Structure and Methylation-Based Silencing of a Gene (DBCCR1) Within a Candidate Bladder Cancer Tumor Suppressor Region at 9q32-q33

Habuchi, Tomonori; Luscombe, Mike; Elder, Patricia A.; Knowles, Margaret A.

doi:10.1016/s0022-5347(01)62003-2

Cited by 14 publications

(27 citation statements)

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“…There was no association, however, between ABO and DAPK1 hypermethylation. Concomitant ABO allelic loss/LOH and hypermethylation were found in 6 patients (Table I), which is in agreement with previous findings showing that known hot‐spots for LOH in cancer are also frequent targets for aberrant hypermethylation 46…”

Section: Discussionsupporting

confidence: 92%

Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma

Gao

Worm

Guldberg

et al. 2003

Intl Journal of Cancer

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Loss of histo-blood group A and B antigen expression is a frequent event in oral carcinomas and is associated with decreased activity of glycosyltransferases encoded by the ABO gene. We examined 30 oral squamous cell carcinomas for expression of A and B antigens and glycosyltransferases. We also examined DNA from these tumors for loss of heterozygosity (LOH) at markers surrounding the ABO locus at chromosome 9q34, for loss of specific ABO alleles, and for hypermethylation of the ABO promoters. Loss of A or B antigen expression was found in 21 of 25 tumors (84%) and was a consistent feature of tumors lacking expression of A/B glycosyltransferases. LOH at 9q34 was found in 7 of 27 cases (26%), and one case showed microsatellite instability. Key words: oral carcinoma; ABO gene; methylation; loss of heterozygosity; genotypingChanges in the glycosylation patterns of cell surface carbohydrates have been demonstrated in most human cancers. Many recent studies have indicated that aberrant glycosylation occurs early during oncogenic transformation and may represent a key event in invasion and metastasis. 1 The blood group ABH antigens are cell surface carbohydrates distributed abundantly in epithelial tissues. Loss or reduction of A and B epitopes in human cancers is well documented, and loss of A and B antigens is correlated with the degree of malignancy and metastatic potential in lung, bladder and oral carcinomas. [2][3][4][5][6][7] In vitro studies have demonstrated that loss or addition of a single glycosyl residue, for example, ␣Gal-NAc on A antigen or ␣Gal on B antigen, may affect tumor cell motility by altering glycosylation of ␣3 and ␣6 integrin receptors and their interaction with ␤1 integrin. This may explain the observed correlation between glycosylation and prognosis. 8 The A and B antigens are terminal carbohydrates synthesized step-by-step by the addition of single sugars catalyzed by a series of specific glycosyltransferases. The phenotypic difference between A and B antigens is due to differences in substrate specificity of A and B glycosyltransferases. Phenotypic O is characterized by the absence of A and B glycosyltransferases and presumably by the presence of an inert protein encoded by the O allele. 9 -15 Expression of A/B antigens in tumors is directly correlated with A and B glycosyltransferase activity. 16 It is, however, not clear how the activity of A and B glycosyltransferases is suppressed in carcinomas. In vitro studies have shown that A antigen negative tumors have reduced levels of ABO transcript as compared to A antigen positive tumors. 17 Loss of heterozygosity (LOH) studies of bladder carcinomas have suggested frequent deletion at chromosome 9q34, which contains the ABO gene. 18 Alternatively, in vitro studies have shown that A antigen negative tumor cell lines have a higher level of DNA methylation at the ABO promotor region compared to A antigen positive cell lines, indicating that ABO promotor hypermethylation could be responsible for transcriptional inactivation. 19,20 As lack of AB...

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Section: Discussionsupporting

confidence: 92%

Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma

Gao

Worm

Guldberg

et al. 2003

Intl Journal of Cancer

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“…The majority of the cancer associated genes examined were tumor suppressor genes including genes operating in the RB1/p16 INK4a pathway ( p14 ARF , p15 INK4b , p16 INK4a , and RB1 ) [32], and two cyclin-dependent kinase inhibitors ( p27 KIP1 [33] and p57 KIP2 ) [34]. Other genes in this subset were a p53 analogue:( p73 ) [33,35], two alternative forms of a tumor suppressors in the Ras mediated signal transduction pathway ( RASSF1A , and RASSF1C [36]), VHL [37], APC [38], PTEN [6], the deleted in bladder cancer chromosome region candidate 1 ( DBCCR1 ) [39], and the Wilms tumor 1 gene( WT1 ) [40]. We included the genes encoding the cell membrane proteins or nuclear receptors which act actively in the intercellular interactions: melanoma specific antigen A1 ( MAGEA1 ) [41], caveolin 1 ( CAV ) [42], chondroitin sulfate proteoglycan 2 ( CSPG2 ) [43], androgen receptor ( AR ) [44], and cadherins ( CDH1 [45] and CDH13 ) [46].…”

Section: Resultsmentioning

confidence: 99%

Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma

Zhang

et al. 2004

BMC Cancer

114

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BackgroundAstrocytoma is a common aggressive intracranial tumor and presents a formidable challenge in the clinic. Association of altered DNA methylation patterns of the promoter CpG islands with the expression profile of cancer-related genes, has been found in many human tumors. Therefore, DNA methylation status as such may serve as an epigenetic biomarker for both diagnosis and prognosis of human tumors, including astrocytoma.MethodsWe used the methylation specific PCR in conjunction with sequencing verification to establish the methylation profile of the promoter CpG island of thirty four genes in astrocytoma tissues from fifty three patients (The WHO grading:. I: 14, II: 15, III: 12 and IV: 12 cases, respectively). In addition, compatible tissues (normal tissues distant from lesion) from three non-astrocytoma patients were included as the control.ResultsSeventeen genes (ABL, APC, APAF1, BRCA1, CSPG2, DAPK1, hMLH1, LKB1, PTEN, p14ARF, p15INK4b, p27KIP1, p57KIP2, RASSF1C, RB1, SURVIVIN, and VHL) displayed a uniformly unmethylated pattern in all the astrocytoma and non-astrocytoma tissues examined. However, the MAGEA1 gene that was inactivated and hypermethylated in non-astrocytoma tissues, was partially demethylated in 24.5% of the astrocytoma tissues (co-existence of the hypermethylated and demethylated alleles). Of the astrocytoma associated hypermethylated genes, the methylation pattern of the CDH13, cyclin a1, DBCCR1, EPO, MYOD1, and p16INK4a genes changed in no more than 5.66% (3/53) of astrocytoma tissues compared to non-astrocytoma controls, while the RASSF1A, p73, AR, MGMT, CDH1, OCT6,, MT1A, WT1, and IRF7 genes were more frequently hypermethylated in 69.8%, 47.2%, 41.5%, 35.8%, 32%, 30.2%, 30.2%, 30.2% and 26.4% of astrocytoma tissues, respectively. Demethylation mediated inducible expression of the CDH13, MAGEA1, MGMT, p73 and RASSF1A genes was established in an astrocytoma cell line (U251), demonstrating that expression of these genes is likely regulated by DNA methylation. AR gene hypermethylation was found exclusively in female patients (22/27, 81%, 0/26, 0%, P < 0.001), while the IRF7 gene hypermethylation preferentially occurred in the male counterparts (11/26, 42.3% to 3/27, 11%, P < 0.05). Applying the mathematic method "the Discovery of Association Rules", we have identified groups consisting of up to three genes that more likely display the altered methylation patterns in concert in astrocytoma.ConclusionsOf the thirty four genes examined, sixteen genes exhibited astrocytoma associated changes in the methylation profile. In addition to the possible pathological significance, the established concordant methylation profiles of the subsets consisting of two to three target genes may provide useful clues to the development of the useful prognostic as well as diagnostic assays for astrocytoma.

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“…Microsatellite markers exhibiting LOH are concentrated around three distinct regions, one region on the short arm (9p21)14 and two regions on the long arm of chromosome 9 (9q32–33 and 9q34)11, 15. These regions contain genes previously associated with bladder cancer, INK 4A mapped to 9p2114–17, DBC1 (deletion in bladder cancer gene 1) mapped to 9q32–3318–20 and TSC1 (tuberous sclerosis gene 1) mapped to 9q3411, 18, 21, 22. Loss of either 9p or 9q in bladder cancer is thought to be an early event8, but whilst homozygous loss of 9p21 has been associated with recurrence in one report, no detailed study of all TSGs on chromosome 9 in relation to recurrence has been reported23.…”

Section: Introductionmentioning

confidence: 99%

Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder

Edwards

Duncan

Going

et al. 2002

The Journal of Pathology

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Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence.

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Structure and Methylation-Based Silencing of a Gene (DBCCR1) Within a Candidate Bladder Cancer Tumor Suppressor Region at 9q32-q33

Cited by 14 publications

References 0 publications

Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma

Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma

Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma

Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder

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