Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families : evidence for additional susceptibility genes

One hundred breast and breast-ovarian cancer familiesidentified at the Helsinki University Central Hospital insouthern Finland and previously screened for mutationsin the BRCA2 gene were now analyzed for mutations inthe BRCA1 gene. The coding region and spliceboundaries of BRCA1 were analyzed by proteintruncation test (PTT) and heteroduplex analysis(HA)/SSCP in all 100 families, and 70 were also screenedby direct sequencing. Contrary to expectations based onFinnish population history and strong founder effects inseveral monogenic diseases in Finland, a wide spectrumof BRCA1 and BRCA2 mutations was found. In theBRCA1 gene, 10 different protein truncating mutationswere found each in one family. Six of these are novelFinnish mutations and four have been previously foundin other European populations. Six different BRCA2mutations were found in 11 families. Altogether only 21%of the breast cancer families were accounted for bymutations in these two genes. Linkage to bothchromosome 17q21 (BRCA1) and 13q12 (BRCA2) wasalso excluded in a subset of seven mutation-negativefamilies with four or more cases of breast or ovariancancer. These data indicate that additional breast andbreast-ovarian cancer susceptibility genes are likely tobe important in Finland.INTRODUCTIONThe most prominent risk factor for breast cancer is a familyhistory. It is estimated that 5–10% of all breast cancers may arisefrom hereditary predisposition (1,2). The two currently knownmajor breast cancer predisposing genes, BRCA1 (3,4) andBRCA2 (5–7) were originally thought to account for the vastmajority of breast cancer families. BRCA1 was reported toaccount for ∼45% of hereditary breast cancer families (especiallythose with ovarian cancer), and BRCA2 for an additional 35%,(including those with male breast cancer) (5,8). These estimateswere largely based on studies of the same large families that wereinitially used to assign linkage to these two genes.Very recently, large scale mutation analyses of these two genesindicate that in many populations only ∼30–60% of breast cancerfamilies are attributable to BRCA1 and BRCA2 mutations. Theproportion of large breast cancer pedigrees that are attributable toBRCA1 and BRCA2 is 21 and 9% in Britain, 24 and 18% inFrance, 40 and 16% in Canada, and 39 and 25% in the USA,respectively (9). In Sweden and in Hungary, ∼35% of familiescarry mutations in these two genes (9). In isolated populationswith a strong founder effect, the situation may be different. InIceland, a single BRCA2 founder mutation accounts for themajority of hereditary breast cancers (10,11), and in theAshkenazi Jewish population, a very high carrier frequency hasbeen reported for the three founder mutations, 185delAG and5382insC in BRCA1 and 6174delT in BRCA2 (12–14).The Finnish population is also considered an isolate. There arestrong founder effects for several characteristic Finnish geneticdiseases, while several genetic diseases that are common elsewherein the world, are rare or even unknown in Finland (15). Therefore,substantial interest in the BRCA1 and BRCA2 mutation spectrumand its significance in this country exists. We recently reported theanalysis of the BRCA2 mutation spectrum in 100 Finnish breastcancer families with three or more breast or ovarian cancers (16).We have now analyzed mutations of the BRCA1 gene in the samefamilies, to complete the survey of the spectrum of mutationspredisposing to breast cancer in the Finnish families. Additional dataon recurrent BRCA2 mutations were also obtained. The mutation