Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization

Davison, Eleanor J.; Tarpey, Patrick; Fiegler, Heike; Tomlinson, Ian; Carter, Nigel P.

doi:10.1002/gcc.20252

Cited by 24 publications

(14 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, if deletions occur at high frequency in certain chromosomal sites in cancer merely as a consequence of the unstable nature of the chromatin domain, their appearance would not justify attributing tumor-suppressive function to the gene product. Similar arguments apply to the very high frequency of deletions in Chr20p21.1 in colorectal cancer, which overlap between 14.85–15.05 Mb [12], in the most active hotspot we have found. CTNNA3 [15] and TUSC3 [23], which have also been cited as candidate TSGs for the same reason, could also have their status as TSG re-evaluated in light of our results, given that for each of these genes we have identified a number of cancer-free adult individuals with exon-disrupting deletions (Table 1).…”

Section: Discussionsupporting

confidence: 80%

“…This region of the genome has also been implicated in colorectal cancer, with the report [12] that 23% of primary tumors and 55% of cell lines had undergone deletion events with the consensus minimum region of loss at 14.85–15.05 Mb, coinciding with the hotspot we defined here. This group provided evidence that RNA molecules encoded in the region may have tumour suppressor activity, but it is also probable that the high frequency of deletions may in part be attributable to the instability of the region.…”

Section: Discussionsupporting

confidence: 54%

“…Nevertheless it is probable that the high frequency of detection of these events reflects the hotspot nature of the genomic domain in at least some instances. Finally, as discussed below, deletions are found in primary tumors as well as tumor-derived cell lines in several of the hotspots we define here, notably 20p12 [12], 6q26 [13] 10q21 [14].…”

Section: Discussionmentioning

confidence: 71%

See 2 more Smart Citations

Hotspots of Large Rare Deletions in the Human Genome

Bradley

Raelson²,

Dubois³

et al. 2010

PLoS ONE

View full text Add to dashboard Cite

BackgroundWe have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parent-parent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder.Methodology/Principal FindingsDNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV combined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98% of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency (‘hotspots’), usually of 0.4–0.6 Mb in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on members of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort.Conclusions/SignificanceNine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others, including MACROD2 and CTNNA3. Our results also offer an alternative interpretation for the observations of deletions in tumors which have been proposed as reflecting tumor-suppressive activity of genes in these hotspots.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Hotspots of Large Rare Deletions in the Human Genome

Bradley

Raelson²,

Dubois³

et al. 2010

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…We posit that such a rearrangement might occur from double strand break in chr20 followed by break-induced replication over the right arm of chr19 (Fig 2B and S4 Table). The region comprising the breakpoint in chr20 is a known rare fragile site and rearrangements involving this region have been implicated in the pathology of Alagille syndrome and in colorectal cancers [31–33]. Also, 3 of the 4 clones from donor2 and 1 clone (left forearm) from donor1 carry different heterozygous deletions in the NRXN1 locus of chr7 (S4 Table).…”

Section: Resultsmentioning

confidence: 99%

The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts

et al. 2016

View full text Add to dashboard Cite

Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts.Trial RegistrationClinicalTrials.gov NCT01087307

show abstract

“…A remarkable example is an array CGH study of deletions discovered in colorectal cancers and lines derived from colorectal cancers [Davison et al, 2005], where, respectively, 23% and 55% of the samples had suffered deletions extending over a 2-Mb stretch in 20p12, with the 300 kb consensus overlap region coinciding perfectly with the most unstable of the hotspots we have identified. The authors of this report noted the presence of two untranslated mRNA genes in the region and showed some sequence variations and a reduction in the level of their transcription in cancers.…”

Section: Implications For Tsg Discoverymentioning

confidence: 91%

More is less: Inactivation and deletion events and the search for tumor suppressor genes

Bradley¹,

Paola²,

Rampakakis³

et al. 2010

J of Cellular Biochemistry

View full text Add to dashboard Cite

Tumor suppressor genes are frequently inactivated in cancer by large-scale deletion events or epigenetic silencing, and experimental demonstration of such inactivation has historically been considered as support for assigning tumor suppressive function to a given gene. However, the discovery of a number of chromosomal domains wherein large deletions naturally occur at frequencies up to 100 times the average for the genome as a whole leads us to reevaluate the significance of sporadic deletions found within genes associated with these hotspots. Similarly, our recent demonstration that epigenetic chromatin silencing frequently spreads in cancer cells from gene-poor into gene-rich regions with apparent indifference to the gene content of the affected domain raises questions about the pertinence of inactivation as a criterion for ascribing tumor suppressor function to a given gene. We suggest that a number of putative suppressor genes for which inactivation and/or deletion events have been documented may simply be victims of collateral damage when these events occur, and the implication that these genes are being selected against during cancer progression should in some cases be reassessed.

show abstract

Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization

Cited by 24 publications

References 28 publications

Hotspots of Large Rare Deletions in the Human Genome

Hotspots of Large Rare Deletions in the Human Genome

The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts

More is less: Inactivation and deletion events and the search for tumor suppressor genes

Contact Info

Product

Resources

About