A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels

Pan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell-cycle activity in 9515 pan-cancer patients with 32 different tumour types. Boxplots showed that cell-cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all cell cycle score (CCS) tertiles but with increasing frequency as cell-cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent in CCS High tumours (P < 0.001). In Kaplan–Meier analysis, patients whose tumours were CCS Low had a longer Progression Free Interval (PFI) relative to Intermediate or High (P < 0.001) and this significance remained in multivariable analysis (CCS Intermediate: HR = 1.37; 95% CI 1.17–1.60, CCS High: 1.54; 1.29–1.84, CCS Low = Ref). These results demonstrate that whilst similar DNA alterations can be found at all cell-cycle activity levels, some notable exceptions exist. Moreover, independent prognostic information can be derived on a pan-cancer level from a simple measure of cell-cycle activity

Separation of breast cancer and organ microenvironment transcriptomes in metastases

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression

Did Galaxy Assembly and Supermassive Black-Hole Growth go hand-in-hand?

In this paper, we address whether the growth of supermassive black-holes has kept pace with the process of galaxy assembly. For this purpose, we first searched the Hubble Ultra Deep Field (HUDF) for "tadpole galaxies", which have a knot at one end and an extended tail. They appear dynamically unrelaxed -- presumably early-stage mergers -- and make up ~6% of the field galaxy population. Their redshift distribution follows that of field galaxies, indicating that -- if tadpole galaxies are indeed dynamically young -- the process of galaxy assembly generally kept up with the reservoir of field galaxies as a function of epoch. Next, we present a search for HUDF objects with point-source components that are optically variable (at the >~3.0 sigma level) on timescales of weeks--months. Among 4644 objects to i_AB=28.0 mag (10 sigma), 45 have variable point-like components, which are likely weak AGN. About 1% of all field objects show variability for 0.1 < z < 4.5, and their redshift distribution is similar to that of field galaxies. Hence supermassive black-hole growth in weak AGN likely also kept up with the process of galaxy assembly. However, the faint AGN sample has almost no overlap with the tadpole sample, which was predicted by recent hydrodynamical numerical simulations. This suggests that tadpole galaxies are early-stage mergers, which likely preceded the ``turn-on'' of the AGN component and the onset of visible point-source variability by >~1 Gyr.Comment: 9 pages, Latex2e requires 'elsart' and 'elsart3' (included), 10 postscript figures. To appear in the Proceedings of the Leiden Workshop on "QSO Host Galaxies: Evolution and Environment", eds. P.D. Barthel & D.B. Sanders (New Astron. Rev., 2006

Generation of in situ sequencing based OncoMaps to spatially resolve gene expression profiles of diagnostic and prognostic markers in breast cancer

Background: Gene expression analysis of breast cancer largely relies on homogenized tissue samples. Due to the high degree of cellular and molecular heterogeneity of tumor tissues, bulk tissue-based analytical approaches can only provide very limited system-level information about different signaling mechanisms and cellular interactions within the complex tissue context. Methods: We describe an analytical approach using in situ sequencing (ISS), enabling highly multiplexed, spatially and morphologically resolved gene expression profiling. Ninety-one genes including prognostic and predictive marker profiles, as well as genes involved in specific cellular pathways were mapped within whole breast cancer tissue sections, covering luminal A/B-like, HER2-positive and triple negative tumors. Finally, all these features were combined and assembled into a molecular-morphological OncoMap for each tumor tissue. Findings: Our in situ approach spatially revealed intratumoral heterogeneity with regard to tumor subtype as well as to the OncotypeDX recurrence score and even uncovered areas of minor cellular subpopulations. Since ISS-resolved molecular profiles are linked to their histological context, a deeper analysis of the core and periphery of tumor foci enabled identification of specific gene expression patterns associated with these morphologically relevant regions. Interpretation: ISS generated OncoMaps represent useful tools to extend our general understanding of the biological processes behind tumor progression and can further support the identification of novel therapeutical targets as well as refine tumor diagnostics. Fund: Swedish Cancerfonden, UCAN, Vetenskapsrådet, Cancer Genomics Netherlands, Iris, Stig och Gerry Castenbäcks Stiftelse, BRECT, PCM Program, King Gustaf V Jubilee Fund, BRO, KI and Stockholm County Council, Alice Wallenberg Foundation

The Boschberg (Somerset East, Eastern Cape) - A floristic cross-roads of the southern Great Escarpment

AbstractThe Boschberg and Groot-Bruintjieshoogde form the wettest and floristically most distinct section of the Sneeuberg mountain complex. As such they warrant a separate detailed investigation, particularly in terms of their connectivity between the main Sneeuberg in the west, the Great Winterberg–Amatolas in the east, and with the Cape Floristic Region (CFR) to the south and south-west. Following a detailed botanical investigation and overview we conclude that the Boschberg and Groot-Bruintjieshoogde are a floristic hub between the CFR and southern Great Escarpment, as well as between the moister eastern and drier western components of the Great Escarpment. Our data confirm that the Boschberg forms part of the south-eastern connection between the CFR and the Afromontane region in southern Africa, a connection first suggested by Weimarck (1941)