Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer

Thompson, Alastair; Morris, Robert G.; Wallace, Mark N.; Wyllie, Andrew H.; Steel, C. M.; Carter, D. C.

doi:10.1038/bjc.1993.287

Cited by 78 publications

(32 citation statements)

References 20 publications

(23 reference statements)

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“…In colorectal cancer a homozygous deletion, point mutations and DNA insertions have been observed within the DCC gene. Moreover, loss of heterozygosity (LOH) and reduction or loss of expression of the DCC transcript are common in prostate, breast, oesophageal, endometrial, glial and germ-cell cancer, as well as some haematological malignancies (Cropp et al, 1990;Hohne et al, 1992; Uchino et al, 1992; Gao et al, 1993;Miyake et al, 1993;Porfiri et al, 1993;Scheckr Coons, 1993;Thompson et al, 1993).…”

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Frequent reduction or loss of DCC gene expression in human osteosarcoma

Horstmann

Pösl²,

Rb³

et al. 1997

Br J Cancer

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Summary The 'deleted in colon carcinoma' (DCC) gene has been considered a candidate tumour-suppressor gene that encodes for a transmembrane protein with strong structural similarity to members of the superfamily of neural cell adhesion molecules. It has been mapped to the chromosomal region 18q21 .1 and it is implicated in cellular differentiation and developmental processes. In human osteosarcoma allelic loss frequently occurs on the long arm of chromosome 18, suggesting a possible involvement of the DCC gene in the pathogenesis of this tumour entity. In the present study the mRNA and protein expression and rearrangements at the DNA level of the DCC gene were addressed in 25 osteosarcomas and several tumour cell lines, including osteosarcoma-and colon carcinoma-derived cell lines. Using an reverse transcriphase polymerase chain reach in (RT-PCR)-based approach DCC expression was found to be lost or substantially reduced in 14 of 19 high-grade osteosarcomas, in three of six lower grade osteosarcomas and most of the tumour cell lines, in contrast to normally differentiated osteoblasts. Immunohistochemical studies on DCC protein expression of 14 selected tumours correlated well with the RT-PCR-based results. In view of the putative tumour-suppressor characteristics of the DCC gene its loss or reduction of expression could be a specific event in the development or progression of many high-grade osteosarcomas.

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Frequent reduction or loss of DCC gene expression in human osteosarcoma

Horstmann

Pösl²,

Rb³

et al. 1997

Br J Cancer

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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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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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“…The two studies specifically studying markers within, or adjacent to APC found modest levels of LOH, in the range 11-28% (Thompson et al, 1993;Medeiros et al, 1994). Allelotype studies including at least one marker on 5q have failed to reveal high levels of LOH (Devilee and Cornelisse, 1994).…”

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confidence: 99%

Section: Casesmentioning

confidence: 99%

“…We used tumour tissue as a source of DNA, and it is possible that I1307K polymorphisms detected could represent somatic mutations. However, loss of heterozygosity (LOH) is not common on 5q in breast cancer (Thompson et al, 1993;Devilee and Cornelisse, 1994;Medeiros et al, 1994) and no shortened forms of the APC protein were observed in cell lines Summary The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk for breast cancer in the same population. In that study, we genotyped 205 paraffin-embedded breast cancers from Ashkenazi Jewish women diagnosed below the age of 65.…”

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The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer

Yuan

Wong

et al. 1999

Br J Cancer

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Three founder mutations in BRCA1 and BRCA2 account for about 10% of breast cancer occurring in Ashkenazi Jewish women diagnosed at 65 years of age or less (Karp et al, 1997). Other genes, such as ATM and RASH may play a role in breast cancer susceptibility, but their contribution to breast cancer incidence is presently unknown. The I1307K polymorphism in APC has recently been found to be associated with an increased risk of colorectal cancer: the odds ratio (OR) of colorectal cancer in association with this polymorphism was 1.78 for all cases and 2.86 for those diagnosed at under age 66 (Laken et al, 1997). Interestingly, in four of the eight pedigrees illustrated in that paper, possible I1307K-carrying women had been diagnosed with breast (three kindreds) or ovarian cancer (one kindred). We and others have shown that the I1307K polymorphism is over-represented in Ashkenazi Jewish women with breast cancer, compared with ethnically-matched controls (OR = 1.5, P = 0.003) . To further understand the way in which the I1307K allele might increase the risk of breast cancer, we used a historical cohort approach to compare the clinicopathological features of breast cancers occurring in those carrying the I1307K polymorphism in APC, with those seen in non-carriers. The effect of the I1307K allele on breast cancer survival was determined. MATERIALS AND METHODS CasesStudy subjects were identified in the medical records department of the Sir Mortimer B Davis Jewish-General Hospital (SMBD-JGH) and included women who self-reported as being Ashkenazi Jewish by birth and who were diagnosed with invasive breast cancer below 65 years of age between 1 January 1986 and 1 November 1995. Two hundred and nine breast cancer blocks from eligible women were identified. All but nine of these samples were used in the primary study . These samples were rendered anonymous after clinicopathological information was obtained from chart review, and therefore we have no family history available for any of these women. All pathological and molecular analyses of the samples were carried out blinded. The study was approved by the Research Ethics Committee of the SMBD-JGH. Specimens were reviewed by one pathologist (LB). Histological tumour type, grade (1-3) and axillary lymph node status (positive or negative for breast cancer metastases, with the number of positive lymph nodes recorded) was determined by specimen and chart review. The specimens were then coded and DNA was extracted from the paraffin wax-embedded blocks using standard techniques. We used tumour tissue as a source of DNA, and it is possible that I1307K polymorphisms detected could represent somatic mutations. However, loss of heterozygosity (LOH) is not common on 5q in breast cancer (Thompson et al, 1993;Devilee and Cornelisse, 1994;Medeiros et al, 1994) and no shortened forms of the APC protein were observed in cell lines Summary The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk...

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Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer

Cited by 78 publications

References 20 publications

Frequent reduction or loss of DCC gene expression in human osteosarcoma

Frequent reduction or loss of DCC gene expression in human osteosarcoma

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

The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer

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