Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren‐2 transgenic hypertensive rats with aorto‐caval fistula

The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren‐2 transgenic rats (TGR), a model of angiotensin II (ANG II)‐dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto‐caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin‐angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy]benzoic acid (c‐AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin‐converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.     

Durability of serologic response after lamivudine treatment of chronic hepatitis B

Forty subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following lamivudine therapy in previous trials were monitored after treatment to assess the durability of serologic responses. Patient follow-up began a median of 4.3 months after completion of therapy in previous trials. At months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter, we tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT). After a median (range) of 36.6 (4.8-45.6) months of follow-up monitoring, HBeAg seroconversion was demonstrated at the last visit by 77% (30 of 39) of patients. In a post hoc analysis of a slightly different population of all 65 patients with HBeAg seroconversion in previous trials, the 3-year durability of HBeAg seroconversion measured from the time immediately after discontinuing lamivudine therapy was 64%. Nine (9 of 40, 23%) patients were HBsAg negative at the last assessment. Seventy-four percent (17 of 23) of patients with baseline undetectable HBV DNA and normal ALT maintained these responses at the last visit. Eight patients (8 of 40, 20%) initiated retreatment for reappearance of HBV markers, and 7 showed biochemical and/or virologic improvement (including regained HBeAg seroconversion in 2). No safety issues of concern emerged. In conclusion, most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression.     

Genomic Instability in Pituitary Adenomas

Pituitary adenomas most commonly are identified as small, incidental microadenomas. They however may progress to macroadenoma forming intra and later suprasellar tumors which in about 1/3 of cases invade surrounding structures at the time of diagnosis. Mechanism of pituitary tumorigenesis remains still elusive. Because the value of karyotyping is limited by the technical problems related to cytogenetic methods, we studied the spectrum of chromosomal imbalances associated with pituitary adenoma using comparative genomic hybridization (CGH). Copy number aberrations on all 22 autosomes were evaluated by CGH using advanced computer software. In total, fifteen patients were included in the study of 9 non-invasive, 4 invasive and two recurrent adenomas. The mean age of the patients were 48 years ranging from 36 to 68 years. Five tumors showed hormonal activity. The histogram of all 15 cases representing the DNA imbalances as an incidence curve along each chromosome showed losses particularly for chromosomes 1p, 2q, 4, 5, 6, 11q, 12q, 13q and 18q as well as overrepresentation on 9q, 16p, 17p, 19, 20q. Functioning adenomas carried more imbalances than non-functioning, specifically deletions on chromosome 4 and 18q as well as overrepresentations of chromosomes 17 and 19. Invasive adenomas carried more overrepresentations at 1p34 than non-invasive tumors. Recurrent adenomas harbored more alterations than primary tumors, particularly DNA gains. The primary data is accessible at our CGH online tumor database at http://amba.charite.de/cgh. Reviewing the existing literature on the genetics of pituitary adenoma and discussing our results in this context, we hope that our study will contribute to the knowledge of this neoplasm.     

A family history of Barrett's oesophagus: another risk factor?

Barrett's oesophagus and oesophageal adenocarcinoma, although increasingly common, have no known genetic cause. In this report we describe a family with a remarkable history of Barrett's oesophagus and adenocarcinoma. The index case is a 76-year-old man with adenocarcinoma arising within Barrett's oesophagus. Two of his three brothers, aged 68 and 78 years, also developed adenocarcinoma arising in Barrett's oesophagus and the remaining 67-year-old brother has severe dysplasia in biopsies from Barrett's oesophagus. The sons and daughters of the index case requested screening and all had histologically confirmed short-segment Barrett's oesophagus. This kindred appears to be genetically susceptible to Barrett's oesophagus and oesophageal adenocarcinoma. Pooling of data from this and other Barrett's families may allow successful linkage analysis.     

Diagnostic conversions from major depressive disorder into bipolar disorder in an outpatient setting: Results of a retrospective chart review

BackgroundThe aim of the study was to check the stability of a diagnosis of major depressive disorder (MDD) in an outpatient setting, as well as to assess the scope of diagnostic conversions into bipolar disorder (BD).Methods: Retrospective chart review of 122 patients with a primary diagnosis of MDD.ResultsDiagnostic conversion from MDD into BD was noticed in 40 subjects (32.8%), 25 patients (20.5%) were treatment-resistant. Mean time to the conversion was 9.27±8.64 years. A negative correlation between the age of illness onset and time to diagnostic conversion was observed (?0.41; p<0.05). Earlier onset of MDD was associated with higher risk of diagnostic conversion (<30vs≥30 years of age at onset: 69% vs 28%, p=0.0001; <35vs≥35 years of age: 50% vs 25%, p=0.0065). Treatment-resistance was more prevalent in the BD conversion group (40% vs 11%; p=0.0002). Diagnostic conversion into BD was also related longer duration of treatment received, higher number of illness episodes, and higher number of hospitalizations.Limitations: Retrospective design of the study.ConclusionsThe problem of diagnosis evolution from MDD to BD was observed in about 1/3 of patients, and was associated with treatment-resistance of depression, earlier onset of depression, longer time of treatment, higher number of depressive episodes and hospitalizations. The variables above may be a useful predictor of bipolar diathesis.