During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spa... more 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.
The aim of the present study is to analyze the relationship of the incidence of mutations in the ... more The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.3%), 59 in BRCA1 and 70 in BRCA2, detecting 396 mutations in this kindred. The incidence of mutations and their distribution between BRCA1 and BRCA2 showed a significantly uneven incidence among the family groups (P < 0.001). We found 179 tumors in the 396 mutation carriers (45%) and detected only 11 cancers among the 272 non-mutation carriers (P < 0.001). No differences in the tumor prevalence or the age of onset of cancer between the genes among the mutation carriers were found. The mutation carriers showed a 50% probability of having BC/OC at a median age of 49 years (95% CI 46-52 years) and 78% at the age of 70 years (95% CI: 71-85%). In conclusion the family burden of BC and OC is strongly associated with the incidence of BRCAs mutations and could foretell which of the two BRCAs genes is more likely to have mutations. Mutation carriers have a 50% risk of having BC/OC by the age of 50 years.
Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian ca... more Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations, but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a novel deletion identified in BRCA1 gene which has not yet been reported to date. Multiplex ligation-dependent probe amplification was used to analyze BRCA1 rearrangements in 255 unrelated index patients with familial breast and/or ovarian cancer negative for BRCA1/BRCA2 mutations studied in Program of Genetic Counselling on Cancer of Valencia Community (Spain). The breakpoints of detected novel rearrangement were characterized by sequencing. Five different rearrangements in the BRCA1 gene were identified in five unrelated index patients out of the 225 (2%). We found four large genomic rearrangements already described consisting in a 1A/1B and 2 deletion; deletion of exons 5-7; deletion of exons 8-13; exon 20 deletion. Additionally, we found the novel g.8097_22733del14637 deletion that encompasses exons 3-5. This deletion affects the RING domain of the BRCA1 protein and it is suggestive of having a negative impact on its function. The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs.
It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of... more It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of breast and ovarian cancer. We here report 23 novel genetic variants of the BRCA1 and BRCA2 genes found in 349 cancer-prone unrelated families from Eastern Spain detected during the first 2 years of performance of the Program of Genetic Counseling of Valencia Community. Mutational screening was performed by pre-screening the heteroduplex formed in the PCR products obtained amplifying BRCA1 and BRCA2 genes by conformation sensitive electrophoresis. We detected 10 deletereous mutations, four in BRCA1 (three frame-shift (FS) and one nonsense mutation (NS)) and six in BRCA2 (four FS and one NS mutation). Moreover, we detected 13 unclassified variants, four in BRCA1 (one missense (MS), two synonymous (SYN) and one intronic (I) variant) and nine in BRCA2 (six MS, one SYN and two I). The relevance of the novel mutations is discussed. Our contribution broadens the BRCA1/2 world mutational spectra.
The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 ... more The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 in the Valencian Community, comparing this spectrum with that reported in Spain. We also analyze the association of the mutations with the family history of the selected families. We analyzed the mutations in the BRCA1 and BRCA2 in 147 families with history of breast and/or ovarian cancer. The detection was based on the amplification of in frame and flanking regions of BRCA1 and BRCA2 genes by polymerase chain reaction, detection of the heteroduplex formed by conformation-sensitive gel electrophoresis and their characterization by sequencing. We identified 24 different pathogenic mutations in 50 out of the 147 families (34.0%; 23 in BRCA1 and 27 in BRCA2). The higher incidence of pathogenic mutations was observed in families with breast and ovarian cancer or with more than 3 cases of breast cancer. The most frequent mutations in BRCA1 were the c.187_188delAG, c.2080delA and the c.3889_38...
During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spa... more 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.
The aim of the present study is to analyze the relationship of the incidence of mutations in the ... more The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.3%), 59 in BRCA1 and 70 in BRCA2, detecting 396 mutations in this kindred. The incidence of mutations and their distribution between BRCA1 and BRCA2 showed a significantly uneven incidence among the family groups (P < 0.001). We found 179 tumors in the 396 mutation carriers (45%) and detected only 11 cancers among the 272 non-mutation carriers (P < 0.001). No differences in the tumor prevalence or the age of onset of cancer between the genes among the mutation carriers were found. The mutation carriers showed a 50% probability of having BC/OC at a median age of 49 years (95% CI 46-52 years) and 78% at the age of 70 years (95% CI: 71-85%). In conclusion the family burden of BC and OC is strongly associated with the incidence of BRCAs mutations and could foretell which of the two BRCAs genes is more likely to have mutations. Mutation carriers have a 50% risk of having BC/OC by the age of 50 years.
Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian ca... more Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations, but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a novel deletion identified in BRCA1 gene which has not yet been reported to date. Multiplex ligation-dependent probe amplification was used to analyze BRCA1 rearrangements in 255 unrelated index patients with familial breast and/or ovarian cancer negative for BRCA1/BRCA2 mutations studied in Program of Genetic Counselling on Cancer of Valencia Community (Spain). The breakpoints of detected novel rearrangement were characterized by sequencing. Five different rearrangements in the BRCA1 gene were identified in five unrelated index patients out of the 225 (2%). We found four large genomic rearrangements already described consisting in a 1A/1B and 2 deletion; deletion of exons 5-7; deletion of exons 8-13; exon 20 deletion. Additionally, we found the novel g.8097_22733del14637 deletion that encompasses exons 3-5. This deletion affects the RING domain of the BRCA1 protein and it is suggestive of having a negative impact on its function. The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs.
It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of... more It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of breast and ovarian cancer. We here report 23 novel genetic variants of the BRCA1 and BRCA2 genes found in 349 cancer-prone unrelated families from Eastern Spain detected during the first 2 years of performance of the Program of Genetic Counseling of Valencia Community. Mutational screening was performed by pre-screening the heteroduplex formed in the PCR products obtained amplifying BRCA1 and BRCA2 genes by conformation sensitive electrophoresis. We detected 10 deletereous mutations, four in BRCA1 (three frame-shift (FS) and one nonsense mutation (NS)) and six in BRCA2 (four FS and one NS mutation). Moreover, we detected 13 unclassified variants, four in BRCA1 (one missense (MS), two synonymous (SYN) and one intronic (I) variant) and nine in BRCA2 (six MS, one SYN and two I). The relevance of the novel mutations is discussed. Our contribution broadens the BRCA1/2 world mutational spectra.
The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 ... more The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 in the Valencian Community, comparing this spectrum with that reported in Spain. We also analyze the association of the mutations with the family history of the selected families. We analyzed the mutations in the BRCA1 and BRCA2 in 147 families with history of breast and/or ovarian cancer. The detection was based on the amplification of in frame and flanking regions of BRCA1 and BRCA2 genes by polymerase chain reaction, detection of the heteroduplex formed by conformation-sensitive gel electrophoresis and their characterization by sequencing. We identified 24 different pathogenic mutations in 50 out of the 147 families (34.0%; 23 in BRCA1 and 27 in BRCA2). The higher incidence of pathogenic mutations was observed in families with breast and ovarian cancer or with more than 3 cases of breast cancer. The most frequent mutations in BRCA1 were the c.187_188delAG, c.2080delA and the c.3889_38...
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Papers by Eduardo de Dueñas