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Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility
  1. K Heikkinen1,
  2. S-M Karppinen1,
  3. Y Soini2,
  4. M Mäkinen2,
  5. R Winqvist1
  1. 1Departments of Clinical Genetics
  2. 2Pathology, University of Oulu, Oulu University Hospital, Oulu, Finland
  1. Correspondence to:
 Dr R Winqvist
 Department of Clinical Genetics, Oulu University Hospital, PO Box 24, FIN-90029 OYS, Finland;

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Approximately 5–10% of all breast and ovarian cancers are due to genetic predisposition.1 Germline mutations in two major susceptibility genes, BRCA1 and BRCA2, explain most of the hereditary ovarian cancer cases, but worldwide have been observed only in a fraction of the breast cancer families; in Finland, about 20%.2–4 A small portion of the remaining cases, perhaps 1–2%, appears to be caused by germline mutations in other cancer susceptibility genes such as TP53, PTEN, AR, and ATM.5 Recently, moderate or low penetrance germline mutations such as 1100delC of CHK2 have also been implicated,6 suggesting that in many cases the phenotypic expression of the disease is accounted for by the combined effect of multiple but more subtle mutations in different target genes.5,7 Despite all these discoveries, many breast cancer families, especially those with fewer than four cases and/or with later disease onset, have cancers due to mutations in still unknown genes. As the protein products of the genes so far indicated are central players in the pathways involved in cell cycle checkpoint functions and in the sensing, transduction, and repair of DNA lesions,5 other similarly acting genes may represent new potential candidates for breast and/or ovarian cancer susceptibility.

The Mre11 complex, composed of the proteins MRE11, NBS1, and RAD50, is a vital component in the DNA damage response and is at least partially responsible for connecting DNA damage detection to DNA repair and cell cycle checkpoint functions. The early association of the complex with damaged DNA suggests its involvement in sensing DNA double strand breaks (DSBs). In eukaryotes, DSB repair is handled by two different pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), and the initial step in both is the recognition and signalling of the damage …

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