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Abstract
BackgroundThe prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain).MethodsIn the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).ResultsA total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family.ConclusionsIn this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.
Highlights
The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families
Frequency of families with BRCA1 and BRCA2 pathogenic mutations according to the inclusion criteria We identified 59 families carrying a pathogenic mutation, 39 in BRCA1 and 20 in BRCA2, which represent 23% of all screened families (Table 1)
The highest mutation detection rate in BRCA1 was observed in families with at least one ovarian cancer and in families with a single case of bilateral breast cancer diagnosed before the age of 40
Summary
The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). Women carrying germ line mutations in these genes have a high lifetime risk of developing both breast and ovarian cancer [7]. Prevalence of BRCA1 or BRCA2 germ line mutations varies considerably among ethnic groups, and in some countries, founder mutations are responsible for a significant proportion of breast cancer cases. Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families have been reported in several Spanish regions, showing a heterogeneous prevalence of recurrent mutations according to the geographical area [10]. There are to date no comprehensive studies in the Asturian population, a geographically isolated area in the North of Spain
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