Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line.

Abstract: Malignant transformation of cells by acute transforming RNA tumour viruses is mediated by the expression of certain specific pro viral DNA sequences (‘oncogenes’). These sequences have been well characterized and, in many cases, molecularly cloned1–8. These viral oncogenes are related to similar genes found in normal uninfected cells9,10. Moreover, these particular sequences are highly conserved in evolution4,11, suggesting that these genes have an important, albeit unknown, role in normal cell function. It has been suggested that an increased dosage of products of such endogenous oncogenes may be responsible for malignant transformation10,12,13. For example, increased expression of the endogenous chick c-myc oncogene has been observed in avian leukosis virus-induced transformation of chick bursal lymphocytes12. Here we demonstrate that sequences in normal human DNA homologous to the avian myc oncogene are present in multiple copies in the chromosomal DNA of the human leukaemia cell line HL-60. Other transformation-specific genes derived from the Abelson leukaemia virus4 and feline sarcoma virus6 are not amplified in HL-60. This myc-related gene amplification is not present in other cultured human myeloid leukaemia cells, including K-56214 and KG-115.

Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours

Abstract: Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies.

Gene expression changes associated with progression and response in chronic myeloid leukemia

Abstract: Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease with distinct biological and clinical features The biologic basis of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases) Three thousand genes were found to be significantly (P < 10−10) associated with phase of disease A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML to advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased numbers of leukemia blast cells Especially noteworthy and potentially significant in the progression program were the deregulation of the WNT/β-catenin pathway, the decreased expression of Jun B and Fos, alternative kinase deregulation, such as Arg (Abl2), and an increased expression of PRAME Studies of CML patients who relapsed after initially successful treatment with imatinib demonstrated a gene expression pattern closely related to advanced phase disease These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy

Estrogen plus progestin and colorectal cancer in postmenopausal women.

Abstract: background Although the Women’s Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. We analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants. methods In the WHI trial, 16,608 postmenopausal women who were 50 to 79 years of age and had an intact uterus were randomly assigned to a combination of conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The main outcome measures were the incidence, stages, and types of colorectal cancer, as determined by blinded central adjudication. results There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean ± SD, 3.2 ± 4.1 vs. 0.8 ± 1.7; P=0.002) and were more advanced (regional or metastatic disease, 76.2 percent vs. 48.5 percent; P = 0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8 ± 4.3 vs. 0.7 ± 1.5 nodes, P=0.006). conclusions Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. However, colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.

Extensive Demethylation of Repetitive Elements During Seed Development Underlies Gene Imprinting

Abstract: DNA methylation is an epigenetic mark associated with transposable element silencing and gene imprinting in flowering plants and mammals. In plants, imprinting occurs in the endosperm, which nourishes the embryo during seed development. We have profiled Arabidopsis DNA methylation genome-wide in the embryo and endosperm and found that large-scale methylation changes accompany endosperm development and endosperm-specific gene expression. Transposable element fragments are extensively demethylated in the endosperm. We discovered new imprinted genes by the identification of candidates associated with regions of reduced endosperm methylation and preferential expression in endosperm relative to other parts of the plant. These data suggest that imprinting in plants evolved from targeted methylation of transposable element insertions near genic regulatory elements followed by positive selection when the resulting expression change was advantageous.