University of Oulu

DNA damage response genes and chromosome 11q21-q24 candidate tumor suppressor genes in breast cancer

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Author: Allinen, Minna1,2
Organizations: 1University of Oulu, Faculty of Medicine, Department of Clinical Genetics
2Oulu University Hospital
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: 2002
Publish Date: 2002-05-31
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium 9 of the University Hospital of Oulu, on May 31st, 2002, at 12 noon.
Reviewer: Docent Anne Kallioniemi
Docent Päivi Peltomäki


As the defects in DNA repair and cell cycle control are known to promote tumorigenesis, a proportion of inherited breast cancers might be attributable to mutations in the genes involved in these functions. In the present study, three such genes, TP53, CHK2 and ATM, which are also associated with known cancer syndromes, were screened for germline mutations in Finnish breast cancer patients.

In combination with our previous results, three TP53 germline mutations, Tyr220Cys, Asn235Ser and Arg248Gln, were detected in 2.6% (3/108) of the breast cancer families. The only observed CHK2 alteration with a putative effect on cancer susceptibility, Ile157Thr, segregated ambiguously with the disease, and was also present in cancer-free controls. The available functional data, however, suggests that the altered CHK2 in some way promote tumorigenesis. Furthermore, compared to the other studied populations, Ile157Thr seems to be markedly enriched in Finland. Thus, the clinical significance of Ile157Thr requires further investigation among Finnish cancer patients.

ATM germline mutations appear to contribute to a small proportion of the hereditary breast cancer risk, as two distinct ATM mutations, Ala2524Pro and 6903insA, were found among three families (1.9%, 3/162) displaying breast cancer. They all originated from the same geographical region as the AT families with the corresponding mutations, possibly referring to a founder effect concerning the distribution of these mutations in the Finnish population.

The genes important for tumorigenesis in sporadic disease might also contribute to familial breast cancer. Therefore, four putative LOH targets genes in chromosome 11q21-q24 were screened for intragenic mutations, and five were analyzed for epigenetic inactivation in sporadic breast tumors. The lack of somatic intragenic mutations in MRE11A, PPP2R1B, CHK1 and TSLC1 led us next to investigate promoter region hypermethylation as a mechanism capable of silencing these genes, as well as the ATM gene. Only TSLC1 demonstrated involvement of CpG island methylation, which was especially prominent in three tumors. This suggests that together with LOH, methylation could result in biallelic inactivation of the TSLC1 gene in breast cancer.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-6714-1
ISBN Print: 951-42-6713-3
Issue: 678
Copyright information: © University of Oulu, 2002. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.