Mismatch Repair Genes hMLH1 and hMSH2 May Not Play an Essential Role in Breast Carcinogenesis

Khilko, Natalya; Bourne, Patricia A.; Yang, Qi; Tang, Ping

doi:10.1177/1066896907302116

Cited by 7 publications

(5 citation statements)

References 55 publications

(83 reference statements)

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“…In this study, methylation of MGMT was rare in both DCIS and invasive tumours, also in concordance with previous studies [36]. Infrequent methylation was also observed for the MLH1 gene, in line with the absence of changes in MLH1 expression during early breast carcinogenesis as assessed by IHC [37,38]. We also found minimal methylation of CDKN2A within the CpGs studied here, which is in concordance with a previous study on DCIS and other proliferative lesions of the breast [16].…”

Section: Discussionsupporting

confidence: 92%

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer

et al. 2010

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IntroductionDuctal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive.MethodsQuantitative DNA methylation analysis of ABCB1, CDKN2A/p16INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1.ResultsAberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation.ConclusionsQuantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.

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Section: Discussionsupporting

confidence: 92%

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer

et al. 2010

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“…55 As well, hMLH1 does not seem to play an essential role in human breast carcinoma. 56 Together, these data are in agreement with our observations that tumor formation in Hoxa5/p53 mammary grafts does not involve Mlh1 misregulation.…”

Section: Org)supporting

confidence: 82%

Influence of Hoxa5 on p53 Tumorigenic Outcome in Mice

Gendronneau

Lemieux

Morneau

et al. 2010

The American Journal of Pathology

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Hox genes encode transcription factors of crucial importance in the pattern formation of a large spectrum of species. Several studies have now proposed a role for these developmental genes in cancer biology. It has been suggested that HOXA5 possesses growthsuppressive properties through activation of p53 expression in human breast tissue. To assess the genetic cooperation that may exist between Hoxa5 and p53 in tumorigenesis, we generated Hoxa5/p53 compound mutant mice. The presence of Hoxa5 null alleles increased the susceptibility of p53 ؊/؊ mice to develop tumors with a high prevalence for thymic lymphoma, suggesting that the loss of function of the two genes collaborate in tumor formation. To extend our analysis to mammary tumorigenesis, we performed Hoxa5/p53 whole mammary gland transplantations into wild-type hosts. In the p53 ؊/؊ background, the presence of one Hoxa5 mutant allele had no impact on mammary tumor formation. In contrast, the complete loss of Hoxa5 function influenced the tumorigenic outcome of p53 ؉/؊ mammary glands. However , the collaborative nature of this interaction did not depend on the transcriptional regulation of p53 by Hoxa5. Altogether , our data establish that Hoxa5 and p53 cooperate in mammary tumorigenesis in vivo. (Am J Pathol 2010, 176

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“…Although an association between the homozygous variant genotype and breast cancer has been suggested, we did not observe a correlation between this polymorphism and head and neck cancer risk. Our findings are consistent with recent studies indicating a lack of relationship between this polymorphism and breast (Khilko et al, 2007) or renal cancers (Rubio-del-Campo et al, 2008). This is the first study to investigate a possible role of the three hMSH2 gene variants in head and neck cancer.…”

Section: Discussionsupporting

confidence: 95%

Analysis of the hMSH2 Gene Variants in Head and Neck Cancer

Demokan

Süoğlu²,

Ulusan³

et al. 2010

DNA and Cell Biology

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The hMSH2 (human MutS homolog 2) gene plays a central role in DNA mismatch repair. Structural variations in the gene may lead to protein instability and deficient mismatch repair. However, the role of polymorphic variants of the hMSH2 gene have not been defined in head and neck cancer. In this study, the roles of three polymorphic variants in the functional domains of the gene were investigated in 166 patients with head and neck cancer by allele-specific PCR, electronical array addressing, and PCR/RFLP (restriction fragment length polymorphism). This is the first study to investigate the gIVS12-6T --> C polymorphism in head and neck cancer. A significant association between the CC genotype and reduced risk of disease suggests that the gIVS12-6T --> C substitution at the splice-acceptor site may affect the risk of head and neck cancer. We did not observe an association between the Asn127Ser and Gly322Asp polymorphisms and cancer risk. A possible role of the gIVS12-6T --> C substitution warrants further validation in larger cohorts because of low allele frequency.

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Mismatch Repair Genes hMLH1 and hMSH2 May Not Play an Essential Role in Breast Carcinogenesis

Cited by 7 publications

References 55 publications

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer

Influence of Hoxa5 on p53 Tumorigenic Outcome in Mice

Analysis of the hMSH2 Gene Variants in Head and Neck Cancer

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