 [PubMed] Free Access to Full Article Related Publications
Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were also found to be correlated to epithelial to mesenchymal transition status of the tumour. We have identified a novel 15-gene expression signature associated with the development of bone metastases in breast cancer patients. This bone metastasis signature is the first to be identified using a supervised classification approach in a large series of patients and will help forward research in this area towards clinical applications.

An Y, Li H, Wang KJ, et al.
Meta-analysis of the relationship between slow acetylation of N-acetyl transferase 2 and the risk of bladder cancer.
Genet Mol Res. 2015; 14(4):16896-904 [PubMed] Related Publications
The incidence of bladder cancer is closely associated with exposure to aromatic amines, that can cause cancer only after metabolic activation regulated by N-acetyl transferase 1 and 2 (NAT1 and NAT2). Many studies have indicated that slow acetylation of NAT2 increases the risk of bladder cancer. The major risk factor is tobacco smoke; however, some studies have failed to prove this. This study attempted to explore the correlation between NAT2 slow acetylation and bladder cancer risk through a meta-analysis of published case-control studies. Studies detecting NAT2 gene status in bladder cancer patients and healthy controls were retrieved from PubMed, Cochrane, EMchrane, CBM, and CNKI. We retrieved the data of cited articles and publications to identify and compare NAT2 gene in bladder cancer patients and healthy controls. The variables within and between the studies were also considered. The META module in the Stata v.6.0 software was used for data analysis. Twenty independent studies were enrolled in our meta-analysis according to the inclusion and exclusion criteria. Individual differences in the bladder cancer susceptibility were, in part, attributed to the effect of carcinogens. The merged odds ratio of the effect of slow acetylation on bladder cancer was 1.31 (95% confidence interval = 1.11-1.55). In conclusion, NAT2 slow acetylation state was associated with bladder cancer risk, and was shown to modestly increase the risk of bladder cancer.

De Carolis S, Bertoni S, Nati M, et al.
Carbonic Anhydrase 9 mRNA/microRNA34a Interplay in Hypoxic Human Mammospheres.
J Cell Physiol. 2016; 231(7):1534-41 [PubMed] Related Publications
The hypoxic environment is a crucial component of the cancer stem cell niche and it is capable of eliciting stem cell features in cancer cells. We previously reported that SNAI2 up-regulates the expression of Carbonic Anhydrase iso-enzyme 9 (CA9) in hypoxic MCF7 cells. Here we show that SNAI2 down-regulates miR34a expression in hypoxic MCF7 cell-derived mammospheres. Next, we report on the capability of miR34a to decrease CA9 mRNA stability and CA9 protein expression. We also convey that the over-expression of cloned CA9-mRNA-3'UTR increases the mRNA half-life and protein levels of two miR34a targets JAGGED1 and NOTCH3. The data here reported shows that the SNAI2-dependent down-regulation of miR34a substantially contributes to the post-transcriptional up-regulation of CA9, and that CA9-mRNA-3'UTR acts as an endogenous microRNA sponge. We conclude that CA9/miR34 interplay shares in the hypoxic regulation of mammospheres and therefore, may play a relevant role in the hypoxic breast cancer stem cell niche.

Montazeri Z, Theodoratou E, Nyiraneza C, et al.
Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas.
Int J Epidemiol. 2016; 45(1):186-205 [PubMed] Related Publications
BACKGROUND: Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/].
METHODS: We performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations.
RESULTS: We considered the association with the rs6983267 variant at 8q24 as 'highly credible', reaching genome-wide statistical significance in at least one meta-analysis model. We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations.
CONCLUSIONS: The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions.

Gehring MP, Kipper F, Nicoletti NF, et al.
P2X7 receptor as predictor gene for glioma radiosensitivity and median survival.
Int J Biochem Cell Biol. 2015; 68:92-100 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is considered the most lethal intracranial tumor and the median survival time is approximately 14 months. Although some glioma cells present radioresistance, radiotherapy has been the mainstay of therapy for patients with malignant glioma. The activation of P2X7 receptor (P2X7R) is responsible for ATP-induced death in various cell types. In this study, we analyzed the importance of ATP-P2X7R pathway in the radiotherapy response P2X7R silenced cell lines, in vivo and human tumor samples. Both glioma cell lines used in this study present a functional P2X7R and the P2X7R silencing reduced P2X7R pore activity by ethidium bromide uptake. Gamma radiation (2Gy) treatment reduced cell number in a P2X7R-dependent way, since both P2X7R antagonist and P2X7R silencing blocked the cell cytotoxicity caused by irradiation after 24h. The activation of P2X7R is time-dependent, as EtBr uptake significantly increased after 24h of irradiation. The radiotherapy plus ATP incubation significantly increased annexin V incorporation, compared with radiotherapy alone, suggesting that ATP acts synergistically with radiotherapy. Of note, GL261 P2X7R silenced-bearing mice failed in respond to radiotherapy (8Gy) and GL261 WT-bearing mice, that constitutively express P2X7R, presented a significant reduction in tumor volume after radiotherapy, showing in vivo that functional P2X7R expression is essential for an efficient radiotherapy response in gliomas. We also showed that a high P2X7R expression is a good prognostic factor for glioma radiosensitivity and survival probability in humans. Our data revealed the relevance of P2X7R expression in glioma cells to a successful radiotherapy response, and shed new light on this receptor as a useful predictor of the sensitivity of cancer patients to radiotherapy and median survival.

Liu F, Ji F, Ji Y, et al.
In-depth analysis of the critical genes and pathways in colorectal cancer.
Int J Mol Med. 2015; 36(4):923-30 [PubMed] Free Access to Full Article Related Publications
The present study aimed to investigate the molecular targets for colorectal cancer (CRC). Differentially expressed genes (DEGs) were screened between CRC and matched adjacent noncancerous samples. GENETIC_ASSOIATION_DB_DISEASE analysis was performed to identify CRC genes from the identified DEGs using the Database for Annotation, Visualization and Integrated Discovery, followed by Gene Οntology (GO) and Kyoto Encyclopedia of Genes and Genomes analysis for the CRC genes. A protein‑protein interaction (PPI) network was constructed for the CRC genes, followed by determination and analysis of the hub genes, in terms of the protein domains and spatial structure. In total, 35 CRC genes were determined, including 19 upregulated and 16 downregulated genes. Downregulated N‑acetyltransferase (NAT)1 and NAT2 were enriched in the caffeine metabolism pathway. The downregulated and upregulated genes were enriched in a number of GO terms and pathways, respectively. Cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA) were identified as the hub genes in the PPI network. The C‑terminal and N‑terminal domains were similar in PCNA, but different in CCND1. The results suggested PCNA, CCND1, NAT1 and NAT2 for use as biomarkers to enable early diagnosis and monitoring of CRC. These results form a basis for developing therapies, which target the unique protein domains of PCNA and CCND1.

Andres SA, Bickett KE, Alatoum MA, et al.
Interaction between smoking history and gene expression levels impacts survival of breast cancer patients.
Breast Cancer Res Treat. 2015; 152(3):545-56 [PubMed] Related Publications
In contrast to studies focused on cigarette smoking and risk of breast cancer occurrence, this study explored the influence of smoking on breast cancer recurrence and progression. The goal was to evaluate the interaction between smoking history and gene expression levels on recurrence and overall survival of breast cancer patients. Multivariable Cox proportional hazards models were fitted for 48 cigarette smokers, 50 non-smokers, and the total population separately to determine which gene expressions and gene expression/cigarette usage interaction terms were significant in predicting overall and disease-free survival in breast cancer patients. Using methods similar to Andres et al. (BMC Cancer 13:326, 2013a; Horm Cancer 4:208-221, 2013b), multivariable analyses revealed CENPN, CETN1, CYP1A1, IRF2, LECT2, and NCOA1 to be important predictors for both breast carcinoma recurrence and mortality among smokers. Additionally, COMT was important for recurrence, and NAT1 and RIPK1 were important for mortality. In contrast, only IRF2, CETN1, and CYP1A1 were significant for disease recurrence and mortality among non-smokers, with NAT2 additionally significant for survival. Analysis of interaction between smoking status and gene expression values using the combined samples revealed significant interactions between smoking status and CYP1A1, LECT2, and CETN1. Signatures consisting of 7-8 genes were highly predictive for breast cancer recurrence and overall survival among smokers, with median C-index values of 0.8 and 0.73 for overall survival and recurrence, respectively. In contrast, median C-index values for non-smokers was only 0.59. Hence, significant interactions between gene expression and smoking status can play a key role in predicting breast cancer patient outcomes.

Matejcic M, Vogelsang M, Wang Y, et al.
NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study.
BMC Cancer. 2015; 15:150 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tobacco smoking and red meat consumption are some of the known risk factors associated with the development of oesophageal cancer. N-acetytransferases (NAT1 and NAT2) play a key role in metabolism of carcinogenic arylamines present in tobacco smoke and overcooked red meat. We hypothesized that NAT1 and NAT2 genetic polymorphisms may influence the risk of oesophageal cancer upon exposure to environmental carcinogens.
METHODS: Single nucleotide polymorphisms (SNPs) in the NAT1 and NAT2 genes were investigated by genotyping 732 cases and 768 healthy individuals from two South African populations to deduce the acetylator phenotype (slow, intermediate or rapid) from the combination of the genotyped SNPs.
RESULTS: The 341 CC genotype (rs1801280) was significantly associated with a reduced risk for oesophageal cancer in the Mixed Ancestry population (OR = 0.31; 95% CI 0.11-0.87). The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58). Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81). In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).
CONCLUSIONS: Our findings indicate that N-acetylation polymorphisms may modify the association between environmental risk factors and oesophageal cancer risk and that N-acetyltransferases may play a key role in detoxification of carcinogens. Prevention strategies in lifestyle and dietary habits may reduce the incidence of oesophageal cancer in high-risk populations.

Cocco P, Zucca M, Sanna S, et al.
N-acetyltransferase polymorphisms are associated with risk of lymphoma subtypes.
Hematol Oncol. 2016; 34(2):79-83 [PubMed] Related Publications
Genes encoding for arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) have been investigated with alternate findings in relation to risk of non-Hodgkin lymphoma (NHL). We tested functional haplotype-based NAT1 and NAT2 gene polymorphisms in relation to risk of lymphoma overall and its major B cell subtypes, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). We used allele specific primers and multiplex PCR to detect NAT1 and NAT2 haplotypes in 248 patients with incident lymphoma and 208 population controls. We inferred the NAT1 rapid and slow acetylator and the NAT2 rapid, intermediate or slow acetylator phenotype, based on published functional data on the respective genotypes. Odds ratios and 95% confidence intervals (95% CIs) for lymphoma, B-NHL, DLBCL, FL, CLL, and other B-NHL combined associated with the inferred rapid NAT1 acetylator and with the intermediate and slow NAT2 acetylator phenotypes were estimated with unconditional and polytomous logistic regression analysis, adjusting for age, gender and education. NAT1 rapid acetylators showed a 2.8-fold excess risk (95% CI 1.5-5.2) for lymphoma (all subtypes combined). Risk was highest for CLL and FL, with significant heterogeneity detected across subtypes. Risk also increased with decreasing NAT2 acetylating capacity with no heterogeneity detected across B cell lymphoma subtypes. Risks did not vary by gender. Although poor statistical power was a major limitation in our study, larger studies and pooled analyses are warranted to test whether NAT1 and NAT2 gene polymorphisms might modulate risk of specific lymphoma subtypes through the varying metabolic activity of their products. Copyright © 2015 John Wiley & Sons, Ltd.

Tiang JM, Butcher NJ, Minchin RF
Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines.
Cancer Med. 2015; 4(4):565-74 [PubMed] Free Access to Full Article Related Publications
Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers.

Endo Y, Yamashita H, Takahashi S, et al.
Immunohistochemical determination of the miR-1290 target arylamine N-acetyltransferase 1 (NAT1) as a prognostic biomarker in breast cancer.
BMC Cancer. 2014; 14:990 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There are many molecular differences between estrogen receptor α (ERα)-positive and ER-negative breast cancers. Recent analyses have shown that the former can be divided into two subtypes, luminal A and luminal B. These differ in response to endocrine therapy and chemotherapy, and in prognosis. In a previous study, we found that microRNA (miR)-1290 that was significantly down-regulated in luminal A tumors and its potential target arylamine N-acetyltransferase 1 (NAT1). The aim of the present study was to determine whether NAT1 is a bona fide target of miR-1290, and to investigate the impact of NAT1 on breast cancer prognosis.
METHODS: Luciferase reporter assays were employed to validate NAT1 as a putative miR-1290 target gene. Expression of NAT1, ERα, progesterone receptor (PgR) and HER2 was analyzed in 394 breast cancer samples by immunohistochemistry.
RESULTS: NAT1 was confirmed to be a direct target of miR-1290. Levels of expression of NAT1 were positively correlated with those of ERα (P < 0.0001) and PgR (P < 0.0001), but negatively correlated with both tumor grade and size (P < 0.0001). Kaplan-Meier analysis showed that the presence of NAT1 was significantly associated with increased overall survival (OS) (P = 0.0416) in these patients. Similarly, significant associations of NAT1 with disease-free survival (DFS) (P = 0.0048) and OS (P = 0.0055) in those patients who received adjuvant endocrine therapy with tamoxifen (n = 176) were found. Moreover, NAT1 was also significantly associated with increased DFS (P = 0.0025) and OS (P = 0.0007) in the subset of lymph node-positive patients (n = 147). Univariate and multivariate analyses showed significant associations between levels of NAT1 and DFS (P = 0.0005 and 0.019, respectively).
CONCLUSIONS: We report that miR-1290 directly targets the NAT1 3'-UTR and that NAT1 protein expression is correlated with improved OS of breast cancer patients. NAT1 is a possible prognostic biomarker for lymph node-positive breast cancer. Thus, miR-1290 and its target NAT1 are associated with important characteristics of breast cancer.

Li L, Sarver AL, Khatri R, et al.
Sequential expression of miR-182 and miR-503 cooperatively targets FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma.
J Pathol. 2014; 234(4):488-501 [PubMed] Related Publications
Genetic changes in colon cancer are known to parallel the tissue abnormalities associated with the disease, namely adenoma and adenocarcinoma. The role of microRNA dysregulation in dysplastic progression, however, is not well understood. Here, we show that miR-182 and miR-503 undergo sequential up-regulation and drive the progression of colon adenoma to adenocarcinoma by cooperatively down-regulating the tumour suppressor FBXW7. We identified that increased expression of miR-182 is a feature of adenomas. A subsequent increase in miR-503 expression works cooperatively with miR-182 to induce transformation of an adenoma to adenocarcinoma. We show that introducing miR-503 into AAC1 cells, which are derived from a benign adenoma, confers tumourigenic potential. We also demonstrated that blocking both miR-182 and miR-503 in HCT116 colon cancer cells resulted in increased FBXW7 expression and significantly reduced tumour size in xenograft models. We confirmed relevance of these results in patients by examining the expression levels of miR-182 and miR-503 in over 200 colon cancer patients with 12 year survival outcome data. Decreased patient survival was correlated with elevated expression of both miRNAs, suggesting that elevated levels of both miR-182 and miR-503 define a novel prognostic biomarker for colon cancer patients. In conclusion, we show that a sequential expression of miR-182 and miR-503 in benign adenoma cooperatively regulates the tumour suppressor FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma and miR-182 and miR-503 may prove to be novel therapeutic targets. Array data are available at: http://www.oncomir.umn.edu/

Sieuwerts AM, Lyng MB, Meijer-van Gelder ME, et al.
Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting.
Mol Oncol. 2014; 8(8):1679-89 [PubMed] Related Publications
To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting. Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT-qPCR) and the length of progression-free survival (PFS) was used as the primary endpoint. A Mann-Whitney U test was used to select for differentially expressed genes between tumors of patients who showed or did not show progressive disease within 6 months after start of tamoxifen treatment. Cox univariate and multivariate regression analysis for PFS were used to further assess their (independent) predictive potential. Five (BCAR3, BCL2, ESR1, IGF1R, and NCOA1) of the 14 genes analyzed showed significantly higher mRNA levels in tumors of patients who showed no disease progression within 6 months. Only BCAR3, BCL2 and NAT1 were significantly associated with a favorable PFS in multivariate analysis that included the traditional predictive factors: age, dominant relapse site, disease-free interval, ER and progesterone receptor (PGR), and adjuvant chemotherapy. This study shows that BCAR3, BCL2 and NAT1 in particular exhibit predictive promise regarding the efficacy of tamoxifen treatment in recurrent disease, in addition to the previously shown favorable outcome in the adjuvant setting.

Cotterchio M, Mirea L, Ozcelik H, Kreiger N
Active cigarette smoking, variants in carcinogen metabolism genes and breast cancer risk among pre- and postmenopausal women in Ontario, Canada.
Breast J. 2014 Sep-Oct; 20(5):468-80 [PubMed] Related Publications
Cigarette smoking is strongly associated with various diseases including many cancers; however, evidence regarding breast cancer risk remains inconclusive with some studies reporting no association, and others an increased risk with long duration and early initiation of smoking. Genetic variation in carcinogen-metabolizing enzymes may modify these associations. Breast cancer cases were identified from the Ontario Cancer Registry (OCR) during 2003-2004 and population controls through random digit dialing methods. All subjects completed self-administered questionnaires. Subsequently, saliva samples were obtained from cases (N = 1,776) and controls (N = 1,839) for deoxyribonucleic acid (DNA) extraction. Multivariate logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for active smoking variables, and interactions were assessed between smoking and 36 carcinogen-metabolizing candidate gene variants. No statistically significant association was found between active smoking and breast cancer risk among all women nor when stratified by menopausal status; however, nonsignificant increased premenopausal breast cancer risk was observed among current smokers and women smoking before first pregnancy. Several statistically significant interactions were observed between smoking and genetic variants (CYP1A2 1548C>T, CYP1A1 3801T>C, CYP1B1 4326G>C, NAT1 c.-85-1014T>A, UGT1A7 W208R 622T>C, SOD2 c.47T>C, GSTT1 deletion). However, in analyses stratified by these genotypes, smoking ORs had wide confidence intervals (and with few exceptions included 1.0) making interpretations difficult. Active smoking was not associated with breast cancer risk, although several significant interactions were observed between smoking, carcinogen-metabolizing genetic variants, and breast cancer risk.

Andres SA, Smolenkova IA, Wittliff JL
Gender-associated expression of tumor markers and a small gene set in breast carcinoma.
Breast. 2014; 23(3):226-33 [PubMed] Related Publications
Breast carcinomas in both genders share pathological features, although differences in incidence, prognosis and survival are reported. Expression of 33 genes was investigated in male and female breast carcinomas in association with ER, PR, HER-2/neu and EGF-receptor. Among 98 male breast cancers, 82 were ER+ and 78 were PR+. ER and PR protein levels were greater in males compared to females, although no differences were observed in ESR1 and PGR expression. A difference was observed in binding affinities of PR but not ER between genders. No differences were observed in HER-2/neu, EGFR protein, or patient age. Expression of NAT1, TBC1D9, IL6ST, RABEP1, PLK1 and LRBA was elevated in carcinomas of males compared to those of females, in which ER status appeared to be related to expression. Over-expression of protein products of these genes represents novel molecular targets for development of gender-specific therapeutics and companion diagnostics.

Van Dyck E, Nazarov PV, Muller A, et al.
Bronchial airway gene expression in smokers with lung or head and neck cancer.
Cancer Med. 2014; 3(2):322-36 [PubMed] Free Access to Full Article Related Publications
Cigarette smoking is the major cause of cancers of the respiratory tract, including non-small cell lung cancer (NSCLC) and head and neck cancer (HNC). In order to better understand carcinogenesis of the lung and upper airways, we have compared the gene expression profiles of tumor-distant, histologically normal bronchial biopsy specimens obtained from current smokers with NSCLC or HNC (SC, considered as a single group), as well as nonsmokers (NS) and smokers without cancer (SNC). RNA from a total of 97 biopsies was used for gene expression profiling (Affymetrix HG-U133 Plus 2.0 array). Differentially expressed genes were used to compare NS, SNC, and SC, and functional analysis was carried out using Ingenuity Pathway Analysis (IPA). Smoking-related cancer of the respiratory tract was found to affect the expression of genes encoding xenobiotic biotransformation proteins, as well as proteins associated with crucial inflammation/immunity pathways and other processes that protect the airway from the chemicals in cigarette smoke or contribute to carcinogenesis. Finally, we used the prediction analysis for microarray (PAM) method to identify gene signatures of cigarette smoking and cancer, and uncovered a 15-gene signature that distinguished between SNC and SC with an accuracy of 83%. Thus, gene profiling of histologically normal bronchial biopsy specimens provided insight into cigarette-induced carcinogenesis of the respiratory tract and gene signatures of cancer in smokers.

Khlifi R, Chakroun A, Hamza-Chaffai A, Rebai A
Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients.
Mol Biol Rep. 2014; 41(4):2591-600 [PubMed] Related Publications
The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.

Pogue-Geile KL, Kim C, Jeong JH, et al.
Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.
J Natl Cancer Inst. 2013; 105(23):1782-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31.
METHODS: Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided.
RESULTS: Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001).
CONCLUSIONS: We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).

Khlifi R, Messaoud O, Rebai A, Hamza-Chaffai A
Polymorphisms in the human cytochrome P450 and arylamine N-acetyltransferase: susceptibility to head and neck cancers.
Biomed Res Int. 2013; 2013:582768 [PubMed] Free Access to Full Article Related Publications
The occurrence of head and neck cancer (HNC) is associated with smoking and alcohol drinking. Tobacco smoking exposes smokers to a series of carcinogenic chemicals. Cytochrome P450 enzymes (CYP450s), such as CYP1A1, CYP1B1, and CYP2D6, usually metabolize carcinogens to their inactive derivatives, but they occasionally convert the chemicals to more potent carcinogens. In addition, via CYP450 (CYP2E1) oxidase, alcohol is metabolized to acetaldehyde, a highly toxic compound, which plays an important role in carcinogenesis. Furthermore, two N-acetyltransferase isozymes (NATs), NAT1 and NAT2, are polymorphic and catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens. Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC. It has been suggested that such polymorphisms may be linked to cancer susceptibility. In this paper, we select four cytochrome P450 enzymes (CYP1A1, CYP1BA1, CYP2D6, and CYP2E1), and two N-acetyltransferase isozymes (NAT1 and NAT2) in order to summarize and analyze findings from the literature related to HNC risk by focusing on (i) the interaction between these genes and the environment, (ii) the impact of genetic defect on protein activity and/or expression, and (iii) the eventual involvement of race in such associations.

Storci G, Bertoni S, De Carolis S, et al.
Slug/β-catenin-dependent proinflammatory phenotype in hypoxic breast cancer stem cells.
Am J Pathol. 2013; 183(5):1688-97 [PubMed] Related Publications
Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.

Andres SA, Brock GN, Wittliff JL
Interrogating differences in expression of targeted gene sets to predict breast cancer outcome.
BMC Cancer. 2013; 13:326 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test.
METHODS: RNA was isolated from 225 frozen invasive ductal carcinomas,and qRT-PCR was performed. Univariate hazard ratios and 95% confidence intervals for breast cancer mortality and recurrence were calculated for each of the 32 candidate genes. A multivariable gene expression model for predicting each outcome was determined using the LASSO, with 1000 splits of the data into training and testing sets to determine predictive accuracy based on the C-index. Models with gene expression data were compared to models with standard clinical covariates and models with both gene expression and clinical covariates.
RESULTS: Univariate analyses revealed over-expression of RABEP1, PGR, NAT1, PTP4A2, SLC39A6, ESR1, EVL, TBC1D9, FUT8, and SCUBE2 were all associated with reduced time to disease-related mortality (HR between 0.8 and 0.91, adjusted p < 0.05), while RABEP1, PGR, SLC39A6, and FUT8 were also associated with reduced recurrence times. Multivariable analyses using the LASSO revealed PGR, ESR1, NAT1, GABRP, TBC1D9, SLC39A6, and LRBA to be the most important predictors for both disease mortality and recurrence. Median C-indexes on test data sets for the gene expression, clinical, and combined models were 0.65, 0.63, and 0.65 for disease mortality and 0.64, 0.63, and 0.66 for disease recurrence, respectively.
CONCLUSIONS: Molecular signatures consisting of five genes (PGR, GABRP, TBC1D9, SLC39A6 and LRBA) for disease mortality and of six genes (PGR, ESR1, GABRP, TBC1D9, SLC39A6 and LRBA) for disease recurrence were identified. These signatures were as effective as standard clinical parameters in predicting recurrence/mortality, and when combined, offered some improvement relative to clinical information alone for disease recurrence (median difference in C-values of 0.03, 95% CI of -0.08 to 0.13). Collectively, results suggest that these genes form the basis for a clinical laboratory test to predict clinical outcome of breast cancer.

Wu K, Wang X, Xie Z, et al.
N-acetyltransferase 1 polymorphism and bladder cancer susceptibility: a meta-analysis of epidemiological studies.
J Int Med Res. 2013; 41(1):31-7 [PubMed] Related Publications
OBJECTIVE: This meta-analysis was conducted to summarize the association between an N-acetyltransferase 1 (NAT1) gene polymorphism and bladder cancer risk.
METHODS: PubMed® and EMBASE databases were searched to identify studies that examined the effect of the NAT1*10 allele on the risk of bladder cancer.
RESULTS: Eleven case-control studies, which included 3311 bladder cancer cases and 3906 control subjects, met the inclusion criteria. The pooled analyses based on all studies showed that there was no significant difference in the NAT1*10 allele between bladder cancer cases and controls (odds ratios [OR] 0.96; 95% confidence interval [CI] 0.81, 1.10). When stratifying for race, the results were similar among Caucasians (OR 0.96; 95% CI 0.81, 1.12) and Asians (OR 0.87; 95% CI 0.48, 1.56). No statistical association was found between the NAT1*10 allele and bladder cancer risk upon stratification for smoking status and study design.
CONCLUSIONS: This meta-analysis suggests that there was no association between the NAT1*10 allele and bladder cancer risk. Further research should focus on other potentially functional genetic polymorphisms.

Andersen V, Holst R, Vogel U
Systematic review: diet-gene interactions and the risk of colorectal cancer.
Aliment Pharmacol Ther. 2013; 37(4):383-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diet contributes significantly to colorectal cancer (CRC) aetiology and may be potentially modifiable.
AIM: To review diet-gene interactions, aiming to further the understanding of the underlying biological pathways in CRC development.
METHODS: The PubMed and Medline were systematically searched for prospective studies in relation to diet, colorectal cancer and genetics.
RESULTS: In a meta-analysis, no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found (P-value for interaction 0.95). We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC. High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype, whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC (OR = 1.25; 95% confidence interval (CI): 0.92-2.01) compared with slow acetylators with low meat intake (reference), P-value for interaction = 0.07. Low meat intake in the studied populations may influence the result. Interactions between meat, cruciferous vegetables, fibres, calcium, vitamins, and alcohol and ABCB1, NFKB1, GSTM1, GSTT1, CCND1, VDR, MGTM, IL10 and PPARG are suggested.
CONCLUSIONS: A number of interactions between genetic variation and diet are suggested, but the findings need replication in independent, prospective, and well-characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached. When the above criteria are met, studies on diet-gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis.

Endo Y, Toyama T, Takahashi S, et al.
miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer.
Endocr Relat Cancer. 2013; 20(1):91-102 [PubMed] Related Publications
Recent analyses have identified heterogeneity in estrogen receptor α (ERα)-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis, are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ER(high) Ki67(low) tumors and ER(low) Ki67(high) tumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these groups. We identified a downregulation of miR-1290 in ER(high) Ki67(low) tumors. Among 11 miRNAs that were upregulated in ER(high) Ki67(low) tumors, quantitative RT-PCR detection analysis using 64 samples of frozen breast cancer tissue identified six miRNAs (let-7a, miR-15a, miR-26a, miR-34a, miR-193b, and miR-342-3p). We picked up 11 genes that were potential target genes of the selected miRNAs and that were differentially expressed in ER(high) Ki67(low) tumors and ER(low) Ki67(high) tumors. Protein expression patterns of the selected target genes were analyzed in 256 ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its putative targets, BCL2, FOXA1, MAPT, and NAT1, were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased expression of NAT1 and FOXA1. Our results suggest that miR-1290 and its potential targets might be associated with characteristics of ER-positive breast cancer.

Gibson TM, Smedby KE, Skibola CF, et al.
Smoking, variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma: a pooled analysis within the InterLymph consortium.
Cancer Causes Control. 2013; 24(1):125-34 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
METHODS: We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case-control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
RESULTS: Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07-1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95-1.69) acetylators (p (interaction) = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
CONCLUSION: The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.

Liu J, Ding D, Wang X, et al.
N-acetyltransferase polymorphism and risk of colorectal adenoma and cancer: a pooled analysis of variations from 59 studies.
PLoS One. 2012; 7(8):e42797 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship.
METHODS/PRINCIPAL FINDINGS: A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk (OR 0.99, 95% CI 0.91-1.07). We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC (OR 1.07, 95% CI 1.01-1.13). There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk (NAT1: OR 1.14, 95% CI 0.99-1.29; NAT2: OR 0.94, 95% CI 0.86-1.03).
CONCLUSION: This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk.

Gilsing AM, Berndt SI, Ruder EH, et al.
Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer.
Carcinogenesis. 2012; 33(7):1332-9 [PubMed] Free Access to Full Article Related Publications
Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

Aschebrook-Kilfoy B, Neta G, Brenner AV, et al.
Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer.
Endocr Relat Cancer. 2012; 19(3):333-44 [PubMed] Free Access to Full Article Related Publications
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (P(trend)) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (P(gene interaction)) were evaluated by combining P(trend) values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (P(trend) ≤ 0.01) and seven genes/regions (P(region)<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (P(gene interaction)=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (P(gene interaction)=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.

Johansson I, Nilsson C, Berglund P, et al.
Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker.
Breast Cancer Res. 2012; 14(1):R31 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC).
METHODS: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs.
RESULTS: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC.
CONCLUSIONS: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

Cai J, Zhao Y, Zhu CL, et al.
The association of NAT1 polymorphisms and colorectal carcinoma risk: evidence from 20,000 subjects.
Mol Biol Rep. 2012; 39(7):7497-503 [PubMed] Related Publications
Published data on the association between N-acetyltransferase 1 (NAT1) gene polymorphisms and colorectal carcinoma (CRC) susceptivity are inconclusive. To derive a more precise estimation of the association, we conducted this meta-analysis. Data were collected from electronic databases: PubMed, EMBASE, with the last report up to May 2010. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 20 individual studies including 8,219 cases and 11,498 controls based on the search criteria were involved. Meta-analysis was performed for slow versus rapid acetylation genotypes of NAT1. We found no association between NAT1 polymorphisms and CRC in overall population (OR = 0.96, 95% CI = 0.88-1.05 P = 0.05 for heterogeneity) without significant publication bias present. In subgroup analyses, similar results were found in different ethnicities, source of controls, genotyping methods and adjustment. Current meta-analysis suggests that lack of association between the NAT1 polymorphisms and individual risk to CRC.

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