Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.

Purpose: 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. Experimental Design: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method. Results: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. Conclusions: 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.

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Three patients presenting with acute leukemic disorder and chromosome 3 rearrangement involving bands q21;q26 are reported, and the literature on chromosome 3q abnormalities is reviewed. All reported patients carrying a paracentric 3q inversion or a translocation 3;3 with breakpoints in q21;q26 had a myelodysplastic or acute leukemic disorder with a normal or elevated platelet count and lack of response to cytotoxic drug therapy. They showed an associated incidence of −7 or 7q− anomalies higher than de novo acute leukemia and appear to constitute a definite subgroup of the leukemic disorders with very poor prognosis. The majority of patients showing other chromosome 3 long arm rearrangements showed evidence of leukemic process, were in blastic crisis, or had been exposed to chemotherapy, exhibiting also a higher incidence of associated −5 or −7 cytogenetic abnormalities than is observed in patients not exposed to toxic agents.

The impact of venous thromboembolism (VTE) and bleeding in patients undergoing major joint surgery has not been thoroughly studied. The Spanish National Discharge Database during the years 2005-2006 was used to assess the frequency and clinical impact of VTE and bleeding after elective total knee (TKA) or hip (THA) arthroplasty. Of 58,037 patients undergoing TKA, 0.18% (95% confidence interval [CI]: 0.15-0.22) were diagnosed with pulmonary embolism (PE), 0.57% (95% CI: 0.51-0.63) with deep-vein thrombosis (DVT), 1.20% (95% CI: 1.12-1.30) had bleeding complications, and 0.09% (95% CI: 0.07-0.12) died. Of 54 patients who died, 20.4% (95% CI: 10.7-35.4) had been diagnosed with PE, 3.70% (95% CI: 0.63-11.7) with DVT, and 13.0% (95% CI: 5.67-25.6) had bled. Of 31,769 patients undergoing elective THA, 0.23% (95% CI: 0.18-0.29) were diagnosed with PE, 0.44% (95% CI: 0.37-0.52) with DVT, 1.21% (95% CI: 1.10-1.34) bled, and 0.16% (95% CI: 0.12-0.21) died. Of 52 patients who died, 13.5% (95% CI: 6.08-24.8) had been diagnosed with PE, and 9.61% (95% CI: 3.52-21.3) had bled. On multivariable analysis, PE (odds ratio [OR]: 157; 95% CI: 75-328), DVT (OR: 6.3; 95% CI: 1.5-27) and bleeding (OR: 8.5; 95% CI: 3.6-20) were independent predictors for death after TKA. After THA, only PE (OR: 65; 95% CI: 26-160) and bleeding (OR: 6.4; 95% CI: 2.3-17) predicted the risk for death. Bleeding, DVT, and PE, arising after TKA were all independent predictors for death. Their increase in risk was, however, substantially higher for PE. After THA, only PE and bleeding independently predicted death.