Somatic Mutations of the APC Gene in Primary Breast Cancers

Furuuchi, Keiji; Tada, Mitsuhiro; Yamada, Hideshi; Kataoka, Akihiko; Furuuchi, Narumi; Hamada, Junichi; Takahashi, Masato; Todo, Satoru; Moriuchi, Tetsuya

doi:10.1016/s0002-9440(10)65072-9

Cited by 106 publications

(79 citation statements)

References 26 publications

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“…22,23 Moreover, they can be related to progression of disease, e.g., breast cancer. 24 Only very few sarcomas carry mutations of the APC gene, 11,25 which is consistent with our finding that none of the 15 analysed myxoid/ round-cell LPS showed a truncated APC protein in the PTT assay. Interestingly, APC mutations found in synovial sarcoma are missense mutations.…”

Section: Discussionsupporting

confidence: 89%

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

Sievers

Fritzsch

Lehnhardt

et al. 2006

Intl Journal of Cancer

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The adenomatous polyposis coli (APC) protein is a key component of the WNT signalling pathway wherein it acts as a scaffolding protein in controlling the level of the proto-oncoprotein b-catenin. Although APC has been shown to be genetically or epigenetically inactivated in a variety of carcinomas, little is known about its role in sarcoma. Liposarcomas (LPSs) are the second most common soft tissue sarcoma in adults. Despite different histology and malignancy, the myxoid and round-cell LPSs belong to one tumour entity characterized by a specific chromosomal translocation. We assessed the extent of genetic and epigenetic inactivation of the APC gene in myxoid/round-cell LPS. Sequencing of the mutation cluster region, the protein truncation test and a loss of heterozygosity (LOH) analysis did not reveal any genetic alterations of the APC gene in all of the liposarcoma samples. Methylation of the APC promoter was detected by methylation-specific PCR in 9 of 20 (45%) tumours. Analysis of APC expression by semiquantitative RT-PCR in a subset of the samples demonstrated that tumours with a methylated APC promoter showed a downregulation of the APC transcript. However, APC downregulation was not correlated with a stabilisation of the b-catenin protein.Thus, the epigenetic regulation of the APC gene might play an important role in the pathogenesis of myxoid/round-cell LPS. However, the impact of APC methylation on liposarcoma development is quite likely not mediated through WNT signalling. ' 2006 Wiley-Liss, Inc.Key words: adenomatous polyposis coli; methylation; liposarcoma Even though genetic hits leading to carcinogenesis have been well characterized, the role of epigenetic factors in tumour formation is just emerging. Epigenetics makes an impact on such different fields as chromosomal stability, silencing of retroelements and the setup and maintenance of a cell's expression status, thereby functioning as cellular memory. In the latter context, the promoter hypermethylation of tumour suppressor genes leading to their aberrant transcriptional silencing has been intensively studied. 1 It has also been shown that epigenetic phenomena such as DNA methylation and histone modification can be considered diagnostic or even prognostic markers. 2,3 The APC tumour suppressor protein exhibits diverse functions in the cell, whereby its role in the WNT signalling pathway is especially well described. It therein acts as a scaffolding protein in a multimeric protein complex, together with Axin and glycogen synthase kinase-3b (GSK-3b), which binds and phosphorylates the proto-oncoprotein b-catenin. Upon binding of a WNT protein to one of its receptors, the intracellular protein dishevelled inactivates GSK-3b. As a consequence, b-catenin can no longer be phosphorylated and hence marked for degradation. b-catenin then translocates into the nucleus, where it interacts with transcription factors of the TCF/LEF (T-cell factor/lymphoid enhancing factor) family. This interaction stimulates the transcription of WNT target genes like myc and...

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Section: Discussionsupporting

confidence: 89%

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

Sievers

Fritzsch

Lehnhardt

et al. 2006

Intl Journal of Cancer

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“…26,27 We also previously reported that there were no mutations of the APC gene in 29 NSCLCs, including 13 specimens analyzed for ␤-catenin gene mutation in the current study. 28 These findings suggest that APC-mediated nuclear export of ␤-catenin can help form the cadherin-catenin complex. Another possible mechanism is apoptosis by ␤-catenin.…”

Section: Discussionmentioning

confidence: 94%

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Hommura

Furuuchi

Yamazaki

et al. 2002

Cancer

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BACKGROUNDβ‐Catenin has been shown to function as a Wnt signaling molecule to stimulate cyclin D1 expression and cell growth in several kinds of tumors.METHODSThe authors immunohistochemically examined specimens of 217 surgically resected primary nonsmall cell lung carcinomas (NSCLCs) for β‐catenin expression and classified them semiquantitatively into three categories, including those with high, moderate, and low scores of expression.RESULTSHigh, moderate, and low scores of expression were found in 37 (17.1%), 145 (66.8%), and 35 (16.1%) tumors, respectively. β‐Catenin expression was not correlated with cyclin D1 expression, but was positively correlated with the Ki‐67 cell growth fraction (P = 0.04). The direct sequencing analysis for the β‐catenin gene mutation of 13 specimens of 217 tumors for the current study revealed no mutations. The relation between survival and β‐catenin expression was evaluated in 148 potentially curatively resected tumors with pathologic Stages I–IIIA. A trend toward better survival was found in patients with tumors having higher scores. In multivariate analysis, high β‐catenin expression was a significant and independent favorable prognostic factor (hazards ratio, 0.31; P = 0.007) as was pathologic stage. Analyzed by cell type, in nonsquamous cell carcinomas, patients with tumors having high scores survived a significantly longer time than those with tumors having moderate or low scores (5‐year survival rates, 84%, 55%, and 32%, respectively; P = 0.02), and high β‐catenin expression tended to be a favorable prognostic factor (hazards ratio, 0.32; P = 0.052).CONCLUSIONSThese results indicate that, in NSCLCs, increased expression of β‐catenin can predict favorable prognosis of patients with resected tumors, suggesting that accumulation of β‐catenin has no or little oncogenic effect via activation of the Wnt pathway, unlike in colon carcinomas or hepatomas. Cancer 2002;94:752–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10213

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“…Loss of APC expression and upregulation of b-catenin have been described in human breast cancer and breast cancer cells (Ho et al, 1999;Jonsson et al, 2000;Schlosshauer et al, 2000). Somatic APC mutations are reported in only a minority of breast cancers (Furuuchi et al, 2000), despite high rates of allelic loss at chromosome locus 5q21 (Thompson et al, 1993;Medeiros et al, 1994). Nevertheless, epigenetic inactivation of APC due to DNA methylation is frequently present in both breast cancer cell lines and breast cancer tissue.…”

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confidence: 99%

Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

et al. 2008

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Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal breast tissues, IBC and non-IBC by both conventional and real-time quantitative methylation-specific PCR (MSP). APC methylation levels were compared with APC mRNA and protein levels. Hypermethylation of the APC gene promoter was present in 71% of IBC samples (n ¼ 21) and 43% of non-IBC samples (n ¼ 30) by conventional MSP (P ¼ 0.047). The APC gene also showed an increased frequency of high methylation levels in IBC (in 74% of cases, n ¼ 19) vs non-IBC (in 46% of cases, n ¼ 35) using a qMSP assay (P ¼ 0.048). We observed no significant association between APC methylation levels by qMSP and APC mRNA or protein expression levels. In conclusion, for the first time, we report the association of aberrant methylation of the APC gene promoter with the IBC phenotype, which might be of biological and clinical importance.

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Somatic Mutations of the APC Gene in Primary Breast Cancers

Cited by 106 publications

References 26 publications

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

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