Germ-Line TP53 Mutations in Finnish Cancer Families Exhibiting Features of the Li-Fraumeni Syndrome and Negative for BRCA1 and BRCA2

Huusko, Pia; Castrén, Katariina; Launonen, Virpi; Soini, Ylermi; Pääkkönen, Kati; Leisti, J; Vähäkangas, Kirsi; Winqvist, Robert

doi:10.1016/s0165-4608(98)00258-1

Cited by 18 publications

(19 citation statements)

References 21 publications

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“…Of the Observed always in cis position with 5557A.-remaining 11 bilateral cases, 1 was found positive for the CHEK2 1100delC germline mutation, which has been proposed to associate with bilateral breast cancer, 22 and 2 cases carried either the previously identified BRCA2 999del5 or TP53 Asn235Ser germline mutation. 10,23 In one of the studied pedigrees, 3 sisters (2 unilateral cases at the age of 47 and 59, and 1 bilateral case at the age of 69) and their maternal cousin (bilateral disease at the age of 52/ 55) were diagnosed with breast cancer. Both of the bilateral cases and the unilateral case diagnosed at age 59 were found to be 5557G?A, IVS38-8T?C composite allele carriers.…”

Section: Resultsmentioning

confidence: 99%

Association of common ATM polymorphism with bilateral breast cancer

Heikkinen

Rapakko

Karppinen

et al. 2005

Intl Journal of Cancer

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The ATM kinase has an essential role in maintaining genomic integrity. Loss of both ATM alleles results in ataxia-telangiectasia (A-T), a rare autosomal recessive neuroimmunologic disorder associated with cancer susceptibility. Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for malignancy, in particular, female breast cancer. In the current study, a full mutation analysis of the ATM gene was carried out in patients from 121 breast or breast-ovarian cancer families. We discovered that the combination of 5557G?A in cis position with IVS38-8 T?C was associated with bilateral breast cancer (OR ¼ 10.2; 95% CI ¼ 3.1-33.8; p ¼ 0.001). As the 5557G?A change has been reported to affect an exonic splicing enhancer, we hypothesized that the observed composite allele could have some effect on the correct splicing of exon 39. However, no aberrant transcripts were detected, but ATM expression levels of lymphoblast cell lines from heterozygous carriers of this combination allele were lower than from noncarriers (p ¼ 0.09). Lowered gene expression levels may have direct influence on the activities in DNA damage recognition and response pathways, as well as other genome integrity maintenance functions. Based on the results, we propose a cancer risk-modifying effect for the ATM 5557G?A, IVS38-8T?C composite allele. ' 2005 Wiley-Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

Association of common ATM polymorphism with bilateral breast cancer

Heikkinen

Rapakko

Karppinen

et al. 2005

Intl Journal of Cancer

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“…In the previous study by Huusko et al (1999), we screened 7 Finnish LFS and Li-Fraumeni-like (LFL) families for TP53 exon 5-8 mutations. Two changes were identified (Tyr220Cys and Asn235Ser), both of which appeared to associate with accumulation of female breast cancer.…”

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“…Of these families, 5 had previously been studied for TP53 exon 5-8 mutations (Huusko et al, 1999). Geographically, the families originated from 3 regions of Finland: 79 from the Oulu University Hospital area, 13 from the Tampere University Hospital area and 16 from the Helsinki University Central Hospital area.…”

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Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

Rapakko¹,

Allinen²,

Syrjäkoski

et al. 2001

Br J Cancer

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SummaryWe have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.

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“…In its mutated form or under certain cellular and/or genotoxic stress, the p53 protein becomes stabilized and its overabundance is readily detectable by immunohistochemical staining (May and May, 1999;WallaceBrodeur and Lowe, 1999). Overabundance of p53 protein may be found even in normal tissues in the nuclei of cells with a morphologically normal appearance (Barnes et al, 1992;Huusko et al, 1999;Varley et al, 1999). Immunohistochemical staining for p53 can be used to identify cells that are potential candidates for TP53 gene mutations.…”

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confidence: 99%

Toward Efficient Analysis of Mutations in Single Cells from Ethanol-Fixed, Paraffin-Embedded, and Immunohistochemically Stained Tissues

Heinmöller

Liu

Sun

et al. 2002

Laboratory Investigation

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SUMMARY:Only a few studies have demonstrated successful molecular analysis after whole genome amplification using single cells dissected from paraffin-embedded tissues. The results in these studies were limited by low-amplification efficiency and high rates of allele dropout. In the present study, the amplification rate using a thoroughly modified primer extension and preamplification-PCR protocol was improved significantly for single cells microdissected from paraffin-embedded and immunohistochemically stained tissues. Tissue fixation with ethanol (85%) and the addition of 0.2 mmol/L EDTA helped to achieve an amplification rate between 67% (segments 200 to 400 bp) and 72% (segments Ͻ200 bp). Normal tissue sections were immunohistochemically double stained for overabundance of p53 protein and proliferating cell nuclear antigen. Microdissection of single cells was performed with a manual micromanipulator equipped with a Tungsten needle. Sequence analysis of the TP53 gene was performed after improved primer extension preamplification-PCR and multiplex PCR from single microdissected cells. The rate of allele dropout was at least 68%. These technical advances facilitate routine mutation analysis using a single cell or a few cells microdissected from routinely processed paraffin-embedded normal and tumor tissues. Allele dropout still represents a serious problem in single-cell mutation analysis, especially in samples with limited template DNA and prone to DNA damage. (Lab Invest 2002, 82:443-453).

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Germ-Line TP53 Mutations in Finnish Cancer Families Exhibiting Features of the Li-Fraumeni Syndrome and Negative for BRCA1 and BRCA2

Cited by 18 publications

References 21 publications

Association of common ATM polymorphism with bilateral breast cancer

Association of common ATM polymorphism with bilateral breast cancer

Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

Toward Efficient Analysis of Mutations in Single Cells from Ethanol-Fixed, Paraffin-Embedded, and Immunohistochemically Stained Tissues

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