Association between <i>BRCA1</i> and <i>BRCA2</i> mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Hoya, Miguel de la; Osorio, Ana; Godino, Javier; Sulleiro, Sara; Tosar, Alicia; Pérez‐Segura, Pedro; Fernández, Cristina; Rodríguez, Raquel; Dı́az-Rubio, Eduardo; Benı́tez, Javier; Devilee, Peter; Caldés, Trinidad

doi:10.1002/ijc.1627

Cited by 64 publications

(44 citation statements)

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“…The literature is not unanimous about the predictive value of multiple primary (ipsilateral or contralateral) breast cancers for finding a mutation. Our results are in agreement with the studies of Bergthorsson et al (2001), de la Hoya et al (2002 and Ford et al (1998); however, others failed to demonstrate such a predictive value (Couch et al, 1997;Steinmann et al, 2001). Male breast cancer in combination with a family history of breast/ovarian cancer was indicative of finding a BRCA2 mutation (P ¼ 0.002), which is consistent with a recent population-based British study (Basham et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

“…In none of our families bearing a BRCA2 OCCR mutation ovarian cancer was part of the phenotypes. Several other investigators (for instance, Frank et al, 1998;Ikeda et al, 2001;de la Hoya et al, 2002) also failed to demonstrate an increased incidence of ovarian cancer in the BRCA2 OCCR. In our study, mutations occurring 5 0 of the OCCR were significantly associated with a higher ovarian cancer risk relative to the central portion of the gene.…”

Section: Discussionmentioning

confidence: 99%

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BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5 þ 3A4G, 2478 -2479insG, E1221X and BRCA2 IVS6 þ 1G4A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (Po0.001), and the presence of a relative with ovarian cancer (Po0.0001) or multiple primary breast cancers (P ¼ 0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P ¼ 0.002). Mutations in the 5 0 -end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast -ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families. Since the mapping and the cloning of two genes that confer susceptibility to both breast and ovarian cancer, BRCA1 and BRCA2 (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996), it became possible to offer genetic testing to families with a predisposition for breast and/or ovarian cancer. Consequently, individuals at risk can now be identified as candidates for surveillance programmes. A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1/2 mutations is well recognised. In some populations or ethnic groups, founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies.To date, no comprehensive studies in the Belgian population have been published. Only data from small series are available (Claes et al, 1999a, b) or from studies in which the analysis was restricted to a few BRCA1/2 exons or to BRCA1 only Sibille-Hoang et al, 1998;Goelen et al, 1999). We performed mutation screening of the complete coding region of BRCA1 and BRCA2 in 349 unrelated Belgian families referred to our family cancer clinic and report here the nature and distribution of the mutations identified. We found phenotypic differences between families in whom a disease-causing mutation was identified vs BRCA1/2 muta...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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“…Six of the deleterious mutations found in this cohort (BRCA1 IVS5+1G>A, 185delAG, 1135insA, A1708E; BRCA2 3492insT, 9254del5) have been reported in the literature in families of Hispanic ancestry (6,(19)(20)(21)(22)(23)(24)(25). We were unable to verify that those reported in the literature were also reported in the BIC database due to inaccessibility of BIC accession numbers for cases identified at other institutions.…”

Section: Resultsmentioning

confidence: 89%

Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families

Weitzel

Lagos

Blazer

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. Methods: One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/ or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board -approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. Results: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-

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“…The families had been investigated for a number of reasons, including research, directed screening of case series of female or male breast cancer, or attendance at cancer genetic clinics. Some of these families had been included in earlier works [Díez et al, 1999a;Osorio et al, 2000;Campos et al, 2001;de la Hoya et al, 2001de la Hoya et al, , 2002Vega et al, 2002].…”

Section: Subjects and Methods Families And Patientsmentioning

confidence: 97%

Analysis ofBRCA1andBRCA2genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effects

et al. 2003

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We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ-line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site-specific female breast cancer families (15.4%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. We found a higher frequency of ovarian cancer associated with mutations localized in the 5' end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the ovarian cancer cluster region (OCCR) region of exon 11 of the BRCA2 gene. The mutations 187_188delAG, 330A>G, 5236G>A, 5242C>A, and 589_590del (numbered after GenBank U14680) account for 46.6% of BRCA1 detected mutations whereas 3036_3039del, 6857_6858del, 9254_9258del, and 9538_9539del (numbered after GenBank U43746) account for 56.6% of the BRCA2 mutations. The BRCA1 330A>G has a Galician origin (northwest Spain), and BRCA2 6857_6858del and 9254_9258del probably originated in Catalonia (northeast Spain). Knowledge of the spectrum of mutations and their geographical distribution in Spain will allow a more effective detection strategy in countries with large Spanish populations.

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Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Cited by 64 publications

References 30 publications

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families

Analysis ofBRCA1andBRCA2genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effects

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