![]() The clinical data of the studied individuals are presented in Table Table1. These relatives with BrCa were screened for the same variant as that identified in the index. We were also able to get blood samples from two affected relatives in 2 out of 11 separate families with healthy index. According to these criteria, our study material also included 11 non-affected females in addition to 71 BrCa and/or OvCa patients. Patient with bilateral BrCa was considered to have two separate cancers. Individuals were chosen to be included in this study according to the following criteria of high-risk HBC: (a) the individual or her first-degree relative (only female family members were included when defining first-degree relatives) had BrCa or ovarian cancer (OvCa) at younger than 30 years of age or (b) two first-degree relatives in the family had BrCa and/or OvCa and at least one of the cancers had been diagnosed at younger than 40 years of age or (c) three first-degree relatives in the family had BrCa and/or OvCa and at least one of the cancers had been diagnosed at younger than 50 years of age or (d) four or more first-degree relatives had BrCa and/or OvCa at any age or (e) the same individual had BrCa and OvCa. The hospital district, in the area of Pirkanmaa, consists of over 20% (1.23 million) of the Finnish population. ![]() Study material had been collected from the individuals, who visited the Tampere University Hospital Genetics Outpatient Clinic between January 1997 and May 2008. All individuals had been detected to be founder mutation-negative by minisequencing of the previously known 28 Finnish BRCA1/2 mutations and by protein truncation test (PTT) of exon 11 for BRCA1 and exons 10 and 11 for BRCA2. Index individuals of 82 high-risk Finnish HBOC families were screened for germline alterations in BrCa-associated genes. In addition, the sensitivity of our current BRCA1/ 2 mutation analysis protocol was defined for genetic counseling purposes. The aim of this study was to screen seven known BrCa susceptibility genes for additional mutations in 82 well-characterized, Finnish, high-risk hereditary breast and/or ovarian cancer (HBOC) individuals tested to be BRCA1/ 2-founder mutation negative. To address the problem of heterogeneous HBC in genetic counseling, we wanted to investigate possible additional mutations in HBC-associated genes. For example, SNPs in the fibroblast growth factor receptor 2 ( FGFR2) gene have shown significant association with increased risk among BrCa cases with strong family history. Genome-wide association studies (GWAs) have revealed multiple low penetrance, single nucleotide polymorphisms (SNPs) in many genes and chromosomal loci with increased risk of BrCa. It is likely that additional BrCa susceptibility gene mutations remain unidentified, especially in the category of moderate- to low-penetrance gene variants that individually confer only minimal risk but that, through multiplicative and/or cumulative effects, can cause relatively high risk for the carriers. Īlthough mutations in many genes have been found to predispose an individual to BrCa, approximately 75 to 80% of HBC cases remain unexplained. In addition, BrCa-associated variants have been reported in the CDH1 ( cadherin-1). As expected, CHEK2 ( checkpoint kinase 2), PALB2 ( partner and localizer of BRCA2), BRIP1 ( BRCA1-interacting protein 1), and RAD50 ( human homolog of Saccharomyces cerevisiae RAD50) have been shown to have rare, moderate-risk BrCa-associated variants, which have also been studied in the Finnish population. Therefore, it has been hypothesized that genes coding for proteins that interact with BRCA1 or BRCA2 or act in the same DNA repair pathway would be likely candidate genes for HBC susceptibility. However, these syndromes very seldom explain HBC.īRCA1 and BRCA2 have many DNA damage response functions in the cell. ![]() In addition to BRCA1 and BRCA2 mutations, there are certain hereditary cancer syndromes, such as Li-Fraumeni, Cowden, Peutz-Jeghers and diffuse gastric cancer syndromes, associated with a high risk of BrCa. ![]() BRCA2 mutations have been found to be more common in the Finnish population than BRCA1. The two major high-penetrance BrCa genes, BRCA1 ( breast cancer 1) and BRCA2 ( breast cancer 2), are responsible for 30% of hereditary breast cancer (HBC) cases worldwide, but only for about 20% in Finland. It has been estimated that a monogenic trait accounts for 5 to 10% of all BrCa cases. Breast cancer (BrCa) is the most common cancer among women in Finland, with about 4,000 cases diagnosed yearly (Finnish Cancer Registry). ![]()
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