MUC1 as a Putative Prognostic Marker for Prostate Cancer.
ABSTRACT: MUC1 is expressed on the apical surface of glandular epithelium. With functions including protection, adhesion and signaling, MUC1 has been implicated in prostate cancer. There are many splice variants, the best characterized of which are MUC1/1 and MUC1/2 which are determined by a SNP (rs4072037, 3506G>A).Blood DNA from the general population, BPH, sporadic and hereditary prostate cancer subjects were genotyped for the rs4072037 SNP. G allele frequencies were significantly reduced in hereditary prostate cancer (15%) compared to population, BPH or sporadic prostate cancer samples (27%, 39% and 26% respectively). In addition, the G allele was lost from 3 of 8 heterozygous sporadic prostate tumor samples compared to matched blood DNA. Bioinformatics analysis of MUC1 protein sequences provides insight into differences between the variants which may be functionally relevant. The literature indicates discrepancies between immuno-histochemical studies, possibly due to the variety of MUC1 epitopes targeting diverse regions of the molecule. The contradictory findings in cell lines highlight the problem associated with inadequate experimental systems.This is the first report of genetic differences in MUC1 between blood and prostatic cancer tissue. This finding is important as proof of principle, given that many association studies focus on blood DNA rather than on the tumor DNA. As yet, potential functional differences between splice variants has been paid little attention. Antibodies which discriminate between the variants and standardization of methods would help to clarify whether there is a role for MUC1 as a prognostic marker.
Project description:BACKGROUND:Mucin 1 (MUC1) contributes to the growth and metastasis of various cancers, including lung cancer, and MUC1 gene length polymorphisms are associated with susceptibility to lung cancer and its prognosis. In contrast, the association between rs4072037, a single nucleotide polymorphism in MUC1, and lung cancer has not been well studied. METHODS:In the present study, we determined the rs4072037 genotype and measured serum KL-6 levels to evaluate the association between lung adenocarcinoma (ADC) and rs4072037 or serum KL-6 levels. DNA samples were available for 172 patients and these were included in the genomic analyses. In addition, 304 patients were included in the serum analyses. Furthermore, 276 healthy volunteers were included in both genomic and serum analyses. RESULTS:The rs4072037 genotype was not associated with susceptibility to lung ADC or its prognosis. Interestingly, serum KL-6 levels significantly differed according to rs4072037 genotype in those with T1 or T2 (P < 0.001), N0 or N1 (P = 0.002) and M0 (P < 0.001), but not in those with T3 or T4 (P = 0.882), N2 or N3 (P = 0.616) and M1a or M1b (P = 0.501). Serum KL-6 levels were significantly associated with the presence of lung ADC, as well as with its progression and prognosis, indicating the crucial involvement of KL-6/MUC1 in the development of lung cancer and its progression. CONCLUSION:Based on these findings, we conclude that rs4072037 does not have a significant impact on the pathogenesis or prognosis of lung ADC, whereas serum KL-6 levels, which might reflecting the molecular length of MUC1, are significantly associated with lung ADC.
Project description:Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/ protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.
Project description: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.
Project description:The association between MUC1 polymorphism rs4072037 and the risk of gastric cancer has been described in several studies. However, these studies yielded inconsistent results, especially in different pathological type of gastric cancer. Therefore, we performed this meta-analysis to evaluate the relationship between MUC1 gene polymorphism and gastric cancer susceptibility. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between MUC1 rs4072037 and risk of gastric cancer. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. PubMed, EMBASE, Web of Science and CNKI databases were systematically searched to identify relevant studies. A total of 9 studies (12 datasets) were included in the meta-analysis including 10,410 cases and 11,437 controls. Overall, the G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR=0.70, 95% CI: 0.64-0.76). The association was significant in both anatomic location and pathological subtype subgroup analyses. However, the association was detected in Asian rather than Caucasian. Our findings demonstrate that the presence of the G allele at rs4072037 of the MUC1 gene may contribute to protection against gastric cancer in Asian. Further large studies of multiethnic groups are needed to validate these findings.
Project description:<h4>Objective</h4>To examine single nucleotide polymorphism (SNPs) in MUC16 (CA125) and MUC1 (CA15.3) in relation to ovarian cancer risk and survival.<h4>Methods</h4>We genotyped germline variants of MUC16 (rs2547065, rs1559168, rs12984471, rs2121133) and MUC1 (rs2070803, rs4072037, rs1045253) using samples collected from 758 ovarian cancer cases and 788 controls enrolled in the New England Case-Control Study between 2003 and 2008. We calculated age-adjusted odds ratios (OR) and 95% confidence intervals (CIs) for disease risk using unconditional and polytomous logistic regression and hazard ratios (HR) for survival using Cox proportional hazard ratios. In a subset of cases, we compared log-normalized CA125 values by genotype using generalized linear models.<h4>Results</h4>Cases homozygous for the variant allele of MUC16 SNP, rs12984471, had poorer overall survival (log-rank p = 0.03) and higher CA125 levels, especially cases over age 65 (p = 0.01). For MUC1 SNP, rs4072037, women homozygous for the G variant had a non-significantly decreased risk for serous invasive types but elevated risk for serous borderline tumors, mucinous borderline and invasive tumors, and endometrioid tumors. Women with the variant allele of MUC16 SNP, rs2547065, especially those who were homozygous had an elevated risk for ovarian cancer; but this association was not confirmed in an independent dataset.<h4>Conclusion</h4>This targeted screen of seven polymorphisms of MUC16 and MUC1 genes failed to identify and confirm effects on ovarian cancer risk overall. However, there may be effects of MUC16 rs12984471 on survival and MUC1 rs4072037 on risk for histologic types of ovarian cancer other than invasive serous. Further study is warranted.
Project description:Objectives: The result of the relationship between the MUC1 rs4072037 polymorphism and cancer risk is controversial, we take this meta-analysis to investigate a more precise result. Methods: Electronic database Pubmed, Web of science and Cochrane library had been used to search relevant articles concerning the relationship between MUC1 rs4072037 polymorphism and cancer risk. We used odds ratios (ORs) and 95% confidence intervals (CIs) to assess the strength of the gene-disease association. We also conducted subgroup analysis, sensitivity analyses and publication bias in the meta-analysis. Results: In our meta-analysis, we involved 17 studies (19 datasets) with 12551 cases and 13436 controls eventually. It showed the MUC1 rs4072037 polymorphism was associated with decreased cancer risk in four genetic models (G vs. A: OR=0.79, 95%CI: 0.71-0.89, P< 0.001; AG vs. AA: OR=0.72, 95%CI: 0.62-0.82, P< 0.001; GG vs. AA: OR=0.78, 95%CI: 0.69-0.88, P< 0.001; AG+GG vs. AA: OR=0.72, 95%CI: 0.63-0.83, P< 0.001). In subgroup analysis, it showed a decreased cancer risk among Asians but not Caucasians and a significant decreased gastric cancer risk in all genetic models. Conclusion: MUC1 rs4072037 polymorphism is associated with decreased cancer risk and can probably be used as a tumor marker, especially for gastric cancer and for Asians.
Project description:Purpose:Mucin 1 (MUC1) was identified as a gastric cancer (GC) susceptibility gene by genome-wide association studies in Asians and candidate gene studies in Europeans. This study aimed to investigate the association between the MUC1 rs4072037 polymorphism and GC in terms of the Lauren classification and long-term clinical outcomes. Materials and Methods:A total of 803 patients with GC and 816 unrelated healthy controls were enrolled in the study. The association between the MUC1 rs4072037 variant and GC histological types and clinical outcomes, including tumor recurrence and prognosis was investigated. Results:The major A allele of rs4072037 was associated with increased GC risk (P<0.05). In subtype analysis, the association was most significant for diffuse-type GC (P<0.05) and in a dominant model (P<0.05), whereas there was no association with intestinal-type GC (P>0.05). Cox proportional hazards analysis revealed the heterozygote AG rs4072037 allele as an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC (P<0.05). but not in intestinal-type GC (P>0.05). Conclusions:The exonic single nucleotide polymorphism rs4072037 in MUC1 was associated with diffuse-type GC and was an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC.
Project description:Background: Prostate cancer is a complex condition in which both genetic and environmental factors concomitantly contribute to the tumor initiation and progression. Recently, HOXB13 has been proposed as a susceptibility gene for prostate cancer. Objective: The present study was conducted to determine the existence of potential variations in HOXB13 gene in Iranian men with prostate cancer (PCa) compared to benign prostatic hyperplasia (BPH) cases. Methods: HOXB13 genetic status was screened in 51 samples, including 21 blood and tissue of PCa cases, and compared to 30 cases affected by BPH using PCR/sequencing. Then, the existence of potential association was investigated between genomic DNA alterations in blood and tissue PCa specimens. Results: Analysis of BPH tissues showed single nucleotide variations c.366C > T (rs) or c.513T > C (rs9900627) in exon 1, but not in exon 2. Evaluation of PCa tissues revealed 2 cases with both synonymous c.366C > T and c.513T > C variants and 2 cases with the synonymous c.366C > T variant in exon 1. The variants c.366C > T and c.513T > C, simultaneously or separately, were found in blood samples of PCa patients. The novel variant c.127A > G in exon 2 was detected in 1 PCa blood sample. Our analysis indicated a significant reciprocal correlation between HOXB13 mutation in the tissue and blood samples of PCa cases (p= 0.02). Conclusion: The variants in exon 2 of HOXB13 may influence the risk of prostate cancer. Also, evaluation of HOXB13 mutation may be considered as a novel marker for screening PCa. Further investigations are warranted to evaluate the clinical significance of HOXB13 in Iranian population.
Project description:Background and objective: To further determine the association between mucin 1 (MUC1) rs4072037 polymorphism and gastric cancer risk on the basis of previously published studies. Methodology: PubMed and Embase were used to search all the available publications. The relative risk of the correlation was shown as odds ratio (OR) with 95% confidence interval (95% CI) under all the genetic comparisons. Subgroup analyses based on ethnicity, study design and HWE were also executed to detect effects of specific factors on the risk of gastric cancer. Results:MUC1 rs4072037 polymorphism was observed to reduce the risk of gastric cancer under the five genetic comparisons [(GG versus AA: OR (95% CI)=0.72 (0.61, 0.84); GG + GA versus AA: OR (95% CI)=0.82 (0.76, 0.88); GG versus AA + GA: OR (95% CI)=0.83 (0.71, 0.96); G versus A: OR (95% CI)=0.78 (0.72, 0.84); GA versus AA: OR (95% CI)=0.80 (0.74, 0.87)]. This decreased risk of gastric cancer was also detected in subgroup analyses based on ancestry (Asian and Caucasian), study design (population-based and hospital-based) and HWE (PHWE>0.05). Conclusions:MUC1 rs4072037 polymorphism may have an important role in gastric cancer, and this protective effect may vary among different ethnic populations and control subjects.
Project description:ARLTS1 is a recently characterized tumor suppressor gene at 13q14.3, a region frequently deleted in both sporadic and hereditary prostate cancer (PCa). ARLTS1 variants, especially Cys148Arg (T442C), increase susceptibility to different cancers, including PCa. In this study the role of Cys148Arg substitution was investigated as a risk factor for PCa using both genetic and functional analysis. Cys148Arg genotypes and expression of the ARLTS1 were explored in a large set of familial and unselected PCa cases, clinical tumor samples, xenografts, prostate cancer cell lines and benign prostatic hyperplasia (BPH) samples. The frequency of the variant genotype CC was significantly higher in familial (OR?=?1.67, 95% CI?=?1.08-2.56, P?=?0.019) and unselected patients (OR?=?1.52, 95% CI?=?1.18-1.97, P?=?0.001) and the overall risk was increased (OR?=?1.54, 95% CI?=?1.20-1.98, P?=?0.0007). Additional analysis with clinicopathological data revealed an association with an aggressive disease (OR?=?1.28, 95% CI?=?1.05-?, P?=?0.02). The CC genotype of the Cys148Arg variant was also contributing to the lowered ARLTS1 expression status in lymphoblastoid cells from familial patients. In addition significantly lowered ARLTS1 expression was observed in clinical tumor samples compared to BPH samples (P?=?0.01). The ARLTS1 co-expression signature based on previously published microarray data was generated from 1587 cancer samples confirming the low expression of ARLTS1 in PCa and showed that ARLTS1 expression was strongly associated with immune processes. This study provides strong confirmation of the important role of ARLTS1 Cys148Arg variant as a contributor in PCa predisposition and a potential marker for aggressive disease outcome.