Clinical and molecular characterization of BRCA-associated breast cancer: results from the DBCG.

BACKGROUND: In breast cancer (BC) patients a cancer predisposing BRCA1/2 mutation is associated with adverse tumor characteristics, risk assessment and treatment allocation. We aimed to estimate overall- (OS) and disease-free survival (DFS) according to tumor characteristics and treatment among women who within two years of definitive surgery for primary BC were shown to carry a mutation in BRCA1/2 . MATERIAL AND METHODS: From the clinical database of the Danish Breast Cancer Group we included 141 BRCA1 and 96 BRCA2 BC patients. Estrogen receptor and HER2 status were centrally reviewed on paraffin-embedded tumor tissue. Information on risk reducing surgery was obtained from the Danish Pathology and Patient Registries and included as time-dependent variables in Cox proportional hazard models. RESULTS: Ten-year OS and DFS for BRCA1 BC patients were 78% (95% CI 69-85) and 74% (95% CI 64-81). Ten-year OS and DFS for BRCA2 BC were 88% (95% CI 78-94) and 84% (95% CI 74-91). BRCA1 BC patients as compared to BRCA2 BC patients had a higher risk of BC relapse or non-breast cancer within ten years of follow-up, independent of ER status (adjusted HR 2.78 95% CI 1.28-6.05, p = .01), but BRCA mutation was not associated with OS (adjusted HR 1.98, 95% CI 0.87-4.52, p = .10). In multivariate analysis, including both BRCA1 and BRCA2 carriers, no chemotherapy was associated with a higher risk of death (adjusted OS HR 3.58, 95% CI 1.29-9.97, p = .01) and risk reducing contralateral mastectomy (RRCM) was associated with a significantly reduced risk of death (adjusted OS HR 0.42, 95% CI =0.21-0.84, p = .01). CONCLUSION: Difference in OS between BRCA1 and BRCA2 BC patients could be ascribed to tumor-biology. BRCA1 BC patients may have a shorter ten-year DFS than BRCA2 BC patients. Chemotherapy and risk reducing contralateral mastectomy reduce mortality for both BRCA1 and BRCA2 BC patients.

[New mutation in the Birt Hogg Dube gene]. / Nueva mutación en el síndrome de Birt Hogg Dubé.

Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome.

New Mutation in the Birt Hogg Dube Gene. / Nueva mutación en el síndrome de Birt Hogg Dubé.

Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome.

An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.

OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METHOD: The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members.

BACKGROUND: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. OBJECTIVE: To report a novel mutation in the NOD2 gene associated with Blau syndrome. METHODS AND RESULTS: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal inflammation. The proband's daughter had arthritis, uveitis, and exanthema from 3 years of age. The proband's second son had uveitis, exanthema, and arthritis from 1.5 years of age. None of the cases had any involvement of the heart or lungs. CONCLUSION: We report a novel Blau syndrome-associated mutation with an autosomal dominant heritage. Most likely the mutation has arisen de novo in the proband. Genetic counselling and antenatal diagnostics should be available to the involved families.