LOH and copy neutral LOH (cnLOH) act as alternative mechanism in sporadic colorectal cancers with chromosomal and microsatellite instability

Melcher, Ralph; Hartmann, Elena; Zopf, Waltraud; Herterich, Sabine; Wilke, Philipp; Müller, Ludwig; Rosler, Eduard; Kudlich, Theodor; Al-Taie, Oliver; Rosenwald, Andreas; Katzenberger, Tiemo; Scholtka, Bettina; Seibold, Stefan; Rogoll, Dorothee; Scheppach, Wolfgang; Scheurlen, Michael; Lührs, Hardi

doi:10.1093/carcin/bgr011

Cited by 33 publications

(45 citation statements)

References 22 publications

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“…Furthermore, recent array based investigations have found MSI cancers with DNA copy number changes in unique regions of the genome [61], [62], [63], as well as copy neutral LOH events [64], [65]. By furthering this type of experimental approach, the relationship between MSI and CIN will be better understood.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Instability in BRAF Mutant, Microsatellite Stable Colorectal Cancers

et al. 2012

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The BRAF oncogene is mutated in 15% of sporadic colorectal cancers. Approximately half of these BRAF mutant cancers demonstrate frequent frameshift mutations termed microsatellite instability (MSI), but are diploid and chromosomally stable. BRAF wild type cancers are typically microsatellite stable (MSS) and instead acquire chromosomal instability (CIN). In these cancers, CIN is associated with a poor outcome. BRAF mutant cancers that are MSS, typically present at an advanced stage and have a particularly poor prognosis. We have previously demonstrated clinical and molecular similarities between MSS cancers with or without a BRAF mutation, and therefore hypothesised that CIN may also be frequent in BRAF mutant/MSS cancers. BRAF mutant/MSS (n = 60), and BRAF wild type/MSS CRCs (n = 90) were investigated for CIN using loss of heterozygosity analysis over twelve loci encompassing chromosomal regions 5q, 8p, 17p and 18q. CIN was frequent in BRAF mutant/MSS cancers (41/57, 72%), which was comparable to the rate found in BRAF wild type/MSS cancers (74/90, 82%). The greatest loss in BRAF mutant/MSS cancers occurred at 8p (26/44, 59%), and the least at 5q (19/49, 39%). CIN in BRAF mutant/MSS cancers correlated with advanced stage (AJCC III/IV: 15/17, 88%; p = 0.02); showed high rates of co-occurrence with the CpG Island Methylator Phenotype (17/23, 74%); and CIN at 18q and 8p associated with worse survival (p = 0.02, p<0.05). This study demonstrates that CIN commonly occurs in advanced BRAF mutant/MSS colorectal cancers where it may contribute to poorer survival, and further highlights molecular similarities occurring between these and BRAF wild type cancers.

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Section: Discussionmentioning

confidence: 99%

Chromosomal Instability in BRAF Mutant, Microsatellite Stable Colorectal Cancers

et al. 2012

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“…However, several studies using cytogenetic analysis have found MSI cell lines and cancers to have a considerable presence of chromosomal aberrations, predominantly cnLOH events [27], [28], [29], [30]. Similarly, studies have reported the presence of CIN and CIMP to be inversely correlated [31], [32], and the incidence of frequent methylation to be associated with reduced rates and lengths of CNAs [33], [34], [35].…”

Section: Introductionmentioning

confidence: 99%

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

et al. 2014

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The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a poor patient prognosis, whereas BRAF mutant microsatellite-unstable (MSI) colorectal cancers have an excellent prognosis. BRAF wild type cancers are typically MSS and display chromosomal instability (CIN). CIN has not been extensively studied on a genome-wide basis in relation to BRAF mutational status in colorectal cancer. BRAF mutant/MSS (BRAFmut/MSS) cancers (n = 33) and BRAF mutant/MSI (BRAFmut/MSI) cancers (n = 30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with BRAF wild type/MSS (BRAFwt/MSS) cancers (n = 18) using Illumina CytoSNP-12 arrays. BRAFmut/MSS and BRAFwt/MSS cancers showed comparable numbers of CNAs/cancer at 32.8 and 29.8 respectively. However, there were differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having significantly greater proportions of focal CNAs compared to BRAFwt/MSS cancers (p<0.0001); whereas whole chromosomal arm CNAs were more common in BRAFwt/MSS cancers (p<0.0001). This related to a reduced average CNA length in BRAFmut/MSS compared to BRAFwt/MSS cancers (20.7 Mb vs 33.4 Mb;p<0.0001); and a smaller average percent of CIN affected genomes in BRAFmut/MSS compared to BRAFwt/MSS cancers (23.9% vs 34.9% respectively). BRAFmut/MSI cancers were confirmed to have low CNA rates (5.4/cancer) and minimal CIN-affected genomes (average of 4.5%) compared to MSS cohorts (p<0.0001). BRAFmut/MSS cancers had more frequent deletion CNAs compared to BRAFwt/MSS cancers on 6p and 17q at loci not typically correlated with colorectal cancer, and greater amplification CNAs on 8q and 18q compared to BRAFwt/MSS cancers. These results indicate that comparable rates of CIN occur between MSS subgroups, however significant differences in their patterns of instability exist, with BRAFmut/MSS cancers showing a ‘focal pattern’ and BRAFwt/MSS cancers having a ‘whole arm pattern’ of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers provides further evidence of the biological distinctions of this important cancer subgroup.

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“…Recently developed single nucleotide polymorphism (SNP) microarrays have facilitated LOH studies because they allow simultaneous detection of copy number and genotype changes. Melcher et al (33) used SNP arrays to examine and compare genome-wide LOH in CIN and MSI tumors. CIN tumors displayed mostly classic LOH (mutation followed by allele loss) at multiple genomic sites, whereas MSI tumors displayed LOH that was mostly copy-neutral.…”

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confidence: 99%

Modeling the Etiology of p53-mutated Cancer Cells

Perez

Duan

Kim

et al. 2016

Journal of Biological Chemistry

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p53 gene mutations are among the most common alterations in cancer. In most cases, missense mutations in one TP53 allele are followed by loss-of-heterozygosity (LOH), so tumors express only mutant p53. TP53 mutations and LOH have been linked, in many cases, with poor therapy response and worse outcome. Despite this, remarkably little is known about how TP53 point mutations are acquired, how LOH occurs, or the cells involved. Nutlin-3a occupies the p53-binding site in MDM2 and blocks p53-MDM2 interaction, resulting in the stabilization and activation of p53 and subsequent growth arrest or apoptosis. We leveraged the powerful growth inhibitory activity of Nutlin-3a to select p53-mutated cells and examined how TP53 mutations arise and how the remaining wild-type allele is lost or inactivated. Mismatch repair (MMR)-deficient colorectal cancer cells formed heterozygote (p53 wild-type/mutant) colonies when cultured in low doses of Nutlin-3a, whereas MMR-corrected counterparts did not. Placing these heterozygotes in higher Nutlin-3a doses selected clones in which the remaining wild-type TP53 was silenced. Our data suggest silencing occurred through a novel mechanism that does not involve DNA methylation, histone methylation, or histone deacetylation. These data indicate MMR deficiency in colorectal cancer can give rise to initiating TP53 mutations and that TP53 silencing occurs via a copy-neutral mechanism. Moreover, the data highlight the use of MDM2 antagonists as tools to study mechanisms of TP53 mutation acquisition and wild-type allele loss or silencing in cells with defined genetic backgrounds.p53 is a stress-responsive tumor suppressor encoded by the TP53 gene. TP53 mutations are among the most common alterations in cancer (1). In most cases, missense mutations in one TP53 allele are followed by loss-of-heterozygosity (LOH), 2 so tumors express only mutant p53. TP53 mutations and LOH have been linked, in many cases, with poor therapy response, increased tumor aggressiveness, and decreased long term survival (2-5). Despite this, remarkably little is known about how TP53 point mutations are acquired, how LOH occurs, or the cells involved.Genomic instability is a hallmark of colorectal cancer (CRC) and is divided into the following two classes: chromosome instability (CIN) and microsatellite instability (MSI) (6 -9). Tumors with CIN include most (ϳ85%) of all CRCs and are characterized by gross karyotypic changes, including alterations in chromosome number and structure (8). The CIN phenotype appears to result, at least in part, from truncating mutations in the tumor-suppressor protein adenomatous polyposis coli, a protein that controls proper chromosome segregation in mitosis (6,8). Tumors with MSI account for the remaining 15% of CRCs. MSI tumors, as the name implies, are characterized by rapid changes (instability) in the length of short repetitive microsatellite sequences in the genome (10). In contrast to CIN, MSI tumors have a relatively stable karyotype, but instead harbor multiple frameshift and missense mu...

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LOH and copy neutral LOH (cnLOH) act as alternative mechanism in sporadic colorectal cancers with chromosomal and microsatellite instability

Cited by 33 publications

References 22 publications

Chromosomal Instability in BRAF Mutant, Microsatellite Stable Colorectal Cancers

Chromosomal Instability in BRAF Mutant, Microsatellite Stable Colorectal Cancers

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

Modeling the Etiology of p53-mutated Cancer Cells

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