Dataset Information

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

ABSTRACT: Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC; PDS1 tumours are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis. PDS2 which is regenerative/ANXA1+ stem-rich, with elevated stromal/immune tumour microenvironmental lineages. PDS3 tumours represent a previously overlooked slow-cycling subset of tumours within CMS2, with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are under-represented in pre-clinical models currently and are not identified using existing subtyping classifiers Mutations: https://www.s-cort.org/sites/default/files/exports/scort_spinal_focus_paper/ws4_spinal_mutations.txt, CNA per gene : https://www.s-cort.org/sites/default/files/exports/scort_spinal_focus_paper/ws4_spinal_cna_gene_subselection_for_paper.txt, CNA segments SPINAL https://www.s-cort.org/sites/default/files/exports/scort_spinal_focus_paper/ws4_spinal_cna.zip, CNA segments FOCUS https://www.s-cort.org/sites/default/files/exports/scort_spinal_focus_paper/ws2.focus_cna.zip

ORGANISM(S): Homo sapiens

PROVIDER: GSE248381 | GEO | 2023/12/12

REPOSITORIES: GEO

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Project description:Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) present in 48 clear cell renal cell carcinoma (ccRCC) genomes result in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes are mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs are classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turn out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. Finally, the diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) are successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreases with the number of G3 related gene losses plus the total number of gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

Project description:We performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using the Affymetrix Genome-Wide Human SNP array 6.0 containing 1.85 million features. Acquired copy number alterations (CNA) were confirmed using an independent, higher resolution, custom array comparative genomic hybridization platform. A total of 201 somatic CNA were found in the 86 AML genomes (mean 2.34 CNA/genome), with FAB M6 and M7 AML genomes containing the most changes (10-29 CNA/genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, while 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several regions contained CNA in multiple AML genomes. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. Array data are available online at <a href="http://www.ncbi.nlm.nih.gov/geo/" target="_blank">http://www.ncbi.nlm.nih.gov/geo/</a> as GEO accession #GSE10358. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes and 6/8 UPD regions occurred in samples with a normal karyotype. Collectively, 40% of AML genomes contained alterations not found with cytogenetics, and 96% of these regions contained known or novel AML associated genes. 43/86 AML genomes had no CNA or UPD at this level of resolution. The number of CNA per genome was not associated with overall survival, independent of cytogenetic classification. In this study of 86 adult AML genomes, subcytogenetic CNAs or UPD did not add prognostic information to standard cytogenetics. However, arrays identified many somatically mutated oncogenes and tumor suppressor genes, and also genes not previously implicated in AML that may be relevant for pathogenesis. AML CNA segments from 86 adult AML patients are available through dbVar at <a href="ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009">ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009</a>.

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Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

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