High-resolution array CGH clarifies events occurring on 8p in carcinogenesis.

BACKGROUND: Rearrangement of the short arm of chromosome 8 (8p) is very common in epithelial cancers such as breast cancer. Usually there is an unbalanced translocation breakpoint in 8p12 (29.7 Mb - 38.5 Mb) with loss of distal 8p, sometimes with proximal amplification of 8p11-12. Rearrangements in 8p11-12 have been investigated using high-resolution array CGH, but the first 30 Mb of 8p are less well characterised, although this region contains several proposed tumour suppressor genes. METHODS: We analysed the whole of 8p by array CGH at tiling-path BAC resolution in 32 breast and six pancreatic cancer cell lines. Regions of recurrent rearrangement distal to 8p12 were further characterised, using regional fosmid arrays. FISH, and quantitative RT-PCR on over 60 breast tumours validated the existence of similar events in primary material. RESULTS: We confirmed that 8p is usually lost up to at least 30 Mb, but a few lines showed focal loss or copy number steps within this region. Three regions showed rearrangements common to at least two cases: two regions of recurrent loss and one region of amplification. Loss within 8p23.3 (0 Mb - 2.2 Mb) was found in six cell lines. Of the genes always affected, ARHGEF10 showed a point mutation of the remaining normal copies in the DU4475 cell line. Deletions within 12.7 Mb - 19.1 Mb in 8p22, in two cases, affected TUSC3. A novel amplicon was found within 8p21.3 (19.1 Mb - 23.4 Mb) in two lines and one of 98 tumours. CONCLUSION: The pattern of rearrangements seen on 8p may be a consequence of the high density of potential targets on this chromosome arm, and ARHGEF10 may be a new candidate tumour suppressor gene

Single-molecule analysis of genome rearrangements in cancer.

Rearrangements of the genome can be detected by microarray methods and massively parallel sequencing, which identify copy-number alterations and breakpoint junctions, but these techniques are poorly suited to reconstructing the long-range organization of rearranged chromosomes, for example, to distinguish between translocations and insertions. The single-DNA-molecule technique HAPPY mapping is a method for mapping normal genomes that should be able to analyse genome rearrangements, i.e. deviations from a known genome map, to assemble rearrangements into a long-range map. We applied HAPPY mapping to cancer cell lines to show that it could identify rearrangement of genomic segments, even in the presence of normal copies of the genome. We could distinguish a simple interstitial deletion from a copy-number loss at an inversion junction, and detect a known translocation. We could determine whether junctions detected by sequencing were on the same chromosome, by measuring their linkage to each other, and hence map the rearrangement. Finally, we mapped an uncharacterized reciprocal translocation in the T-47D breast cancer cell line to about 2 kb and hence cloned the translocation junctions. We conclude that HAPPY mapping is a versatile tool for determining the structure of rearrangements in the human genome

Evaluation of Treatment-Related Mortality Among Paediatric Cancer Deaths: a population based analysis.

BACKGROUND: Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients

Diminished vagal activity and blunted diurnal variation of heart rate dynamics in posttraumatic stress disorder

Affected autonomic heart regulation is implicated in the pathophysiology of cardiovascular diseases and is associated with posttraumatic stress disorder (PTSD). However, although sympathetic hyperactivation has been repeatedly shown in PTSD, research has neglected parasympathetic function. The objective of this study is the long-term assessment of heart rate (HR) dynamics and its diurnal changes as an index of autonomic imbalance in PTSD. Since tonic parasympathetic activity underlies long-range correlation of heartbeat interval fluctuations in the healthy state, we included nonlinear (unifractal) analysis as an important and sensitive readout to assess functional alterations. We conducted electrocardiogram recordings over a 24-h period in 15 deployed male subjects with moderate to high levels of combat exposure (PTSD: n = 7; combat controls: n = 8) in the supine position. HR dynamics were assessed in two 5-h sub-epochs in the time and frequency domains, and by nonlinear analysis based on detrended fluctuation analysis. Psychiatric symptoms were assessed using structured interviews, including the Clinician Administered PTSD Scale. Subjects with PTSD showed significantly higher baseline HR, higher LF/HF ratio in the frequency domain, blunted differences between day and night-time measures, as well as a higher scaling coefficient αfast during the day, indicating diminished tonic parasympathetic activity. Diminished diurnal differences and blunted tonic parasympathetic activity altering HR dynamics suggest central neuroautonomic dysregulation that could represent a possible link to increased cardiovascular disease in PTSD. © Informa Healthcare USA, Inc