Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence

Abstract

During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22. The BRCA1 mutations with higher recurrence were c.66_68delAG, c.5123C > A, c.1961delA, c.3770_3771delAG and c.5152+5G > A that covered 45.2% of mutations of this gene. The age of onset of BCs of c.68_69delAG mutation carriers occurs later than for the other recurrent mutations of this gene (45 vs. 37 years; p = 0.008). The BRCA2 mutations with higher recurrence were c.9026_9030delATCAT, c.3264insT and c.8978_8991del14 which represented 43.2% of all mutations in this gene, being the most recurrent mutation by far c.9026_9030delATCAT that represents 21.3% of BRCA2 mutations and 10.6% of all mutations. Probands with family histories of BC and OC, or OC and/or BC in at least two first degree relatives, were the more likely to have BRCA1/BRCA2 mutations (35.2% of the total mutations). And that most BRCA1mutations (73.19% mutations) occurred in probands with early-onset BC or with family history of OC.

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines

“…These founder mutations have also been reported in Spain [28–30]. Therefore, these Ashkenazi Jew mutations are thought to come from areas of Spain where Jews communities settled during the early Common Era.…”

“…For example, women from Argentina, Mexico, and Brazil have a higher prevalence of BRCA1 mutations [13, 18, 27], whereas in women from the Caribbean (Cuba and Puerto Rico), BRCA2 is more frequently mutated [24, 25]. Studies of women with BC from Spain showed a larger number of rearrangements in both BRCA genes when compared to Hispanic women [28–30]. Additionally, several mutations for both BRCA genes were found in Hispanic subpopulations, especially in Argentina where there is a higher proportion European admixture.…”

“…)del (exon deletion)1–13c. (?_-48)_(4357 + 1_4358-1)del (exon deletion)de Juan Jimenez I et al 2013 [30]Spain17631-2c. (?_-48)_(80 + 1_81-1)del (exon deletion)3c.145G > Tp.Glu49*1-24c.…”

BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study

“…Three BRCA2 recurrent mutations were identified (c.2808_2811delACAA, c.3264dupT and c.9026_9030delATCAT), representing 21.3 % of the total mutations (Table 4). These recurrent mutations have also been found in ICs and most of them have already been reported in studies carried out in Spanish population [26][27][28][29][34][35][36][37][38] or included in mutation databases [30,31] (Table 4). …”

“…Sixteen mutations detected in ICs, one in BRCA1 and 15 in BRCA2, previously reported in the Spanish population [26][27][28][29]38] (Table 2). In addition, prevalent BRCA2 mutations have been reported in previous Spanish population studies.…”