Mass Homozygotes Accumulation in the NCI-60 Cancer Cell Lines As Compared to HapMap Trios, and Relation to Fragile Site Location

Abstract

Runs of homozygosity (ROH) represents extended length of homozygotes on a long genomic distance. In oncology, it is known as loss of heterozygosity (LOH) if identified exclusively in cancer cell rather than in matched control cell. Studies have identified several genomic regions which show consistent ROH in different kinds of carcinoma. To query whether this consistency can be observed on broader spectrum, both in more cancer types and in wider genomic regions, we investigated ROH patterns in the National Cancer Institute 60 cancer cell line panel (NCI-60) and HapMap Caucasian healthy trio families. Using results from Affymetrix 500 K SNP arrays, we report a genome wide significant association of ROH regions between the NCI-60 and HapMap samples, with much a higher level of ROH (11 fold) in the cancer cell lines. Analysis shows that more severe ROH found in cancer cells appears to be the extension of existing ROH in healthy state. In the HapMap trios, the adult subgroup had a slightly but significantly higher level (1.02 fold) of ROH than did the young subgroup. For several ROH regions we observed the co-occurrence of fragile sites (FRAs). However, FRA on the genome wide level does not show a clear relationship with ROH regions.

Early genetic aberrations in patients with sporadic colorectal cancer

“…It is of interest to note that similar LOH enrichment was also observed in our previous study on breast infiltrating ductal carcinoma distant normal tissue, albeit on different arms . Concurrent with our previous work on NCI‐60 cancer cell lines, these findings suggest that these aberrant genetic patterns are tissue specific and may be the precursors for the larger genetic aberrations present in tumor.…”

Using drug response data to identify molecular effectors, and molecular “omic” data to identify candidate drugs in cancer

“…It includes 60 cell lines, and its molecular data include: i) karyotypic analysis with multiple parameters of genomic instability (Roschke et al 2003), ii) DNA copy number (Bussey et al 2006; Reinhold et al 2010; Reinhold et al 2014), iii) single nucleotide polymorphisms (Ruan et al 2012), iv) whole exome sequencing identification of 140,171 variants (germline and somatic) (Abaan et al 2013), v) gene transcript expression (done using five platforms) (Liu et al 2010; Reinhold et al 2012), vi) microRNA expression (Blower PE et al 2007; Liu et al 2010), vii) global proteomic analysis (Moghaddas Gholami et al 2013), and viii) metabolite profiling (Jain et al 2012). Additional, more narrow profiles for the NCI-60 include; i) DNA fingerprinting (Lorenzi et al 2009), ii) putative tumor stem cell marker identification (Stuelten et al 2010), iii) genotyping of HLA class I and II antigens (Adams et al 2005), iv) nuclear receptor and ABC transporter quantitative RT-PCR expression profiling (Holbeck et al 2010a; Szakacs et al 2004), and v) reverse-phase protein lysate microarrays (Nishizuka et al 2003).…”

Using CellMiner 1.6 for Systems Pharmacology and Genomic Analysis of the NCI-60

“…CellMiner previously has enabled us to: i) identify promoter-proximal transcriptional pausing in human genes (37, 38), ii) discover the helicase SLFN11 as a causal determinant of response to DNA-damaging agents (18), iii) recognize the regulation of MYC expression by miR-375 (39), iv) recognize the importance of MYC as a driver of mitochondrial genes (40), v) reveal genetic inactivation or endogenous activation of CHEK2 across the NCI-60 (40); vi) link USP7 and Daxx to taxane resistance (41), vi) link TP53 wild type status, Mdm2 transcript level, and miR-34a transcript level with nutlin activity (10), viii) reveal the interrelationship between RAS (H, K, and NRAS)-BRAF-PTEN mutational status, EGFR expression, and ERBB2 expression with erlotinib activity (10), ix) demonstrate the strong correlation between ABCB1 expression and doxorubicin activity (2), x) recognize both known and novel genes expression levels, microRNA expression levels, and drug activities with a colon-specific pattern input to “Pattern comparison” (2), xi) identify predominant co-regulation among cell migration genes (42), xii) identify co-regulation among kinetochore genes, their prospective regulatory elements, and their association with genomic instability (43), xiii) show the connection between accumulation of mass homozygotes in the cancer cell lines as compared to non-cancerous HapMap trios (44), xiv) identify the drug Ro5-3335 as a candidate treatment for core binding factor leukemias (45), xv) associate CDKN2A DNA copy number and expression to mitoxantrone activity (8), xvi) define an epithelial gene expression signature (46), and xvii) recognize the composite relationship between the mutational status of multiple genes from the EGFR-ERBB2 pathway and drug response, including the directionality of that influence as a function of molecular pathway considerations (14). The diversity among these observations gives an indication of the boundless scope and range of the types of possible discoveries that can be made using the NCI-60 database and CellMiner set of tools.…”