Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling

Abstract

The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population.

Broad BRCA1 and BRCA2 mutational spectrum and high incidence of recurrent and novel mutations in the eastern Spain population

“…We observed greater diversity and higher incidence for BRCA2 mutations than for BRCA1 (50.7% in BRCA2 vs. 41.9% in BRCA1) in correspondence with our previous reports [6], and with other studies performed in the Spanish population [14][15][16][17], but in disagreement with the other one [13]. We think that the larger incidence of mutations in BRCA2 could be a trait of the population of certain geographical areas of Spain, not related with the presence of the c.187_188delAG BRCA1 Ashkenazim mutation, as suggested by Infante et al [15], since in this study, we observed larger incidence of BRCA2 mutations in spite of having high incidence of this mutation.…”

“…Eight of the mutations detected in BRCA1 were also observed in recent studies carried out in the Spanish population [13][14][15]. However, our results are not as concordant as those expected with the larger study carried out in the Spanish population [13].…”

“…However, our results are not as concordant as those expected with the larger study carried out in the Spanish population [13]. [11] c.1538_1541delAAGA Stop458 F 1 [11,13] c.1594_1595delGA Stop460 F 1 [11] c.1676_1677delAGinsTTAC Stop513 F 1 [11] c.1835insT a Stop542 F 2 [7,13] c. [6,11,[13][14][15] c.3492insT a Stop1098 F 5 [6,11,14] c.4075_4076delGT Stop1284 F 1 [11] c.4150G[T a p.E1308X N 3 [6,11,13,15] c.5025delT a Stop1616 F 3 [6,7] c.5164_5167delGAAA a Stop1668 F 1 [6,11,15] c.5340_5343delAATA Stop1710 F 1 [11] c.5514_5515delTC Stop1766 F 1 [11] c.5804_5807delTTAA Stop1862 F 2 [11,13,14] c.5946_5949delCTCT Stop1909 F 1 [11] c. For BRCA2, there is a coincidence of 11 mutations with other reports performed in the Spanish population [13][14][15]. The 2003 report of Diez et al [13] is concordant with our study in 10 out of the 22 different mutations (45%), c.1538_1541delAAGA, c.3036_3039delACAA, c.3492insT, c.4150G[T, c.5804_5807delTTAA, c.6503_6504delTT, c.6857_6858delAA, c.9206_9219del14, c.9246C[A, and c.9254_9258delATCAT, which represent 70% (37/53) of the families reported by that study [13] and 58% of the families (41/71) of this study.…”

A High Proportion of DNA Variants ofBRCA1andBRCA2Is Associated with Aberrant Splicing in Breast/Ovarian Cancer Patients

“…1A; refs. [24][25][26]. Apart from the classic mutations of the donor and acceptor splice sites, two variants should be highlighted.…”

Heterogeneous prevalence of recurrent BRCA1 and BRCA2 mutations in Spain according to the geographical area: implications for genetic testing

“…We compared the results of BRCA1 and BRCA2 genetic testing previously reported in seven different areas of Spain: Galicia (North West) [5], Salamanca (West) [8], Castilla-León (North West-central) [9], Basque Country (North) [10], Aragón (North East) [11], Catalonia (North East-Mediterranean) [12], and Valencia (East) [13] ( Fig. 1).…”