BACKGROUND: BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas. METHODS: Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (!10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms. RESULTS: Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P ¼ .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P ¼ .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P ¼ .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P ¼ .002). CONCLUSIONS: The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion. Cancer 2010;116:5261-71.
Objectives-Cystic fibrosis (CF), an autosomal recessive disease affecting the lung, pancreas, gut, liver, and reproductive tract, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cyclic adenosine 3′, 5′ monophosphateregulated chloride channel. The variability of disease progression among patients with CF suggests effects of genetic modifiers of disease. Beta-2 adrenergic receptors (β 2 AR), which are abundant in airway epithelial cells, accelerate the formation of cyclic adenosine 3′, 5′ monophosphate, which can modulate CFTR activity and affect smooth muscle contractility. We tested the hypothesis that genetic variants of the β 2 AR gene, which have been shown to influence receptor desensitization, are more frequent in patients than in controls.Methods-We genotyped 130 adult CF patients and 1 : 1 age-matched, sex-matched, and ethnicity-matched normal volunteers for Gly 16 Arg and Gln 27 Glu β 2 AR.Results-We found that CF patients were more likely than controls to be Gly 16 homozygotes (48 and 32%, respectively) (P < 0.01) and Glu 27 homozygotes (29 and 10%, respectively) (P < 0.01). Conclusions-Our results, showing a higher frequency of Gly 16 and Glu 27 β 2 AR alleles in adult CF patients than in the control population, contrast with data from children with CF, who are reported to have lower frequency of Gly 16 and similar frequency of G1u 27 , and with data from young adults with CF, who showed no differences in frequencies of β 2 AR variants. The Gly 16 Glu 27 variant of β 2 AR may have properties that lead to enhanced β 2 AR function, resulting in the upregulation of CFTR activity and the improvement of CF disease.
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