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Ana Blanco,
Miguel de la Hoya,
Judith Balmaña,
Teresa Ramón y Cajal,
Alex Teulé,
María-Dolores Miramar,
Eva Esteban,
Mar Infante,
Javier Benítez,
Asunción Torres, [......],
Ana Osorio,
Eladio A Velasco, Isabel Chirivella,
María-Teresa Calvo,
Lidia Feliubadaló,
Adriana Lasa,
Orland Díez,
Angel Carracedo,
Trinidad Caldés,
Ana Vega
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ABSTRACT: It has been demonstrated that monoallelic PALB2 (Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline PALB2 mutations presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline PALB2 mutations in a set of 131 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of PALB2 gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several PALB2 variants, but no other obvious deleterious PALB2 mutation has been found. Thus, our study does not support an enrichment of PALB2 germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the PALB2 gene.
Breast Cancer Research and Treatment 11/2011; 132(1):307-15. · 4.43 Impact Factor
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Roger L Milne,
Ana Osorio,
Teresa Ramón y Cajal,
Montserrat Baiget,
Adriana Lasa,
Eduardo Diaz-Rubio,
Miguel de la Hoya,
Trinidad Caldés,
Alex Teulé,
Conxi Lázaro, [......],
Eladio Velasco,
Eduardo Martínez de Dueñas,
María-Isabel Tejada,
María-Dolores Miramar,
María-Teresa Calvo,
Carmen Guillén-Ponce,
Raquel Salazar,
Carlos San Román,
Miguel Urioste,
Javier Benítez
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ABSTRACT: Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre. The results for ever being parous and number of live-births were very similar for carriers of mutations in both genes. For all mutation carriers combined, the estimated HR associated with ever having had a live-birth was 0.74 (95% confidence interval [CI] = 0.55-1.01, P = 0.06), and that associated with each live-birth was 0.87 (95%CI = 0.77-0.98, P = 0.02). The latter association was observed only in women aged 40 and above (HR = 0.81, 95%CI = 0.70-0.94, P = 0.004 vs. HR = 0.99, 95%CI = 0.83-1.18, P = 0.9 for women under age 40), and this trend was highly consistently observed for carriers of mutations in each gene. There was no evidence of an association between breast cancer risk and age at first birth for parous BRCA1 or BRCA2 mutation carriers (P-trend >or= 0.3). The power to detect associations with ovarian cancer risk was much lower, especially for BRCA2 mutation carriers. Nevertheless, having a live-birth was associated with protection for BRCA1 mutation carriers (HR = 0.41, 95%CI = 0.18-0.94, P = 0.03), and a strong and consistent protective effect of age at first birth was observed for parous carriers of mutations in both genes (HR = 0.65, 95%CI = 0.52-0.83, P < 0.001). This is the third independent study to find that, as in the general population, parity appears to be associated with protection from breast cancer in women with mutations in BRCA1 and BRCA2. Parity appears to be protective for ovarian cancer in BRCA1 mutation carriers, but its role in BRCA2 mutation carriers remains unclear. Whether later age at first birth is also protective for ovarian cancer in mutation carriers requires further confirmation.
Breast Cancer Research and Treatment 04/2009; 119(1):221-32. · 4.43 Impact Factor
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Roger L Milne,
Ana Osorio,
Teresa Ramón Y Cajal,
Ana Vega,
Gemma Llort,
Miguel de la Hoya,
Orland Díez,
M Carmen Alonso,
Conxi Lazaro,
Ignacio Blanco, [......],
Elena Beristain,
María-Dolores Miramar,
María-Teresa Calvo,
Eduardo Martínez,
Carmen Guillén,
Raquel Salazar,
Carlos San Román,
Antonis C Antoniou,
Miguel Urioste,
Javier Benítez
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ABSTRACT: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain.
We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method.
The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A>G (R71G) in BRCA1 may have lower breast cancer penetrance.
These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.
Clinical Cancer Research 05/2008; 14(9):2861-9. · 7.74 Impact Factor
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José I Martinez-Ferrandis,
Raquel Rodríguez-López,
Roger L Milne,
Emilio González,
Elvira Cebolla, Isabel Chirivella,
Pilar Zamora,
José I Arias,
Santiago Palacios,
Andrés Cervantes,
Orland Díez,
Javier Benitez,
M-Eugenia Armengod
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ABSTRACT: TRAIL is a potent inducer of apoptosis in malignant but not in normal cells. TRAIL binds to the proapoptotic death receptor DR4 and DR5 as well as to the decoy receptors DcR1 and DcR2. To evaluate the involvement of TRAIL receptor genes in breast cancer, we carried out a case-control study of eight selected polymorphisms in a large sample of Spanish women. Three of the eight selected SNPs (626G/C and 1322G/A in DR4 and 2699A/G in DcR2) showed some evidence of different genotype distributions in a random selection of 535 cases and 480 controls and were therefore studied in our entire sample (1008 cases and 768 controls). For the two DR4 polymorphisms, no differences in genotype or haplotype distribution were found between cases and controls. Interestingly, allele 2699G in the decoy receptor DcR2 appears associated with reduced breast cancer risk (P=0.05). Given that it is located in the 3' UTR, its effect might be related to DcR2 mRNA instability, or linkage disequilibrium with a functional variant residing in either DcR2 or neighbouring genes. A decreased efficiency of DcR2 to work as decoy receptor for TRAIL, would facilitate the apoptotic pathway in cells at risk.
Cancer biomarkers: section A of Disease markers 02/2007; 3(2):89-93. · 1.08 Impact Factor
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ABSTRACT: To define the maximum-tolerated dose of oxaliplatin given with cisplatin, protacted 96-h infusion of fluorouracil, and radiotherapy for patients with advanced esophageal cancer.
Seventeen patients with locally advanced esophageal cancer and 2 patients with local recurrence were treated. Escalating doses of oxaliplatin, cisplatin, and fluorouracil were administered on Days 1 and 29 of radiotherapy. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy. Dose-limiting toxicity was defined as a Grade 4 hematologic or Grade 3-4 nonhematologic toxicity.
Dose-limiting toxicity caused by diarrhea and asthenia was observed at the IV level. The recommended dose was 85 mg/m- oxaliplatin, 55 mg/m2 cisplatin, and 3000 mg/m2 96-h fluorouracil infusion. Two pathologic complete responses were observed in 12 patients selected for surgery (16%).
Oxaliplatin, cisplatin, fluouracil, and radiotherapy can be administered together with acceptable toxicity. A Phase II trial is ongoing with resectable esophageal and gastric carcinoma.
International Journal of Radiation OncologyBiologyPhysics 06/2005; 62(1):91-6. · 4.11 Impact Factor
